Psyllium Pre & Probiotic Fiber Original by Organic India

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Asthma. It is unclear if oral garden cress is beneficial for asthma. Details: Preliminary clinical research in untreated patients with mild to moderate asthma symptoms shows that taking garden cress seed powder 1 gram three times daily for 4 weeks modestly improves symptoms including dyspnea, wheezing, cough, and chest tightness, as well as some measures of pulmonary function when compared with baseline (110899).
• Diabetes. Although there has been interest in using oral garden cress for diabetes, there is insufficient reliable information about the clinical effects of garden cress for this condition.
• Hemorrhoids. Although there has been interest in using oral garden cress for hemorrhoids, there is insufficient reliable information about the clinical effects of garden cress for this condition.
• Hypertension. Although there has been interest in using oral garden cress for hypertension, there is insufficient reliable information about the clinical effects of garden cress for this condition.
• Lactation. It is unclear if oral garden cress is beneficial for stimulating lactation. Details: Preliminary clinical research in hypogalactic individuals who had delivered an infant at < 32 weeks gestation shows that taking garden cress seeds 2.5 grams daily for 28 days modestly increases volume of milk produced when compared with not taking garden cress. Seeds were soaked in water for 30 minutes before use (110901). More evidence is needed to rate garden cress for these uses.

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POSSIBLY EFFECTIVE

• Dyslipidemia. Oral Indian gooseberry seems to be beneficial for dyslipidemia. Details: Meta-analyses of 12 small clinical studies in healthy adults or patients with dyslipidemia, diabetes, hypertension, or metabolic syndrome show that taking Indian gooseberry fruit extract or powder 0.5-3 grams daily or Indian gooseberry fruit 12 grams daily for 2-12 weeks reduces total cholesterol by around 39 mg/dL, low-density lipoprotein (LDL) cholesterol by around 15-34 mg/dL, and triglycerides by around 22-52 mg/dL when compared with control groups. Results are conflicting whether Indian gooseberry increases high-density lipoprotein (HDL) cholesterol (111567,111568). Subgroup analysis suggests that Indian gooseberry is more effective at doses greater than 1 gram daily and in adults with triglycerides above 150 mg/dL (111568). Clinical research in patients with dyslipidemia shows that taking Indian gooseberry whole fruit extract (Tri-low, Arjuna Natural Ltd.) 500 mg twice daily for 12 weeks reduces triglyceride and low-density lipoprotein (LDL) cholesterol levels by 34% and 20%, respectively, compared with 15% and 5%, respectively, in patients taking placebo (99238).
• Gastroesophageal reflux disease (GERD). Oral Indian gooseberry seems to be beneficial for reducing symptoms of GERD. Details: Clinical research in adults who have had non-erosive symptoms of GERD for at least 3 months shows that taking Indian gooseberry fruit extract 1000 mg twice daily for 4 weeks reduces the frequency and severity of heartburn and regurgitation by about 63% and 50%, respectively, compared with reductions of 24% and 5%, respectively, in patients taking placebo (99240).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. Oral Indian gooseberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in healthy, middle-aged females shows that drinking 50 mL of a juice containing Indian gooseberry extract 30-60 mg and lingonberry extract 25-50 mg daily for 12 weeks improves skin elasticity, thickness, wrinkles, and hydration when compared with placebo (102856). It is unclear if these effects are due to Indian gooseberry, lingonberry, or the combination. Another small clinical study in healthy, middle-aged females shows that applying a topical emulsion containing extracts of Indian gooseberry 3% and gotu kola 3% twice daily for 60 days improves skin hydration, some measures of skin wrinkles, and elasticity of the cheek but not the eye when compared with placebo (111571). It is unclear if these effects are due to Indian gooseberry, gotu kola, or the combination.
• Androgenic alopecia. Topical Indian gooseberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In individuals with self-perceived hair loss, preliminary clinical research shows that applying a hair product containing Indian gooseberry modestly improves hair growth rate and density, as well as hair thinning, when compared with baseline. Patients used a leave-in product containing Indian gooseberry (Saberry), coconut water solids (Cococin), gamma-L-glutamyl-selenomethionine (Peptiselect), and other ingredients as 3.5 mL in females and 2 mL in males, once daily for 3 months (105353).
• Cancer. Although there is interest in using oral Indian gooseberry for cancer, there is insufficient reliable information about the clinical effects of Indian gooseberry for this purpose.
• Cardiovascular disease (CVD). It is unclear if oral Indian gooseberry is beneficial for the prevention of CVD. Details: A meta-analysis of 9 small clinical studies in adults who are healthy or have CVD risk factors shows that taking Indian gooseberry fruit extract or powder 500-1500 mg daily for 2-12 weeks reduces low-density lipoprotein (LDL) cholesterol by around 15 mg/dL, very low-density lipoprotein (VLDL) cholesterol by around 5 mg/dL, triglycerides by around 22 mg/dL, and high-sensitivity C-reactive protein when compared with control groups. However, the meta-analysis suggests that Indian gooseberry does not improve high-density lipoprotein (HDL) cholesterol, systolic blood pressure, or diastolic blood pressure (111567). The validity of these findings is limited by small sample sizes and considerable heterogeneity among the included studies.
• Coronavirus disease 2019 (COVID-19). It is unclear if oral Indian gooseberry is beneficial for the treatment of COVID-19 in hospitalized adults. Details: A small clinical trial in adults hospitalized with COVID-19 shows that receiving Indian gooseberry powder 2 grams twice daily for 10 days does not impact RT-PCR positivity rate at day 10 when compared with placebo. Additionally, there were no clear trends in clinical improvement in patients receiving Indian gooseberry when compared with placebo. All patients in this study also received oral hydroxychloroquine and lopinavir/ritonavir (110012).
• Diabetes. Several small or limited-quality clinical studies suggest that oral Indian gooseberry may modestly improve glycemic control and blood lipid levels in patients with type 2 diabetes. Details: A moderate-sized, open-label study in adults with newly-diagnosed type 2 diabetes and dyslipidemia shows that taking Indian gooseberry extract, standardized to 10% beta-glucogallin, 2 grams daily for 90 days reduces glycated hemoglobin (HbA1c), fasting blood glucose, and postprandial blood glucose when compared to baseline, with superior effects on fasting blood glucose and postprandial blood glucose when compared with metformin 500 mg (111569). A smaller clinical study in patients with type 2 diabetes on stable doses of metformin shows that taking Indian gooseberry fruit extract (Capros, Natreon Inc) 500 mg twice daily for 12 weeks reduces HbA1c by around 0.5% and improves low-density lipoprotein (LDL) cholesterol, triglyceride, and high-density lipoprotein (HDL) levels when compared with placebo. Taking a lower dose, 250 mg twice daily, does not seem to improve HbA1c but has a modest effect on lipid levels (105356). Another small clinical study in patients with type 2 diabetes using various antidiabetes drugs shows that taking powdered Indian gooseberry fruit 1 gram, 2 grams, or 3 grams daily for 3 weeks modestly reduces fasting and 2-hour postprandial blood glucose levels and improves lipid levels when compared to baseline (105355). The validity of these findings is limited by the lack of a comparator group.
• Hangover. It is unclear if oral Indian gooseberry is beneficial for hangover prevention. Details: A small clinical trial shows that taking Indian gooseberry leaf extract (Phyllpro) 750 mg daily for 10 days prior to alcohol intoxication modestly reduces some hangover symptoms 10 hours later, including nausea, headache, lack of appetite, and dizziness, when compared with placebo. Blood alcohol levels after 12 hours were also reduced. However, the overall hangover score was not significantly different between groups (99846).
• Hepatitis B. Although there is interest in using oral Indian gooseberry for hepatitis B, there is insufficient reliable information about the clinical effects of Indian gooseberry for this condition.
• Hypercholesterolemia. Small studies suggest that oral Indian gooseberry might help to reduce low-density lipoprotein (LDL) cholesterol levels. Details: Preliminary clinical research shows that taking Indian gooseberry might reduce levels of LDL cholesterol in patients with hypercholesterolemia. One preliminary clinical study shows that taking Indian gooseberry 50 grams for 4 weeks decreases LDL cholesterol by 15% when compared to baseline (2077). Other preliminary clinical research shows that taking Indian gooseberry fruit extract (Amlamax, Arjuna Natural Ltd.) 500 mg or 1000 mg daily for 6 months reduces levels of LDL cholesterol by about 13% when compared with baseline (99241). Also, one small study shows that taking an Indian gooseberry fruit juice powder 500 mg daily for 6 weeks modestly decreases LDL cholesterol and triglyceride levels when compared with baseline (99242). Some preliminary clinical research also shows that Indian gooseberry reduces LDL cholesterol in obese individuals. One small study shows that taking Indian gooseberry fruit extract (Capros, Natreon Inc.) 500 mg twice daily for 12 weeks reduces LDL cholesterol by 16 mg/dL in this population when compared to baseline (92515). However, the validity of these studies is limited by the lack of comparator groups.
• Hypertension. It is unclear if oral Indian gooseberry is beneficial for hypertension. Details: In patients with uncontrolled hypertension using standard therapies, clinical research shows that taking Indian gooseberry dried fruit powder 500 mg three times daily for 8 weeks reduces systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 16% and 12%, respectively, from baseline, which is significantly greater than reductions seen with placebo. The frequency of response to treatment, based on a reduction in SBP or DBP of at least 10 mmHg or 5 mmHg, respectively, was also increased from up to 50% to at least 83% of patients (105352). However, other clinical research in adults with cardiovascular risk factors shows that taking Indian gooseberry 500-1500 mg twice daily for 2-12 weeks does not reduce SBP or DBP more than placebo (105354,111567).
• Irritable bowel syndrome (IBS). Indian gooseberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small, open-label study of adults with IBS shows that taking 7 grams of an Unani medicinal product called Jawarish Shahi, containing Indian gooseberry, terminalia, coriander, cardamom, and willow bark, twice daily for 45 days reduces the severity of IBS, as measured by improvements in abdominal pain and distension, bowel habits, and quality of life, when compared to baseline (111570). The validity of these findings is limited by insufficient blinding and the lack of a comparator group. It is unclear if these effects are due to Indian gooseberry, other ingredients, or the combination.
• Metabolic syndrome. It is unclear if oral Indian gooseberry is beneficial for metabolic syndrome. Details: Preliminary clinical research in adults with metabolic syndrome shows that taking a specific Indian gooseberry extract (Capros, Natreon Inc.) 250 mg twice daily for 12 weeks reduces total cholesterol by nearly 10%, low-density lipoprotein (LDL) cholesterol by 15%, and triglycerides by 10%, and increases high-density lipoprotein (HDL) cholesterol by about 7% when compared with placebo. Additionally, taking this product as 500 mg twice daily reduces total cholesterol by 14%, LDL cholesterol by 26%, and triglycerides by 19%, and increases HDL cholesterol by 22% when compared with placebo. Both doses also seem to improve markers of endothelial function, oxidative stress, and systemic inflammation (102857).
• Obesity. It is unclear if oral Indian gooseberry is beneficial for improving weight loss or metabolic parameters in adults with obesity. Details: Preliminary clinical research in overweight or obese individuals shows that taking Indian gooseberry fruit extract (Capros, Natreon Inc.) 500 mg twice daily for 12 weeks reduces low-density lipoprotein (LDL) cholesterol by 16 mg/dL when compared to baseline. However, there was no effect on other lipids or on blood pressure, body weight, or body mass index (92515). The validity of these findings is limited by the lack of a comparator group.
• Oral mucositis. It is unclear if oral Indian gooseberry is beneficial in patients with radiation-induced mucositis. Details: A retrospective observational study in patients with head and neck cancer receiving radiotherapy suggests that rinsing the mouth with Indian gooseberry 1% and povidone-iodine twice daily is associated with delayed development of mucositis and intolerable mucositis and a decreased incidence of intolerable mucositis when compared with povidone-iodine alone (111566). The validity of these findings is limited by the retrospective study design.
• Osteoarthritis. Oral Indian gooseberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with knee osteoarthritis suggests that specific Ayurvedic formulas containing Indian gooseberry may be equivalent to glucosamine sulfate 2 grams daily or celecoxib 200 mg daily for reducing pain. Two capsules containing Indian gooseberry 166.66 mg/capsule, ginger 33.33 mg/capsule, and Tinospora cordifolia 73.33 mg/capsule, with or without Boswellia serrata 100 mg/capsule, taken three times daily for 24 weeks, were used. All four treatments reduced active pain by about 28% to 38%, functional pain by 19% to 29%, and functional difficulty by 18% to 25%, with no significant between-group differences in the observed improvements (89557). It is not clear if these effects are due to Indian gooseberry, the other ingredients, or the combination.
• Periodontitis. It is unclear if subgingival Indian gooseberry is beneficial for periodontitis. Details: Clinical research in patients with chronic periodontitis shows that the subgingival application of a sustained-release Indian gooseberry fruit 10% gel following scaling and root planing does not affect plaque or gingivitis development over 2-3 months when compared with placebo. However, there was a modest benefit on periodontal destruction based on probing pocket depth (105358).
• Vitiligo. Oral Indian gooseberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with vitiligo shows that taking 1 tablet containing Indian gooseberry 100 mg, vitamin E 10 mg, and carotenoids 4.7 mg orally 3 times daily for 6 months, in combination with conventional topical therapy and/or phototherapy, increases re-pigmentation in the head, neck, and trunk and decreases signs of inflammation when compared with conventional treatment alone (92513). More evidence is needed to rate Indian gooseberry for these uses.

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EFFECTIVE

• Anemia of chronic disease. Oral and intravenous iron in combination with erythropoiesis-stimulating agents (ESAs) are effective for treating anemia of chronic disease. Details: Iron supplementation with ESAs is effective for treating anemia associated with chronic kidney disease (CKD) or chemotherapy. During therapy with ESAs, iron levels should be monitored and supplementation provided as needed to ensure that the response is not limited by lack of iron for erythropoiesis (1087,1091,20110,20111,110192). Research shows that intravenous iron appears to be more effective than oral supplements for this purpose (20112,20113). In patients with CKD, intravenous iron at total doses from 2232 mg over 6 months to 1020 mg over one week increases hemoglobin levels more than oral doses of 4-6 mg/kg daily or 325 mg daily for up to 6 months (20112). Some research has evaluated the effect of intravenous or oral iron in patients not treated with ESAs. In patients with cancer or CKD, oral iron supplements have been shown to improve iron status (110184,110192). However, overall benefits of iron alone remain unclear in treated or untreated patients with cancer and more research is needed to rule out an increase in mortality and to determine any effect on blood transfusion requirements (110192). Preliminary clinical research shows that children aged 6 months to 10 years with HIV and anemia who take elemental iron 3 mg/kg daily along with a multivitamin for 3 months have a 41% lower chance of having persistent anemia at 3 months when compared with multivitamins alone (95432).
• Iron deficiency anemia. Oral and intravenous iron are effective for treating or preventing iron deficiency anemia. The benefits of iron supplementation in people with iron deficiency without anemia are unclear. Details: Oral iron supplements, mainly as ferrous sulfate, are effective for treating and preventing iron deficiency anemia in adults, children, and infants (1089,7135,17495,17496,17497,103806,20114,20115,91183,96621)(104680,104681,112601). Other forms are also effective, including sodium iron ethylenediaminetetra-acetate (NaFeEDTA), iron(III)-hydroxide polymaltose complex (IPC), iron protein succinylate, iron bisglycinate, and lactoferrin with iron (20117,20118,110189). Treatment with iron supplements should increase hemoglobin levels by 1 gram/dL every 2-3 weeks. However, even after hemoglobin has normalized, it may take up to 4 months for iron stores to be replenished (17497). Historically, treatment of iron deficiency anemia with oral iron supplements has typically consisted of a daily dosing regimen, often taken in divided doses to reduce adverse effects. In more recent years, however, intermittent iron supplementation (1-3 doses/week) has become preferred for some patients, particularly those with mild anemia, due to better absorption and a possible reduction in side effects compared to daily dosing. One small clinical study shows that taking ferrous sulfate 60 mg on alternate days in single doses improves iron absorption when compared to once daily dosing (96630). Another small clinical study in females with iron-deficiency anemia shows that fractional iron absorption is 40% to 50% higher with alternate-day dosing compared with daily dosing. Furthermore, total iron absorption was shown to be similar for alternate day dosing of elemental iron 200 mg compared with daily dosing of 100 mg, but the incidence of gastrointestinal adverse effects may be lower for the alternate day dosing regimen (101514). A meta-analysis of 25 clinical trials, including 10,996 menstruating females with or without pre-existing iron deficiency and/or anemia, shows that intermittent iron reduces the risk of anemia and increases hemoglobin and serum ferritin when compared with placebo or no intervention. This meta-analysis did not identify differences in the risk of anemia, hemoglobin, or serum ferritin between intermittent and daily iron supplementation. However, it did show that females receiving intermittent dosing had a 59% reduction in the risk for adverse effects. The validity of these findings is limited by significant heterogeneity in the enrolled populations and selected dosing strategies, including frequency of intermittent dosing, total weekly dose, and duration of follow-up. In addition, the subgroup analyses performed by baseline anemia, hemoglobin, and serum ferritin, as well as duration of follow-up, showed differing overall conclusions when comparing intermittent and daily iron supplementation. While intermittent dosing appears to be beneficial when compared with daily dosing for some patients with iron deficiency anemia, intermittent dosing may be less effective than daily iron supplementation in some patients (103806). For patients with severe anemia, twice daily dosing may be preferred to alternate day dosing due to faster response. A small clinical study in patients with iron deficiency anemia shows that taking ferrous sulfate 200 mg twice daily is more effective at increasing hemoglobin levels by 3 weeks when compared with ferrous sulfate 400 mg taken on alternate days in single doses (102864). Intermittent iron supplementation has also been investigated in children. A meta-analysis of clinical research in children and adolescents with or without pre-existing iron deficiency and/or anemia shows that taking iron supplements 1-2 times weekly is similarly effective as 3-7 times weekly for decreasing iron deficiency and iron deficiency anemia. However, ferritin and hemoglobin levels increased to a greater extent with 3-7 times weekly supplementation (112601). Blood transfusion may be required for some patients with severe iron deficiency anemia who have symptoms such as dyspnea and fatigue (17497). Intravenous iron should be considered in patients who cannot tolerate oral iron or in patients with chronic bleeding or intestinal malabsorption (17497). Guidelines from the British Society of Gastroenterology recommend treatment with iron while awaiting investigations to rule out gastrointestinal issues in adults in the absence of an alternative explanation. The guidelines recommend ferrous sulfate, fumarate, or gluconate as one tablet daily. If adverse effects occur, intake can be reduced to once every other day, or alternative oral or parenteral sources of iron can be used. Parenteral sources should be used if oral sources are contraindicated or ineffective. Treatment should be monitored and continued after hemoglobin levels are normalized (110193). Iron supplementation may also be beneficial in patients with iron deficiency without anemia, which can cause fatigue and reduced well-being, although guidelines are lacking. A meta-analysis of randomized controlled trials in adults with iron deficiency but not anemia shows that supplemental iron improves iron stores and hemoglobin levels. In addition, iron moderately reduces self-reported fatigue, but not physical capacity, when compared with placebo. Oral ferrous sulfate was used in most studies included in the analysis; however, intravenous or intramuscular iron were also used (104684).
• Pregnancy-related iron deficiency. Oral iron is effective for preventing pregnancy-related iron deficiency. Details: Clinical research shows that taking iron orally at an average daily dose of 20-225 mg of elemental iron increases maternal hemoglobin levels by up to 1 gram/dL when compared with placebo and reduces the risk of maternal anemia by 62% to 100% (20122,20123,20124,110180,110188). Some clinicians may recommend alternating days of iron administration to reduce gastrointestinal adverse effects. A pooled analysis shows that taking iron supplements on alternating days during pregnancy maintains adequate iron intake and reduces gastrointestinal adverse effects when compared with taking iron daily (96625). Various forms of oral iron seem to be equally effective for raising hemoglobin levels (110185,110188). However, in patients with anemia during pregnancy, a meta-analysis of clinical research shows that intravenous iron sucrose and ferric carboxymaltose were more effective than oral ferrous sulfate for improving hemoglobin levels (110185).

POSSIBLY EFFECTIVE

• Breath-holding attacks. Oral iron seems to be effective for reducing the frequency of breath-holding attacks in children with iron deficiency. Details: The incidence of breath-holding attacks is increased in children with iron deficiency or iron deficiency anemia. Most research shows that oral supplementation with ferrous sulfate 3-6 mg/kg daily for 4-16 weeks reduces the frequency of breath-holding attacks in children aged 1-72 months (20128,104682,104683). The best evidence comes from a meta-analysis of one randomized controlled trial and 11 observational single arm studies (104682). In this analysis, approximately 84% of children experienced at least a 50% decreased frequency of breath-holding attacks (104682). Some preliminary clinical research also shows that administering intramuscular iron reduces the frequency of breath-holding attacks and increases remission in children with iron deficiency anemia (20128).
• Cognitive function. Oral iron seems to be effective for improving cognitive function in children and adolescents with iron deficiency. Details: Taking iron orally seems to improve cognitive function in iron-deficient children and adolescents (20121,112600). For example, ferrous sulfate 650 mg twice daily for 8 weeks improved verbal learning and memory in non-anemic iron-deficient adolescent females (1095). Ferrous sulfate 50 mg twice weekly for 16 weeks appeared to improve attention measures in adolescent females with possible anemia (91186). Iron also appears to reverse developmental and learning deficits caused by iron-deficiency in anemic infants (1104). Some clinical research is focused on children and adolescents from low- and middle-income countries. In children aged 5-19 years with or without iron-deficiency anemia, a meta-analysis of clinical research shows that iron supplementation for 3-8 months dose-dependently improves measured intelligence by a modest amount. However, there was no effect on other measures of cognition, including attention or memory (110181). Another meta-analysis of clinical research in school age children shows that taking iron for 2-12 months modestly improves intelligence, attention, and memory, but not educational achievement, when compared with placebo or no intervention. However, sub-analyses show that any benefits are limited to children with anemia (112600).
• Heart failure. Intravenous iron seems to be effective for improving recovery in patients with heart failure and iron deficiency. It is unclear if oral iron is effective. Details: Iron deficiency is common in patients with heart failure (17499,112597,112598,112599). Individual clinical trials and meta-analyses of clinical research in patients with heart failure show that administering intravenous iron, as ferric carboxymaltose, iron dextran, iron isomaltoside, or iron sucrose, for at least 12 weeks modestly improves quality of life, increases exercise capacity, and reduces hospitalizations when compared with placebo or standard care. However, there was no effect on all-cause mortality or cardiovascular mortality (17498,91179,110176,110187,112597,112598,112599). Some individual clinical trials have used intravenous ferric carboxymaltose 200 mg or iron sucrose 200 mg in patients with mild or moderate heart failure and iron deficiency (17498,91179). Guidelines from the British Society of Gastroenterology suggest that treatment with parenteral iron improves symptoms and quality of life in patients with functional iron deficiency related to CHF (110193). Limited research has investigated the effect of oral iron in this population. A small meta-analysis of clinical research shows with low certainty that taking iron orally has beneficial effects on serum ferritin and left ventricular ejection fraction (110178). Most research shows that taking oral iron does not improve hemoglobin levels, quality of life, or exercise capacity when compared with placebo (100970,110178). However, one small clinical trial shows that taking oral iron modestly improves iron status and overall symptoms and increases the 6-minute walking distance by about 46 meters, compared with a reduction of only 14 meters in those taking placebo (110183). Some doses used in individual clinical studies have included iron polysaccharide 150 mg twice daily for 16 weeks and ferrous sulfate 200 mg three times daily for 12 weeks (100970,110183).
• Restless legs syndrome (RLS). Oral and intravenous iron seem to be beneficial for RLS. The American Academy of Neurology recommends a combination of oral ferrous sulfate and vitamin C or intravenous ferric carboxymaltose for patients with RLS. Details: RLS is commonly associated with iron deficiency anemia. Some clinical research shows that taking iron in the form of ferrous sulfate 325 mg twice daily for 12 weeks reduces RLS symptoms comparably to pramipexole. Symptoms such as leg discomfort, need to move, and sleep disturbances improved considerably in about half of the patients taking either treatment (91181). Additional clinical research shows that taking ferrous sulfate 325 mg twice daily along with vitamin C 100 mg twice daily for 12 weeks reduces symptoms of RLS when compared with vitamin C alone in patients with RLS and low-normal serum ferritin levels (94189). Based on these results, clinical practice guidelines by the American Academy of Neurology report that taking this combination of oral ferrous sulfate and vitamin C is likely to improve symptoms in patients with RLS and low-normal serum ferritin (93587). Intravenous iron may also reduce symptoms of RLS. Clinical practice guidelines by the American Academy of Neurology report that two doses of intravenous ferric carboxymaltose 500 mg given 5 days apart are likely to improve symptoms and quality of life within 28 days in patients with moderate to severe RLS, regardless of serum ferritin levels. Intravenous iron sucrose has also been evaluated in patients with RLS, but there is currently insufficient available evidence to support or refute the use of this form of iron for treating RLS (93587).

POSSIBLY INEFFECTIVE

• Athletic performance. Oral iron does not seem to improve athletic performance. Details: A meta-analysis of clinical research in adults of childbearing age shows that iron supplementation improves some exercise performance measures, such as maximal oxygen uptake capacity, but not others, such as time until exhaustion and energy consumption, when compared with control (91184). Another meta-analysis of clinical research in patients with iron deficiency without anemia shows that iron supplementation improves subjective measures of fatigue, but does not improve exercise time to exhaustion or other measures of physical capacity (104684). A small clinical study in healthy children shows that taking iron supplements or consuming food providing iron 30-200 mg daily for 1-2 months improves running performance when compared with placebo. This was demonstrated by reductions of heart rate of 6.6 to 8 beats per minute during the running exercise. One preliminary study included in this analysis also showed that iron supplementation improved treadmill endurance time (20140).
• Child growth. Oral iron does not seem to be beneficial for child growth. Details: Meta-analyses of mainly preliminary clinical research show that oral iron supplementation, at doses averaging 2-80 mg or 1-10 mg/kg elemental iron daily for up to 52 weeks, does not increase growth rate in children (20131,20132,20133,95434).
• Preterm labor. Oral iron does not seem to prevent preterm labor and may actually increase the risk in malaria-endemic regions. Details: A meta-analysis of results from five clinical studies shows that maternal intake of iron as ferrous sulfate 20-60 mg daily for 14-26 weeks starting in the second trimester of pregnancy does not affect the length of gestation or increase birthweight of the infant (95434). In females from a malaria-endemic area who have never been pregnant before, another clinical study shows that taking ferrous gluconate 60 mg and folic acid 2.8 mg weekly, starting before conception and continuing to the first antenatal visit, may more than double the risk of preterm birth, defined as a delivery under 37 weeks gestation, when compared with folic acid alone (100969). Some research suggests that the adverse outcome in this latter study may be explained by a rise in hepcidin levels in pregnant patients with malaria. Hepcidin is a hormone that regulates iron absorption and distribution, and malaria can upregulate hepcidin. High levels of hepcidin can decrease iron absorption, stimulate inflammatory processes, and cause progesterone withdrawal, leading to preterm labor (102863).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• ACE inhibitor-induced cough. It is unclear if oral iron is beneficial in patients with this condition. Details: A small clinical trial shows that taking ferrous sulfate 256 mg daily reduces or eliminates cough induced by ACE inhibitors such as captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestril), and others, when compared with placebo (7307).
• Androgenic alopecia. Oral iron has only been evaluated in combination with other ingredients, its effect when used alone is unclear. Details: A moderate-sized clinical study in adults with androgenic alopecia or telogen effluvium shows that taking one tablet daily of a specific product (GFM Oral, Cantabria Labs), providing an unknown dose of iron in combination with selenium, taurine, cysteine, methionine, and hydrolyzed collagen, along with conventional therapy, consisting primarily of finasteride or minoxidil, for 12 weeks improves hair loss when compared with conventional therapy alone (111636). It is unclear if this effect is due to iron, other ingredients, or the combination.
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral iron is beneficial in children with ADHD. Details: Three small clinical studies in children with ADHD and iron deficiency shows that taking oral iron improves some measures of ADHD after 1-3 months of treatment when compared with baseline or placebo. These studies used ferrous sulfate 5 mg/kg daily, ferrous sulfate 80 mg daily, ferrous fumarate 200 mg daily for children weighing up to 30 kg, or ferrous fumarate 400 mg daily for children weighing more than 30 kg (1093,16013,110191).
• Child development. It is unclear if oral iron is beneficial for improving development in non-anemic children. Details: Some observational research has found that iron deficiency in infancy is associated with poor verbal performance and social skills in childhood (102862). It is unknown whether iron supplementation can ameliorate these developmental issues. In non-anemic infants and children, preliminary clinical research shows that iron does not improve cognitive performance; the evidence for the benefits of iron on psychomotor development is conflicting (20129,20130,91315,96616,96626).
• Esophageal cancer. It is unclear if oral iron is beneficial for esophageal cancer prevention. Details: Population research has found that taking iron supplements is associated with a 32% lower risk of esophageal adenocarcinoma when compared to never taking iron supplements. However, use of iron supplements is not associated with a lower risk of esophageal squamous cell carcinoma (95435).
• Fatigue. It is unclear if oral iron is beneficial in patients with fatigue due to iron deficiency without anemia. Details: A meta-analysis of mainly preliminary clinical research in adults with iron deficiency without anemia shows that iron reduces self-reported fatigue moderately more than placebo (104684). A specific ferrous sulfate supplement (Tardyferon; Pierre Fabre Médicament) providing 80 mg of elemental iron daily for 4-12 weeks was used in two studies included in this analysis (11406,91188).
• Inflammatory bowel disease (IBD). In patients with active IBD, intravenous iron may be more beneficial than oral iron due to impaired absorption. However, it may also increase the risk of infection in these patients. Details: Since the absorption of oral iron may be impaired in patients with active symptoms of IBD, guidelines from the British Society of Gastroenterology suggest that treatment with parenteral iron may be needed in patients with IBD who have moderate to severe iron-deficiency anemia (110193). However, a meta-analysis of clinical research in this population shows that administering IV iron, usually as iron sucrose or ferric carboxymaltose, increases the risk of infection by 73% when compared with oral iron or no iron (110186).
• Postoperative recovery. It is unclear if intravenous iron is beneficial for recovery following cardiac surgery. Details: A meta-analysis of low- to moderate-quality clinical research in patients with preoperative iron-deficiency anemia shows that treatment with intravenous iron before cardiac surgery does not improve the rate of transfusions or the length of stay in the intensive care unit or hospital when compared with control groups, including placebo, oral iron, or no treatment. Also, a meta-analysis of clinical research shows that intravenous iron does not reduce postoperative mortality rates (110182).
• Postpartum depression. Although there has been interest in using iron for postpartum depression, there is insufficient reliable information about the clinical effects of iron for this condition.
• Prematurity. Enteral iron seems to be beneficial for some measures of development in preterm infants. Details: A meta-analysis of clinical research in preterm or low birthweight infants fed human milk shows that enteral iron supplementation increases linear growth and reduces the risk of anemia when compared with control groups receiving no iron supplementation. However, there was no effect on serum ferritin, weight, head circumference, cognitive development, risk of infection, or risk of necrotising enterocolitis (110177). Additional clinical research in infants born at 24-28 weeks' gestation shows that a higher average enteral iron dose by 60 days of age is positively associated with cognitive performance at 2 years of corrected age. However, this association was not present for iron doses received at 90 days of age (110190). More evidence is needed to rate iron for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Diabetes. It is unclear if oral stevia is beneficial in patients with diabetes; the available research is conflicting. Details: A small single-dose study shows that taking stevia leaf extract 1000 mg, standardized to contain 91% stevioside, along with a meal reduces postprandial glucose levels by 18% in adults with type 2 diabetes when compared with a starch control (11812). However, clinical research in patients with type 1 or type 2 diabetes shows that taking stevioside 250 mg three times daily for 3 months does not affect blood glucose levels or glycated hemoglobin (HbA1C) when compared with baseline (16705). Also, a small clinical study in patients with diabetes shows that drinking 200 mL of black tea, sweetened with stevia extract 2%, three times daily for 8 weeks does not affect glycemic indices when compared with drinking tea sweetened with sucralose (103695).
• Hypertension. It is unclear if oral stevia is beneficial in patients with hypertension; the available research is conflicting. Details: Some clinical research in patients with mild to moderate hypertension shows that taking stevioside, a constituent of stevia, 750-1500 mg in three divided doses daily reduces systolic blood pressure by 10-14 mmHg and diastolic blood pressure by 6-14 mmHg within one week to three months of treatment initiation and continuing for up to 2 years (11809,11810). However, other clinical research in patients with mild hypertension shows that taking stevioside in doses up to 15 mg/kg daily does not significantly reduce blood pressure (16706).
• Obesity. It is unclear if oral stevia is beneficial in patients with obesity; the available research is conflicting. Details: Although a small clinical study in healthy adults shows that drinking water with stevia (Truvia) 245 ppm as a single dose reduces appetite and energy intake when compared with drinking water alone (103697), other small, single-dose studies have shown no effect of stevia 15.3 mg or 1 gram as a single dose on satiety, energy intake, or fullness when compared with either water alone or a non-nutritive sweetener (103696,110124). A small clinical study in healthy adults shows that taking an aqueous stevia leaf extract (SweetLeaf) twice daily for 12 weeks does not affect body weight, compared with an increase in weight in the control group. This suggests that stevia extract may have attenuated weight gain in this study (106458). More evidence is needed to rate stevia for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Angina. It is unclear if oral Terminalia arjuna is beneficial in patients with angina. Details: Low-quality clinical research in patients with angina shows that taking Terminalia arjuna extract 500-2000 mg orally daily for 3 months reduces the frequency of angina symptoms by 50% to 71% when compared with baseline. These results were similar to taking conventional therapy (2502,2503). Other preliminary research in adults with chronic stable angina shows that taking Terminalia arjuna 500 mg orally three times daily for 7 days reduces the need for rescue treatment and improves exercise tolerance when compared with placebo. Improvements were similar to taking isosorbide mononitrate 20 mg twice daily (92833).
• Asthma. Although there has been interest in using oral Terminalia arjuna for asthma, there is insufficient reliable information about the clinical effects of Terminalia arjuna for this purpose.
• Athletic performance. It is unclear if oral Terminalia arjuna is beneficial for athletic performance. Details: A small clinical study in young regular exercising males shows that taking Terminalia arjuna extract (Oxyjun, Enovate Biolife Pvt Ltd, India) 400 mg daily for 8 weeks increases the time to exhaustion by approximately 117 seconds when compared with placebo. There were also modest improvements in feelings of perceived exertion and the left ventricular ejection fraction, a measure of blood pumped from the heart with each heartbeat (111093). It is unclear if oral Terminalia arjuna is beneficial other populations such as athletes and females.
• Coronary heart disease (CHD). It is unclear if oral Terminalia arjuna is beneficial in patients with CHD. Details: Preliminary clinical research in patients with CHD shows that taking Terminalia arjuna bark powder 500 mg orally daily for 30 days decreases levels of total cholesterol by about 10% and low-density lipoprotein (LDL) cholesterol by about 16% when compared with baseline. Taking Terminalia arjuna bark powder did not improve high-density lipoprotein (HDL) cholesterol levels (92832).
• Heart failure. The effects of Terminalia arjuna in patients with heart failure is unclear; evidence to date comes from small, short-term clinical studies, and results are conflicting. Details: Preliminary, low-quality clinical research in patients with severe, refractory congestive heart failure shows that taking Terminalia arjuna bark extract 500 mg orally three times daily for 2 weeks, as an adjunct to conventional therapy, improves left ventricular ejection fraction (LVEF) by 17% when compared with placebo (2504). However, other preliminary clinical research in adults with stage II heart failure shows that taking an extract of Terminalia arjuna bark 750 mg orally twice daily as an adjunct to conventional therapy for 12 weeks does not improve LVEF, functional class, or functional capacity when compared with placebo (96726). However, the validity of these trials is limited by short-term treatment and variation in the conventional therapies used to manage heart failure.
• Hyperlipidemia. It is unclear if oral Terminalia arjuna is beneficial for improving lipid levels. Details: Preliminary clinical research in patients with elevated cardiovascular risk factors, such as hypertension, dyslipidemia, or obesity, shows that taking Terminalia arjuna 5 grams orally twice daily for 60 days decreases levels of low-density lipoprotein (LDL) cholesterol and triglycerides by 17% and 35%, respectively, and increases high-density lipoprotein (HDL) cholesterol levels by 9%, when compared with baseline. Improvements in lipid parameters were similar to taking amlodipine 5 mg and atorvastatin 10 mg daily (109677). However, this study may have been inadequately powered to detect a difference between groups.
• Hypertension. It is unclear if oral Terminalia arjuna is beneficial for reducing blood pressure. Details: Preliminary clinical research in patients with elevated cardiovascular risk factors such as hypertension, dyslipidemia, or obesity, shows that taking Terminalia arjuna 5 grams orally twice daily for 60 days reduces systolic and diastolic blood pressure by 11% and 14%, respectively, when compared with baseline. Improvements in blood pressure were similar to taking amlodipine 5 mg and atorvastatin 10 mg daily (109677). However, this study may have been inadequately powered to detect a difference between groups.
• Obesity. It is unclear if oral Terminalia arjuna is beneficial for weight loss. Details: Preliminary clinical research in patients with elevated cardiovascular risk factors, such as hypertension, dyslipidemia, or obesity, shows that taking Terminalia arjuna 5 grams orally twice daily for 60 days reduces body mass index (BMI) by 6% when compared with baseline. Improvements in BMI were similar to taking amlodipine 5 mg and atorvastatin 10 mg daily (109677). This study may have been inadequately powered to detect a difference between groups. More evidence is needed to rate Terminalia arjuna for these uses.

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LIKELY SAFE ...when the above ground parts are used orally in amounts commonly found in foods. Garden cress is a commonly consumed vegetable (47780).

POSSIBLY SAFE ...when the seeds are used orally and appropriately. Garden cress seeds have been used safely in doses of up to 3 grams daily for 4 weeks in clinical research (110899,110901). There is insufficient reliable information available about the safety of the above ground parts of garden cress when used in medicinal amounts or of garden cress seeds when used in amounts larger than 2.5 grams daily.

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

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LIKELY SAFE ...when consumed in amounts commonly found in foods (6,2076).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts. Indian gooseberry fruit extract has been used safely in doses of up to 1000 mg daily for up to 6 months, 1500 mg daily for up to 8 weeks, or 2000 mg daily for up to 4 weeks (92515,99238,99240,99241,102855,102857,105352,105354,105356). Indian gooseberry leaf extract has been used with apparent safety at a dose of 750 mg daily for 10 days (99846). ...when used topically and appropriately. An emulsion containing Indian gooseberry extract 3% and other ingredients has been applied safely to the skin twice daily for up to 60 days (111571).

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

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LIKELY SAFE ...when used orally and appropriately. For people age 14 and older with adequate iron stores, iron supplements are safe when used in doses below the tolerable upper intake level (UL) of 45 mg per day of elemental iron. The UL is not meant to apply to those who receive iron under medical supervision (7135,96621). To treat iron deficiency, most people can safely take up to 300 mg elemental iron per day (15). ...when used intravenously and appropriately. Ferric carboxymaltose 200 mg and iron sucrose 200 mg have been given intravenously for up to 10 doses with no reported serious adverse effects (91179). A meta-analysis of clinical studies of hemodialysis patients shows that administering high-dose intravenous (IV) iron does not increase the risk of hospitalization, infection, cardiovascular events, or death when compared with low-dose IV iron, oral iron, or no iron treatment (102861). A more recent meta-analysis of clinical studies of all patient populations shows that administering IV iron does not increase the risk of hospital length of stay or mortality, although the risk of infection is increased by 16% when compared with oral iron or no iron (110186). Despite these findings, there are rare reports of hypophosphatemia and/or osteomalacia (112603,112608,112609,112610).

LIKELY UNSAFE ...when used orally in excessive doses. Doses of 30 mg/kg are associated with acute toxicity. Long-term use of high doses of iron can cause hemosiderosis and multiple organ damage. The estimated lethal dose of iron is 180-300 mg/kg; however, doses as low as 60 mg/kg have also been lethal (15).

CHILDREN: LIKELY SAFE
when used orally and appropriately (7135,91183,112601).

CHILDREN: LIKELY UNSAFE
when used orally in excessive amounts. Tell patients who are not iron-deficient not to use doses above the tolerable upper intake level (UL) of 40 mg per day of elemental iron for infants and children. Higher doses frequently cause gastrointestinal side effects such as constipation and nausea (7135,20097). Iron is the most common cause of pediatric poisoning deaths. Doses as low as 60 mg/kg can be fatal (15).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Iron is safe during pregnancy and breast-feeding in patients with adequate iron stores when used in doses below the tolerable upper intake level (UL) of 45 mg daily of elemental iron (7135,96625,110180).

PREGNANCY AND LACTATION: LIKELY UNSAFE
when used orally in high doses. Tell patients who are not iron deficient to avoid exceeding the tolerable upper intake level (UL) of 45 mg daily of elemental iron. Higher doses frequently cause gastrointestinal side effects such as nausea and vomiting (7135) and might increase the risk of preterm labor (100969). High hemoglobin concentrations at the time of delivery are associated with adverse pregnancy outcomes (7135,20109).

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LIKELY SAFE ...when certain stevia constituents, including stevioside and rebaudiosides A, D, and M, are used orally as sweeteners in foods. These constituents have generally recognized as safe (GRAS) status in the US for this purpose (16699,16700,16702,16705,16706,108049). The stevia constituent stevioside has been safely used in doses of up to 1500 mg daily for 2 years (11809,11810,11811). There is insufficient reliable information available about the safety of whole stevia or stevia extracts when used orally. The European Food Safety Authority (EFSA) has determined that the acceptable intake of steviol glycosides is 4 mg/kg daily (106456); however, it is unclear how this relates to the use of whole stevia or stevia extract.

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

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POSSIBLY SAFE ...when used orally and appropriately, short-term. Several small studies have used Terminalia arjuna powdered bark or bark extract with apparent safely in doses up to 2000 mg or 400 mg daily, respectively, for 2 weeks to 3 months (2502,2503,2504,111012,111093); however, patients should avoid self-treatment with this product due to potentially significant cardiovascular effects. Further study is needed to determine the safety of Terminalia arjuna for long-term use.

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

(Read more about TERMINALIA ARJUNA)

AMLODIPINE (Norvasc) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking garden cress seeds with amlodipine might increase the risk of hypotension.  Details Animal research indicates that giving garden cress seeds with amlodipine increases maximum concentrations of amlodipine by 83%. Blood pressure was also reduced when compared with amlodipine alone. However, the area under the curve was not significantly affected (110896).

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, garden cress seed may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Animal research suggests that garden cress seed extract can increase bleeding time when used in combination with the antiplatelet agent clopidogrel (108701). This has not been shown in humans and it is unclear if garden cress seed itself has anticoagulant or antiplatelet effects.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking garden cress with antidiabetes drugs might increase the risk of hypoglycemia.  Details Evidence from animal research suggests that an extract of garden cress can reduce blood glucose levels (51193,105745,108929,110893,110902). This has not been shown in humans.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking garden cress with antihypertensive drugs might increase the risk of hypotension.  Details Garden cress has shown hypotensive effects in animal research and increases levels and effects of the antihypertensive medications amlodipine and losartan (51202,108703,110896,110897). This has not been shown in humans.

CARBAMAZEPINE (Tegretol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, garden cress might increase the absorption rate of carbamazepine and result in blood concentrations outside of the therapeutic window.  Details Animal research shows that taking garden cress seed daily for 8 days prior to a single dose of carbamazepine does not significantly affect maximum concentrations or area under the curve of carbamazepine. However, the absorption rate is increased, with a 50% reduction (2 hours) in time to peak concentration, resulting in increased plasma levels within 3 hours of dosing and then decreased plasma levels from 5-12 hours after dosing (94476). This has not been shown in humans.

CLOPIDOGREL (Plavix) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking garden cress seed with clopidogrel might prolong bleeding.  Details Animal research shows that taking garden cress seed daily for 2 weeks prior to a single dose of clopidogrel does not affect the pharmacokinetics of clopidogrel. However, bleeding time was increased by 7% (108701). This has not been shown in humans and the mechanism of action is unclear.

DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking garden cress with diuretic drugs might increase the risk of hypokalemia.  Details Evidence from animal research suggests that garden cress has diuretic effects and can increase the urinary excretion of potassium (51202). This has not been shown in humans. Initiation of potassium supplementation or an increase in potassium supplement dose may be necessary for some patients.

GLICLAZIDE (Diamicron, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking garden cress seed with gliclazide might increase the risk of hypoglycemia.  Details Evidence from animal research suggests that garden cress seed increases the area under the curve of a single dose of gliclazide by approximately 70%. However, there was no statistically significant effect on maximum concentrations of gliclazide or on the effects of gliclazide on blood glucose (110893). This has not been shown in humans.

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, garden cress might reduce excretion and increase levels of lithium due to diuretic effects.  Details Animal research suggests that garden cress has diuretic properties (51202).

LOSARTAN (Cozaar) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, garden cress seed might have additive hypotensive effects when used with losartan.  Details Animal research suggests that giving garden cress seed extract for two weeks before a single dose of losartan increases levels of plasma losartan by at least 2.4-fold and potentiates its blood pressure-lowering effects. Maximum concentrations of losartan were not significantly affected (110897). So far, this interaction has not been reported in humans.

METOPROLOL (Toprol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, garden cress seed might have additive hypotensive effects when used with metoprolol.  Details Animal research shows that garden cress seed for 2 weeks decreases systolic and diastolic blood pressure by 9% and 32%, respectively, when administered alone, and by 15% and 33%, respectively, when given with metoprolol 10 mg/kg (108703). So far, this interaction has not been reported in humans.

PHENYTOIN (Dilantin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, garden cress might increase levels and side effects of phenytoin.  Details Animal research shows that garden cress seed for 1 week increases maximum concentrations and the area under the curve of a single dose of phenytoin by 16% and 49%, respectively. This seems to be related to decreased clearance (110905). So far, this interaction has not been reported in humans.

SILDENAFIL (Viagra) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concurrent use of sildenafil and L-arginine might reduce levels and therapeutic effects of sildenafil.  Details Animal research shows that garden cress seed for 1 week reduces maximum concentrations and the area under the curve of a single dose of sildenafil by 40% and 51%, respectively (110898). So far, this interaction has not been reported in humans.

THEOPHYLLINE Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concurrent use of sildenafil and theophylline might increase levels and adverse effects of theophylline.  Details Animal research shows that garden cress can increase theophylline concentrations by approximately 37%. It is hypothesized that this increase is due to possible inhibition of cytochrome P450 (CYP) 1A2 (90118). So far, this interaction has not been reported in humans.

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, Indian gooseberry may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs; however, research is conflicting.  Details Clinical research shows that taking Indian gooseberry 500 mg as a single dose or twice daily for 10 days reduces platelet aggregation by about 24% to 36%, increases bleeding time by about 3.8-5.9 seconds, and increases clotting time by about 9.8-12.7 seconds when compared to baseline. However, taking Indian gooseberry 500 mg along with clopidogrel 75 mg or ecosprin 75 mg, as a single dose or for 10 days, does not significantly reduce platelet aggregation or increase bleeding time or clotting time when compared with clopidogrel 75 mg or ecosprin 75 mg alone (92514). Until more is known, use caution when taking Indian gooseberry in combination with anticoagulant/antiplatelet drugs.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Taking Indian gooseberry with antidiabetes drugs might increase the risk of hypoglycemia.  Details Clinical research shows that taking Indian gooseberry fruit or fruit extract alone or in conjunction with antidiabetes medications can lower blood glucose levels (31025,105355,105356,111569). Dose adjustments to diabetes medications might be necessary.

ASPIRIN Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, Indian gooseberry may increase the risk of bleeding if used with aspirin; however, research is conflicting.  Details Clinical research shows that taking Indian gooseberry 500 mg as a single dose or twice daily for 10 days reduces platelet aggregation by about 24% to 36%, increases bleeding time by about 3.8-5.9 seconds, and increases clotting time by about 9.8-12.7 seconds when compared to baseline. However, taking a single dose of Indian gooseberry 500 mg along with ecosprin 75 mg, or taking a combination of Indian gooseberry 500 mg twice daily plus ecosprin 75 mg once daily for 10 days, does not significantly reduce platelet aggregation or increase bleeding time or clotting time when compared with ecosprin 75 mg alone (92514).

CLOPIDOGREL (Plavix) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, Indian gooseberry may increase the risk of bleeding if used with clopidogrel; however, research is conflicting.  Details Clinical research shows that taking Indian gooseberry 500 mg as a single dose or twice daily for 10 days reduces platelet aggregation by about 24% to 36%, increases bleeding time by about 3.8-5.9 seconds, and increases clotting time by about 9.8-12.7 seconds when compared to baseline. However, taking a single dose of Indian gooseberry 500 mg along with clopidogrel 75 mg, or taking a combination of Indian gooseberry 500 mg twice daily plus clopidogrel 75 mg once daily for 10 days, does not significantly reduce platelet aggregation or increase bleeding time or clotting time when compared with clopidogrel 75 mg alone (92514).

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BISPHOSPHONATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Iron reduces the absorption of bisphosphonates.  Details Advise patients that doses of bisphosphonates should be separated by at least two hours from doses of all other medications, including supplements such as iron. Divalent cations, including iron, can decrease absorption of bisphosphonates by forming insoluble complexes in the gastrointestinal tract (15).

CHLORAMPHENICOL Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, taking chloramphenicol with iron might reduce the response to iron therapy in iron deficiency anemia.  Details Chloramphenicol interferes with erythrocyte maturation (15,3046). However, since chloramphenicol isn't usually taken for prolonged periods, this isn't likely to be clinically significant.

DOLUTEGRAVIR (Tivicay) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Iron might decrease dolutegravir levels by reducing its absorption.  Details Advise patients to take dolutegravir at least 2 hours before or 6 hours after taking iron. Pharmacokinetic research shows that iron can decrease the absorption of dolutegravir from the gastrointestinal tract through chelation (93578). When taken under fasting conditions, a single dose of ferrous fumarate 324 mg orally along with dolutegravir 50 mg reduces overall exposure to dolutegravir by 54% (94190).

INTEGRASE INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking iron along with integrase inhibitors might decrease the levels and clinical effects of these drugs.  Details Iron is a divalent cation. There is concern that iron may decrease the absorption of integrase inhibitors from the gastrointestinal tract through chelation (93578). One pharmacokinetic study shows that iron can decrease blood levels of the specific integrase inhibitor dolutegravir through chelation (94190). Also, other pharmacokinetic research shows that other divalent cations such as calcium can decrease the absorption and levels of some integrase inhibitors through chelation (93578,93579).

LEVODOPA Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Iron might decrease levodopa levels by reducing its absorption.  Details Advise patients to separate doses of levodopa and iron as much as possible. There is some evidence in healthy people that iron forms chelates with levodopa, reducing the amount of levodopa absorbed by around 50% (9567). The clinical significance of this hasn't been determined.

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Iron might decrease levothyroxine levels by reducing its absorption.  Details Advise patients to separate levothyroxine and iron doses by at least 2 hours. Iron can decrease the absorption and efficacy of levothyroxine by forming insoluble complexes in the gastrointestinal tract (9568).

METHYLDOPA (Aldomet) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Iron might decrease methyldopa levels by reducing its absorption.  Details Advise patients to separate methyldopa and iron doses by at least 2 hours. Iron can decrease the absorption of methyldopa from the gastrointestinal tract through chelation, resulting in increases in blood pressure (7900,20151).

MYCOPHENOLATE MOFETIL (CellCept) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, iron might decrease mycophenolate mofetil levels by reducing its absorption.  Details Advise patients to take iron 4-6 hours before, or 2 hours after, mycophenolate mofetil. It has been suggested that a decrease of absorption is possible, probably by forming nonabsorbable chelates. However, mycophenolate pharmacokinetics are not affected by iron supplementation in available clinical research (3046,20152,20153,20154,20155).

PENICILLAMINE (Cuprimine, Depen) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Iron might decrease penicillamine levels by reducing its absorption.  Details Advise patients to separate penicillamine and iron doses by at least 2 hours. Oral iron supplements can reduce absorption of penicillamine by 30% to 70%, probably due to chelate formation. In people with Wilson's disease, this interaction has led to reduced efficacy of penicillamine (3046,3072,20156).

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Iron might decrease levels of quinolone antibiotics by reducing their absorption.  Details Advise patients to separate quinolone antibiotics and iron doses by at least 2 hours. Iron decreases the absorption of quinolones due to formation of insoluble complexes in the gastrointestinal tract (15,3072).

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Iron might decrease levels of tetracycline antibiotics by reducing their absorption.  Details Advise patients to take iron at least 2 hours before or 4 hours after tetracycline antibiotics. Concomitant use can decrease absorption of tetracycline antibiotics from the gastrointestinal tract by 50% to 90% (15).

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ANTIDIABETES DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, stevia might increase the risk for hypoglycemia when combined with antidiabetes drugs.  Details Preliminary clinical research in patients with type 2 diabetes suggests that taking a single dose of stevia extract 1000 mg reduces postprandial blood glucose levels when taken with a meal (11812). However, other clinical research in patients with type 1 or type 2 diabetes suggests that taking stevioside 250 mg three times daily does not significantly affect blood glucose levels or glycated hemoglobin (HbA1C) after three months of treatment (16705).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, combining stevia or stevia constituents with antihypertensive agents might increase the risk of hypotension.  Details Stevia extract and stevioside might lower blood pressure in patients with hypertension (3745,3747,5031,11809,11810). However, other clinical research suggests that stevioside does not significantly lower blood pressure in patients with hypertension (16706).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, stevia might decrease clearance and increase levels of lithium.  Details Animal research suggests that stevia extracts might have diuretic activity (3746,3747). Theoretically, increased reabsorption of lithium along with sodium might reduce excretion and increase levels of lithium.

(Read more about STEVIA)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of Terminalia arjuna with anticoagulant or antiplatelet drugs may increase the risk of bleeding in some patients.  Details In vitro, Terminalia arjuna bark extract inhibits platelet aggregation, decreases platelet activation, and shows antithrombotic properties (92831).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, use of Terminalia arjuna may increase the levels and clinical effects of CYP2C9 substrates.  Details In vitro research shows that Terminalia arjuna extract inhibits CYP2C9 enzymes and reduces CYP2C9 substrate metabolism (96729).

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, use of Terminalia arjuna may increase the levels and clinical effects of CYP2D6 substrates.  Details In vitro research shows that Terminalia arjuna extract inhibits CYP2D6 enzymes and reduces CYP2D6 substrate metabolism (96729).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, use of Terminalia arjuna may increase the levels and clinical effects of CYP3A4 substrates.  Details In vitro research shows that Terminalia arjuna extract inhibits CYP3A4 enzymes and reduces CYP3A4 substrate metabolism (96729).

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General ...Orally, garden cress is generally well-tolerated. When used in medicinal amounts, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.

Gastrointestinal ...Orally, consuming large amounts of garden cress may cause gastrointestinal irritation (18).

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General ...Orally, Indian gooseberry seems to be well tolerated.

Dermatologic ...Orally, itching has been reported by one individual in a clinical trial (105354).

Gastrointestinal ...Orally, epigastric discomfort or dyspepsia have been reported by up to four individuals in clinical trials (105354,105356).

Hepatic ...In clinical research, increased serum glutamic pyruvic transaminase (SGPT) levels, with otherwise normal liver function, occurred in patients taking Ayurvedic formulations containing ginger, Tinospora cordifolia, and Indian gooseberry, with or without Boswellia serrata. The SGPT levels normalized after discontinuing the treatments (89557). It is unclear if these hepatic effects were due to Indian gooseberry or other ingredients contained in the formulations.

Musculoskeletal ...Orally, musculoskeletal pain has been reported by three individuals in a clinical trial (105354).

Neurologic/CNS ...Orally, fatigue has been reported by one individual in a clinical trial (105354).

Pulmonary/Respiratory ...Orally, breathlessness has been reported by one individual in a clinical trial (105354).

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General ...Orally or intravenously, iron is generally well tolerated when used appropriately.
Most Common Adverse Effects:
Orally: Abdominal pain, constipation, diarrhea, gastrointestinal irritation, nausea, and vomiting.
Serious Adverse Effects (Rare):
Orally: Case reports have raised concerns about oral or gastric ulcerations.
Intravenously: Case reports have raised concerns about hypophosphatemia and osteomalacia.

Cardiovascular ...There is debate regarding the association between coronary heart disease (CHD) or myocardial infarction (MI) and high iron intake or high body iron stores. Some observational studies have reported that high body iron stores are associated with increased risk of MI and CHD (1492,9542,9544,9545,15175). Some observational studies reported that only high heme iron intake from dietary sources such as red meat are associated with increased risk of MI and CHD (1492,9546,15174,15205,15206,91180). However, the majority of research has found no association between serum iron levels and cardiovascular disease (1097,1099,9543,9547,9548,9549,9550,56469,56683).
There is one case of Kounis syndrome, also referred to as allergic angina or allergic myocardial infarction, in a 39-year-old female patient without previous coronary artery disease given intravenous ferric carboxymaltose. The patient experienced anaphylactic symptoms, including headache, abdominal pain, and breathing difficulties, 3 minutes after starting the infusion. She was further diagnosed with non-ST-elevation myocardial infarction (112607).

Dermatologic ...Cutaneous hemosiderosis, or skin staining, has been reported following intravenous iron infusion in various case reports. Most of these cases are due to extravasation following iron infusion (112605,112611). In one case, extravasation has occurred following iron derisomaltose infusion in a 41-year-old female with chronic kidney disease (112605). Rarely, diffuse cutaneous hermosiderosis has occurred. In one case, a 31-year-old female with excessive sweating developed cutaneous hemosiderosis in the armpits following an intravenous iron polymaltose infusion (112611).

Endocrine ...Population research in females shows that higher ferritin levels are associated with an approximately 1. 5-fold higher odds of developing gestational diabetes. Increased dietary intake of heme-iron, but not non-heme iron, is also associated with an increased risk for gestational diabetes. The effects of iron supplementation could not be determined from the evaluated research (96618). However, in a sub-analysis of a large clinical trial in pregnant adults, daily supplementation with iron 100 mg from 14 weeks gestation until delivery did not affect the frequency or severity of glucose intolerance or gestational weight gain (96619).

Gastrointestinal ...Orally, iron can cause dry mouth, gastrointestinal irritation, heartburn, abdominal pain, constipation, diarrhea, nausea, or vomiting (96621,102864,104680,104684,110179,110185,110188,110189,110192). These adverse effects are uncommon at doses below the tolerable upper intake level (UL) of 45 mg per day of elemental iron in adults with normal iron stores (7135). Higher doses can be taken safely in adults with iron deficiency, but gastrointestinal side effects may occur (1095,20118,20119,56698,102864). Taking iron supplements with food seems to reduce gastrointestinal side effects (7135). However, food can also significantly reduce iron absorption. Iron should be taken on an empty stomach, unless it cannot be tolerated.
There are several formulations of iron products such as ferrous sulfate, ferrous gluconate, ferrous fumarate, and others. Manufacturers of some formulations, such as polysaccharide-iron complex products (Niferex-150, etc), claim to be better tolerated than other formulations; however, there is no reliable evidence to support this claim. Gastrointestinal tolerability relates mostly to the elemental iron dose rather than the formulation (17500).
Enteric-coated or controlled-release iron formulations might reduce nausea for some patients, however, these products also have lower absorption rates (17500).
Liquid oral preparations can blacken and stain teeth (20118).
Iron can also cause oral ulcerations and ulcerations of the gastric mucosa (56684,91182,96622,110179). In one case report, an 87-year-old female with Alzheimer disease experienced a mucosal ulceration, possibly due to holding a crushed ferrous sulfate 80 mg tablet in the mouth for too long prior to swallowing (91182). The ulceration was resolved after discontinuing iron supplementation. In another case report, a 76-year old male suffered gastric mucosal injury after taking a ferrous sulfate tablet daily for 4 years (56684). In a third case report, a 14-year-old female developed gastritis involving symptoms of upper digestive hemorrhage, nausea, melena, and stomach pain. The hemorrhage was attributed to supplementation with ferrous sulfate 2 hours after meals for the prior 2 weeks (96622). In one case report, a 43-year old female developed atrophic gastritis with non-bleeding ulcerations five days after starting oral ferrous sulfate 325 mg twice daily (110179).
Intravenously, iron can cause gastrointestinal symptoms sch as nausea (104684,110192).

Immunologic ...Although there is some clinical research associating iron supplementation with an increased rate of malaria infection (56796,95432), the strongest evidence to date does not support this association, at least for areas where antimalarial treatment is available (95433,96623). In an analysis of 14 trials, iron supplementation was not associated with an increased risk of malaria (96623). In a sub-analysis of 7 preliminary clinical studies, the effect of iron supplementation was dependent upon the access to services for antimalarial treatment. In areas where anemia is common and services are available, iron supplementation is associated with a 9% reduced risk of clinical malaria. In an area where services are unavailable, iron supplementation was associated with a 16% increased risk in malaria incidence (96623). The difference in these findings is likely associated with the use of malaria prevention methods.
A meta-analysis of clinical studies of all patient populations shows that administering IV iron, usually iron sucrose and ferric carboxymaltose, increases the risk of infection by 16% when compared with oral iron or no iron. However, sub-analyses suggest this increased risk is limited to patients with inflammatory bowel disease (IBD) (110186).
Intravenously, iron has rarely resulted in allergic reactions, including anaphylactoid reactions (110185,110192,112606,112607). There is one case of Kounis syndrome, also referred to as allergic angina or allergic myocardial infarction, in a 39-year-old female patient without previous coronary artery disease given intravenous ferric carboxymaltose. The patient experienced anaphylactic symptoms, including headache, abdominal pain, and breathing difficulties, 3 minutes after starting the infusion. She was further diagnosed with non-ST-elevation myocardial infarction (112607).

Musculoskeletal ...Intravenously, iron rarely results in osteomalacia related to hypophosphatemia (112609). At least 2 cases exist of hypophosphatemic osteomalacia. In one case, a 70-year-old male with a genetic hemorrhagic disorder infused with ferric carboxymaltose developed lower limb pain with hypophosphatemia and diffuse bone demineralization in the feet (112609). In a second case, a 61-year-old male developed femoral neck insufficiency fractures following repeated ferric carboxymaltose transfusions for anemia related to vascular malformation in the bowel (112603). Severe hypophosphatemia requiring intravenous phosphate in the absence of osteomalacia has also occurred following intravenous ferric carboxymaltose (112608,112610).

Oncologic ...There is a debate regarding the association between high levels of iron stores and cancer. Data are conflicting and inconclusive (1098,1099,1100,1102). Epidemiological studies suggest that increased body iron stores may increase the risk of cancer or general mortality (56703).
Occupational exposure to iron may be carcinogenic (56691). Oral exposure to iron may also be carcinogenic. Pooled analyses of population studies suggest that increasing the intake of heme iron increases the risk of colorectal cancer. For example, increasing heme iron intake by 1 mg/day is associated with an 11% increase in risk (56699,91185).

Other ...Intravenously, sodium ferric gluconate complex (SFGC) caused drug intolerance reactions in 0. 4% of hemodialysis patients including 2 patients with pruritus and one patient each with anaphylactoid reaction, hypotension, chills, back pain, dyspnea/chest pain, facial flushing, rash and cutaneous symptoms of porphyria (56527).

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General ...Orally, stevia and steviol glycosides appear to be well tolerated. Most minor adverse effects seem to resolve after the first week of use.
Most Common Adverse Effects:
Abdominal bloating, dizziness, headache, myalgia, nausea, and numbness.
Serious Adverse Effects (Rare):
Allergic reactions.

Gastrointestinal ...Orally, stevia and steviol glycosides such as stevioside, can cause gastrointestinal adverse effects such as abdominal fullness and nausea. However, these generally resolve after the first week of use (11809,11810).

Immunologic ...Theoretically, stevia might cause allergic reactions in individuals sensitive to plants in the Asteraceae/Compositae family (11811). Members of this family include ragweed, chrysanthemums, marigolds, daisies, and many other herbs.

Musculoskeletal ...Orally, stevia and steviol glycosides may cause myalgia, but this generally resolves after the first week of use (11809,11810).

Neurologic/CNS ...Orally, stevia and steviol glycosides may cause headache, dizziness, and numbness (11809,11810).

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General ...There is currently a limited amount of information available on the adverse effects of oral Terminalia arjuna. A thorough evaluation of safety outcomes has not been conducted.

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