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POSSIBLY EFFECTIVE

• Anxiety. Small clinical studies suggest that oral ashwagandha might reduce anxiety. Details: A meta-analysis of small randomized controlled trials in adults with anxiety and/or insomnia shows that taking ashwagandha 600-12,000 mg orally daily for 6-10 weeks moderately improves anxiety scores when compared with placebo. However, the validity of this study is limited by high heterogeneity (114787). One small clinical study in postal workers reporting moderate or severe anxiety shows that taking ashwagandha root (Swiss Herbals) 300 mg twice daily for 12 weeks, in combination with standard psychotherapy interventions, including dietary counseling, deep breathing exercise instruction, and a multivitamin, reduces anxiety scores when compared with standard psychotherapy interventions and placebo (19271). Additionally, two small clinical studies in adults with mild to moderate anxiety, depression, or stress show that taking a specific ashwagandha root extract standardized to contain 2.5% withanolides (Shagandha, Sabinsa Corp.) 500 mg with piperine 5 mg daily for 60-90 days reduces anxiety symptoms and perceived stress and improves sleep and quality of life when compared with placebo (113608,113609). However, another clinical study in young adults shows that taking a specific ashwagandha root and leaf extract (NooGandha, Specnova LLC) 225 mg or 400 mg daily for 30 days does not improve anxiety, stress, and depression scores when compared with placebo (107370).
• Generalized anxiety disorder (GAD). Oral ashwagandha may modestly improve symptoms of anxiety in patients with GAD. Details: Clinical practice guidelines from the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) provisionally recommend ashwagandha root extract at doses of 300-600 mg, standardized to 5% withanolides, daily as monotherapy or adjunctive therapy in patients with GAD. This recommendation is based on a review of three preliminary clinical trials with consistent results (110318). Two of these studies are described below. A small clinical trial in patients with GAD who are taking selective serotonin reuptake inhibitors (SSRIs) shows that taking ashwagandha 1 gram daily for 6 weeks reduces symptoms of anxiety by 48%, compared with a 27% reduction in patients taking placebo. Furthermore, by the end of treatment, 72% of patients taking ashwagandha were determined to have mild symptoms of GAD, compared with only 32% of those taking placebo (102687). Another preliminary clinical trial in patients aged 16 years and older with GAD shows that taking ashwagandha root powder granules 4 grams three times daily for 60 days moderately improves anxious mood in 58% of patients, compared with no moderate improvement in the placebo group. Mild improvement occurred in 82% of patients in the placebo group and 40% of patients in the ashwagandha group (90654). Another small clinical trial in adults with general anxiety disorder shows that taking ashwagandha, standardized to 35% withanolides, 60-120 mg orally daily for 60 days improves anxiety scores by about 60% when compared with placebo (114792).
• Insomnia. Oral ashwagandha may modestly improve sleep in patients with insomnia or non-restorative sleep. Details: A small meta-analysis in patients with insomnia and healthy patients shows that taking a specific ashwagandha root extract (KSM-66, Ixoreal Biomed) 250-600 mg daily or a specific root and leaf extract (Shoden, Arjuna Natural) 120 mg daily for 6-12 weeks modestly improves overall sleep, as well as sleep quality, sleep latency, total sleep time, wake time after sleep onset, and sleep efficiency, when compared with placebo. Effects were more pronounced in those with insomnia, with doses of at least 600 mg daily, and with treatment durations of at least 8 weeks (106784). These findings may be limited by heterogeneity of the included studies. A meta-analysis of 2 small randomized controlled trials in adults with anxiety and/or insomnia shows that taking ashwagandha 600 mg orally daily for 8-10 weeks modestly improves sleep onset latency, total sleep time, sleep efficiency, and sleep quality scores, but not wake after sleep onset or total time in bed, when compared with placebo. However, the validity of this study is limited by moderate heterogeneity (114787). In patients with non-restorative sleep, clinical research shows that taking a specific ashwagandha extract (Shoden, Arjuna Natural Private Ltd) 125 mg daily for 6 weeks increases sleep quality by 72%, compared with an improvement of 29% in patients taking placebo. Small to moderate improvements also occurred in total sleep time, sleep latency, and number of times awake (103476). Ashwagandha has also been evaluated as part of a combination treatment. A very small clinical trial in adults with poor quality sleep shows that taking milk fortified with ashwagandha 250-600 mg, or ashwagandha 250 mg and tryptophan, orally daily for 90 days moderately improves sleep quality scores when compared with placebo (114791). Additional data are needed to determine if the addition of tryptophan improves results more than ashwagandha alone.
• Stress. Oral ashwagandha seems to help reduce stress and may also reduce stress-related weight gain. Details: A meta-analysis of seven small clinical studies in healthy adults, patients with chronic stress, or patients with psychiatric conditions shows that taking ashwagandha 240-1000 mg daily for 8-12 weeks improves stress when compared with placebo (109587). Clinical studies, some of which are included in the meta-analysis mentioned above, evaluating adults with chronic stress show that taking specific ashwagandha root extracts 240 mg daily (Shoden, Arjuna Natural Ltd.), 300 mg twice daily (KSM-66, Ixoreal Biomed), or 500 mg daily (Shagandha, Sabinsa Corp.) with piperine 5 mg for 60 days, or a specific slow-release capsule containing ashwagandha root extract (Prolanza) 300 mg daily for 90 days reduces perceived stress and cortisol levels when compared with baseline and placebo (90652,95617,101816,102682,107371,113608). Additionally, a small clinical study in adults with stress and a related comorbidity, such as anxiety or depression, shows that taking ashwagandha root and leaf extract (Sensoril, Kerry Group) 125-500 mg orally daily for 8 weeks improves stress scores in a dose-dependent manner when compared with placebo (114112). In contrast, a moderate-sized study in adults with overweight or mild obesity with moderate-to-high levels of stress and fatigue shows that taking ashwagandha root extract (Witholytin, Verdure Sciences Inc) 200 mg twice daily for 12 weeks reduces stress when compared to baseline, but not when compared with placebo (113611).In healthy college students, clinical research also shows that taking ashwagandha root extract 350 mg twice daily for 30 days improves qualitative perceptions of stress management, but not stress scores, when compared with placebo (109589,109590). Other clinical research shows that taking ashwagandha root extract 500 mg twice daily may prevent stress-related weight gain when compared with placebo (95617).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging. A small clinical study suggests that oral ashwagandha may modestly improve well-being, sleep, and alertness in elderly patients. Details: A small clinical trial in individuals aged 65-80 years shows that taking ashwagandha root extract (KSM-66, Ixoreal Biomed) 600 mg daily for 12 weeks improves overall well-being, sleep quality, and mental alertness by small to moderate amounts when compared with placebo (102684).
• Androgenic alopecia. It is unclear if topical ashwagandha is beneficial for androgenic alopecia. Details: A small clinical study in adults with mild to moderate hair loss, including androgenic alopecia, shows that applying ashwagandha root extract serum (KSM-66, Ixoreal Biomed) 1-2 drops to the scalp daily for 75 days reduces hair shedding and increases hair density, growth, and thickness when compared with placebo (113613).
• Antipsychotic-induced metabolic side effects. It is unclear if ashwagandha is beneficial for attenuating the metabolic side effects of antipsychotic agents. Details: One preliminary clinical trial shows that taking a specific ashwagandha extract (Cap Strelaxin, M/s Pharmanza Herbal Pvt. Ltd.) 400 mg three times daily for one month reduces serum triglycerides by 12% and fasting blood glucose by 15% when compared with baseline levels. Patients were taking atypical antipsychotics and had modestly elevated triglycerides and fasting blood glucose levels at baseline (90649). The validity of these findings is limited by the lack of a comparator group.
• Asthma. Although there has been interest in using oral ashwagandha for asthma, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Athletic performance. It is unclear if ashwagandha is beneficial for improving athletic performance. Details: A meta-analysis of four small clinical trials shows that taking ashwagandha increases aerobic capacity in athletes and non-athletes based on the measurement of maximum oxygen consumption. Effective doses ranged from 500-1000 mg daily for up to 12 weeks (102683). Another meta-analysis shows that taking ashwagandha in doses of 120-1250 mg daily, as a single dose or divided twice daily, for up to 6 months seems to improve muscle strength, speed, time to exhaustion, recovery time, and cardiorespiratory fitness in athletes and non-athletes (105824). However, the validity of this analysis is reduced by the lack of a control group, the varied training levels of the subjects, and the wide range of outcomes assessed. A moderate-sized clinical trial in active adults shows that taking a specific ashwagandha root extract (KSM-66, Ixoreal Biomed) 300 mg orally twice daily, in addition to resistance training, for 8 weeks improves the maximum rate of oxygen consumption (VO2 max) as a measure of cardiorespiratory endurance, but not muscle strength when compared with placebo (114788). More research is needed to determine whether taking ashwagandha can improve athletic performance.
• Attention deficit-hyperactivity disorder (ADHD). Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In a preliminary clinical trial, children with ADHD were given a combination herbal extract formula (Nurture & Clarity), containing ashwagandha, white peony root, gotu kola, blue-green algae, bacopa, and sage, 3 mL three times daily for 4 months. Measures of attention, cognition, and impulse control improved significantly in children receiving ashwagandha when compared with placebo (19272). The dose of ashwagandha in the combination product was not reported, and the effect of ashwagandha alone in ADHD is unclear. Back pain.Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in adults with back pain shows that taking a specific combination product (Berelief, Monteloeder S.L.) containing ashwagandha 66%, rosemary, and sesame seed, 200-400 mg orally daily for 12 weeks moderately improves pain scores and reduces the need for adjunct pain medication when compared with placebo (114793). It is unclear if this effect is due to ashwagandha, other ingredients, or the combination.
• Bipolar disorder. It is unclear if oral ashwagandha is beneficial for improving cognitive function in adults with bipolar disorder. Details: Clinical research shows that taking ashwagandha extract (Sensoril, Natreon, Inc.) 250 mg daily for 1 week and then 250 mg twice daily for 7 weeks, improves some, but not all, measures of cognition by a small-to-moderate amount when compared with placebo (90653).
• Bronchitis. Although there has been interest in using oral ashwagandha for bronchitis, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Cerebellar ataxia. It is unclear if oral ashwagandha is beneficial for improving balance in patients with cerebellar ataxia. Details: A small, open-label study evaluating ashwagandha 500 mg three times daily in combination with Ayurvedic therapy for one month showed improvement in balance indices in subjects with cerebellar ataxia when compared with baseline (19273). The validity of this finding is limited by the lack of a comparator group. Additionally, it is unclear if this effect is due to ashwagandha, other ingredients, or the combination.
• Chemotherapy-related fatigue. Evidence is limited to one small clinical study in patients with breast cancer. Details: In preliminary clinical research in patients with breast cancer, taking ashwagandha powdered root extract 2 grams (Himalaya Drug Co) three times daily through six cycles of chemotherapy decreases chemotherapy-related fatigue when compared with no treatment. Fatigue scores were 16% to 52% higher in the control group when compared to the ashwagandha group (90651).
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral ashwagandha is beneficial in patients with COPD. Details: A small clinical study in patients with stable COPD shows that taking ashwagandha root extract 250 mg twice daily for 12 weeks, along with conventional therapy, improves measures of lung function and exercise tolerance, but not quality of life, when compared with conventional therapy alone (109588).
• Cognitive function. Although there has been interest in using oral ashwagandha for cognitive function, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Constipation. Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in adults with constipation shows that taking a combination product containing ashwagandha root and ambrette fruit extracts 300 mg or 500 mg daily for 14 days improves bowel movement frequency and abdominal, rectal, and stool symptoms when compared with placebo (112114). Additionally, a moderate-sized clinical study in adults with functional constipation shows that using the same combination of ashwagandha and ambrette 300 mg or 500 mg daily for 60 days moderately improves constipation symptom scores and bowel movement scores when compared with placebo (114115). It is unclear if these effects are due to ashwagandha, ambrette, or the combination.
• Coronavirus disease 2019 (COVID-19). Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults hospitalized with COVID-19 shows that taking a specific combination product, (Artovid-20, Bioved Pharmaceuticals) containing ashwagandha, ginger, turmeric, and Boswellia, 1,776 mg orally twice daily for 14 days shortens the duration of symptoms by 0.9 days when compared with placebo. Taking the combination product also modestly reduced the severity ratings of some symptoms, such as sore throat and cough, however, these improvements are unlikely to be clinically relevant (109899). Another small clinical study in adults with mild to moderate COVID-19 shows that taking ashwagandha 500 mg and ginger 1000 mg twice daily for 15 days reduces time to recovery by around 6 days and increases the rate of clinical cure 14-fold and 2.6-fold at days 5 and 7, respectively, when compared with a control. However, taking this combination does not appear to improve the proportion of patients with a negative COVID-19 test, viral clearance, serum antibodies, chest findings, or disease progression when compared with control (112094). The validity of these findings is limited by a lack of blinding, and the study may have been inadequately powered to detect a difference between groups. Other clinical research in adults hospitalized with mild to moderate COVID-19 shows that taking a specific combination product (Coroprotect) containing ashwagandha, pomegranate, turmeric, bacopa, licorice, and other ingredients, twice daily for 10 days improved cough, breathlessness, and fatigue symptoms when compared with placebo (114114). It is unclear if any effects are due to ashwagandha, other ingredients, or the combination.
• Depression. It is unclear if oral ashwagandha is beneficial for depression. Details: A small clinical study in adults with mild to moderate depression, anxiety, or stress shows that taking a specific ashwagandha root extract standardized to contain 2.5% withanolides (Shagandha, Sabinsa) 500 mg with piperine 5 mg daily for 90 days reduces the severity of depressive symptoms, improves sleep and quality of life, and increases serum serotonin levels when compared with placebo (113609).
• Diabetes. It is unclear if oral ashwagandha is beneficial for type 2 diabetes. Details: In patients with type 2 diabetes, preliminary clinical research shows that ashwagandha 3 grams daily for 30 days decreases blood glucose to a degree similar to oral hypoglycemic drugs (19274). However, this study did not compare ashwagandha directly to a group taking oral hypoglycemic drugs.
• Fatigue. It is unclear if oral ashwagandha is beneficial for fatigue. Details: A moderate-sized clinical study in adults with overweight or obesity and moderate-to-high levels of fatigue and stress shows that taking ashwagandha root extract (Witholytin, Verdure Sciences Inc.) 200 mg twice daily for 12 weeks reduces self-reported fatigue when compared with placebo (113611).
• Fibromyalgia. Although there has been interest in using oral ashwagandha for fibromyalgia, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Hiccups. Although there has been interest in using oral ashwagandha for hiccups, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Hypercholesterolemia. It is unclear if ashwagandha is beneficial for hypercholesterolemia. Details: A very small clinical study in subjects with hypercholesterolemia shows that ashwagandha 3 grams daily for 30 days decreases serum cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol, and very low-density lipoprotein (VLDL) cholesterol levels when compared with baseline (19274). The validity of these findings is limited by the lack of a comparator group.
• Hypothyroidism. It is unclear if ashwagandha is beneficial for hypothyroidism. Details: Preliminary clinical research in adults with subclinical hypothyroidism shows that taking a specific ashwagandha root extract (KSM-66, Ixoreal Biomed) 300 mg twice daily for 8 weeks increases triiodothyronine (T3) and thyroxine (T4) levels by 42% and 20%, respectively, and reduces serum TSH levels by 17% from baseline. These changes are significant when compared with placebo (97292). However, the effects of ashwagandha on thyroid hormone levels in patients with overt hypothyroidism, or in patients taking prescription thyroid hormones, is unknown.
• Infertility. Although there has been interest in using oral ashwagandha for infertility in females, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Male infertility. It is unclear if oral ashwagandha is beneficial for male infertility. Details: Preliminary clinical research in males with infertility shows that taking ashwagandha root powder for approximately 3 months modestly improves hormone levels, as well as sperm count and motility, when compared with baseline (19275,90650). The validity of these findings is limited by the lack of a comparator group. One study used a specific ashwagandha root extract (KSM-66 Ashwagandha, Ixoreal Biomed) 225 mg three times daily; another study provided doses of 5 grams daily (19275,90650).
• Menopausal symptoms. Oral ashwagandha may be beneficial for menopausal symptoms. Details: A small clinical study in healthy adults in perimenopause shows that taking a specific ashwagandha root extract (KSM-66, Ixoreal Biomed) 300 mg twice daily for 8 weeks improves menopausal symptom severity by 24%, compared with 11% in those receiving placebo. Quality of life and hot flashes also were improved in those taking ashwagandha (106785).
• Obsessive-compulsive disorder (OCD). It is unclear if ashwagandha is beneficial for OCD. Details: Preliminary clinical research shows that taking ashwagandha root extract 120 mg after meals for 6 weeks, in conjunction with prescribed selective-serotonin reuptake inhibitors (SSRIs), might reduce OCD symptom severity when compared with prescribed SSRIs alone. The dose was initiated at 30 mg daily and increased by 30 mg every 4 days. Although OCD scores were significantly reduced when compared with placebo, it should be noted that scores were already significantly lower in the placebo group at baseline (95618).
• Osteoarthritis. Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In patients with osteoarthritis, taking a specific combination supplement, containing ashwagandha 450 mg, Ayurvedic zinc complex 50 mg, guggul 100 mg, and turmeric 50 mg (Articulin-F) two capsules three times daily for 3 months reduces symptoms of pain and swelling when compared with placebo. However, there were no radiological improvements (19276). It is unclear if this effect is due to ashwagandha, other ingredients, or the combination.
• Parkinson disease. Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In patients with Parkinson disease, a small clinical study shows that taking a product containing ashwagandha 14.5 grams, cowhage 4.5 grams, Hyoscyamus reticulantus 0.75 grams, and Sida cordifolia 14.5 grams in lukewarm milk twice daily for 56 days improves symptoms like tremor, stiffness, and cramps when compared with baseline. The therapy followed 28 days of cleansing or eliminative therapy using Ayurvedic remedies (6899). The validity of these findings is limited by the lack of a comparator group. Also, it is unclear if these effects are due to ashwagandha, other ingredients, or the combination. Cowhage contains levodopa, which may contribute to any benefit seen with this combination product.
• Psychological well-being. It is unclear if oral ashwagandha is beneficial for improving psychological well-being in college students. Details: A small clinical study in healthy college students shows that taking ashwagandha root extract 350 mg twice daily for 30 days improves perceptions of well-being, including improvements in energy, mental clarity, food cravings, and sleep quality, when compared with placebo. Qualitative analysis also suggests these students had improvements in stress management, but stress scores were not reduced when compared with placebo (109589,109590).
• Rheumatoid arthritis (RA). It is unclear if oral ashwagandha is beneficial for improving symptoms of RA. Details: Preliminary clinical research shows that taking ashwagandha powder 5 grams twice daily for 3 weeks, followed by 4 weeks of sidh makardhwaj (a mixture of gold, mercury, and sulfur) 100 mg with honey daily, modestly improves symptoms in about 50% of males and 60% of females with RA when compared with baseline (95620). The lack of a control group limits the validity of this finding. Additionally, the effect of ashwagandha powder alone is unclear. Another small study in adults with RA shows that taking a combination product containing ashwagandha, ginger, black pepper, and colchicum luteum orally twice daily for 4 weeks does not improve RA disease scores when compared with celecoxib 100 mg orally twice daily (114785). However, the interpretation of these results is limited by poor methodology, and the study may have been inadequately powered to detect a difference between groups.
• Sexual dysfunction. Small clinical studies suggest that oral ashwagandha root extract may help improve sexual arousal and sexual desire in some females and males with sexual dysfunction. Details: Two, small clinical studies in adult females with sexual dysfunction show that taking ashwagandha root extract (KSM-66, Ixoreal Biomed) 300 mg twice daily with food for 8 weeks in conjunction with or without counseling increases the number of successful sexual encounters and improves orgasms, satisfaction, lubrication, and arousal when compared with placebo or counseling alone (95619,110492). Also, a small clinical study in adult males with low sexual desire shows that taking the same ashwagandha root extract 300 mg twice daily after meals for 8 weeks improves subjective sexual functioning scores, including measures of sexual arousal, sexual desire, sexual behavior, and orgasm, when compared with placebo (109586).
• Smoking cessation. Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in adults with a history of smoking 5 or more cigarettes daily for at least 3 years shows that taking a specific combination product containing ashwagandha 100 mg, Indian gooseberry, tribulus, bacopa, Albizia lebbeck, licorice, clove, ginger, cowhage, holy basil, and turmeric (Smotect, Smotect India) 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 ashwagandha, other ingredients, or the combination.
• Tuberculosis. Although there has been interest in using oral ashwagandha for tuberculosis, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Vitiligo. Although there has been interest in using oral ashwagandha for vitiligo, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Wrinkled skin. It is unclear if topical ashwagandha is beneficial in individuals with wrinkled skin. Details: A small clinical study in healthy adults with photoaged skin shows that applying ashwagandha root extract 8% lotion daily for 60 days improves physician-rated scores for skin wrinkles, hydration, brightness, tone, and pigmentation and improves other measures of skin elasticity and hydration when compared with placebo. However, changes in melanin content did not differ between treatment groups (111538).
• Wound healing. Although there has been interest in using topical ashwagandha for healing of skin ulcers and skin sores, there is insufficient reliable information about the clinical effects of ashwagandha for this condition. More evidence is needed to rate ashwagandha for these uses.

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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)

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. However, it is unclear if this reduction is clinically significant. Details: Many clinical trials and observational studies show that intake of calcium supplements or dietary calcium modestly reduces 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 salt-sensitive people and patients with low baseline dietary calcium intake (945,972,974,976,984,1818,1819,1820,1821,6852)(13138,14406,38803,39063,39094,39221). Also, a meta-analysis of clinical research shows that calcium intake during pregnancy reduces systolic blood pressure in offspring by 1-2 mmHg (38852). 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 supplement 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).
• 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 in high risk pregnancies, especially if calcium intakes are low. Details: Although there is some conflicting evidence (971,38756), most clinical research shows that taking calcium orally 1-2 grams daily reduces pregnancy-related hypertension and pre-eclampsia (973,1833,8828,39043,39319,39426,96480). Calcium appears to reduce the risk of pre-eclampsia by about 50% when compared with placebo. One meta-analysis of 19 controlled trials involving over 29,000 pregnancies found that for every 19 females treated with calcium, one episode of pre-eclampsia would be avoided (96480). Calcium appears to have the greatest effect in individuals at high-risk of pre-eclampsia or with low calcium levels, and when taken at greater than or equal to 20 weeks of gestation (15029,38497,96480,99714). 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. 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 supplementation 1.5-2 grams daily during pregnancies at high risk of pre-eclampsia if dietary calcium intakes are low, in order to prevent pre-eclampsia (97347).
• 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 does not seem to be beneficial for breast cancer prevention. Details: Although some population research disagrees (15631,39041,95811,107237), most research shows that increased calcium intake is not associated with a reduced risk of breast cancer (15631,16715,98895,107236,107237). Subgroup analyses of population research suggest that calcium intake may reduce the risk of breast cancer in postmenopausal, but not pre-menopausal, adults (15631,107237). Another subgroup analysis in a large meta-analysis of population research also suggests that dietary intake may reduce estrogen receptor(ER)-negative breast cancer, but not ER-positive breast cancer (107236). However, most other 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: The most recent and robust meta-analysis of clinical research shows that calcium supplementation with or without vitamin D is NOT associated with reduced fractures in older adults without osteoporosis (95822). A large-scale study in postmenopausal females aged 50-79 years suggests 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 Women's Health Initiative study found that, in older females with the lowest genetic susceptibility to low bone mineral density (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. 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), most clinical research has found that increased calcium intake does not increase weight loss (12052,13138,15396,15399,38985,39004,97356). The most recent 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).

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).
• 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 oral calcium is beneficial for type 2 diabetes prevention. Details: Some population research has found that a higher intake of calcium from 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). However, population research is often limited by confounding variables. For example, one analysis found that any beneficial effect might be influenced by concomitant magnesium intake (96473). 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. This study is limited because it was not determined whether increased serum calcium was due to increased calcium intake or another factor such as parathyroid function (95815).
• 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).
• 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).
• Hypercholesterolemia. It is unclear if oral calcium is beneficial for hypercholesterolemia. Details: Some evidence shows that taking calcium carbonate 400 mg three times daily reduces low-density lipoprotein (LDL) cholesterol levels by 4% and increases high-density lipoprotein (HDL) cholesterol levels by 4% after 6 weeks of treatment when used in combination with a low-fat diet (American Heart Association Step 1) (2557). In contrast, a study in females with dyslipidemia shows that taking calcium 800 mg daily for 2 years might INCREASE total cholesterol levels by about 12 mg/dL when compared with placebo. This same study showed an association between calcium supplementation and an increase in total cholesterol levels and carotid intimal thickness in postmenopausal females, but not premenopausal females (97350). A recent meta-analysis of randomized controlled trials which included both healthy patients and patients with 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 more effective in patients with dyslipidemia at baseline. It is unclear if this effect is due to calcium, vitamin D, or the combination (107227). However, other research shows that taking a specific supplement containing calcium 600 mg plus vitamin D 200 IU (Caltrate 600 D, Wyeth Consumer Healthcare Inc.) twice daily in combination with calorie restriction does not reduce total or LDL cholesterol levels when compared with placebo (15601).
• 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).
• 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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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Dental plaque. It is unclear if oral or topical gum arabic is beneficial for preventing or treating dental plaque. Details: Preliminary clinical research shows that chewing gum arabic for 10 minutes, five times daily for 7 days, reduces dental plaque when compared with chewing sugar-free gum (30220). Another small clinical study in adults with mild or moderate plaque-induced gingivitis shows that applying half a teaspoon of gum arabic powder to the buccal surface of dentogingivial areas for 5 minutes then rinsing with tap water twice daily for 60 days reduces dental plaque in patients with moderate, but not high, plaque accumulation when compared with placebo (111508). Gum arabic has also been evaluated in combination with other ingredients for this purpose. A small clinical study shows that applying a pea-size amount of gel containing gum arabic, barleria, medlar, terminalia, and melia (Gum Tone Gel, Charak Pharma Pvt Ltd.) after brushing for 6 weeks decreases plaque severity when compared with placebo. The gel is similar in effectiveness to chlorhexidine 1% gel (92887). However, it's unclear if these findings are due to gum arabic, other ingredients, or the combination.
• Diabetes. It is unclear if oral gum arabic is beneficial in patients with diabetes. Details: Clinical research in adults with type 2 diabetes who are taking oral antidiabetes medications shows that taking gum arabic powder 30 grams daily in the morning for 3 months modestly reduces fasting blood glucose and glycated hemoglobin (HbA1c) when compared with baseline. Gum arabic also modestly reduces low-density lipoprotein (LDL) cholesterol levels, body mass index, and hip circumference, but not waist circumference or blood pressure, when compared with baseline (98700,99098). The validity of these findings is limited by the lack of a comparison to the placebo group.
• Gingivitis. It is unclear if topical gum arabic is beneficial in patients with gingivitis. Details: A small clinical study in adults with mild or moderate plaque-induced gingivitis shows that applying half a teaspoon of gum arabic powder to the buccal surface of dentogingivial areas for 5 minutes then rinsing with tap water twice daily for 60 days reduces gingival inflammation in patients with mild, but not moderate, gingivitis when compared with placebo (111508). Another small clinical study in patients with chronic gingivitis shows that applying a pea-size amount of gel containing a mixture of ingredients including gum arabic, barleria, medlar, terminalia, and melia (Gum Tone Gel, Charak Pharma Pvt Ltd.) after brushing for 6 weeks decreases gingivitis severity when compared with placebo. The gel was no better than using chlorhexidine 1% gel (92887). However, it's unclear if these findings are due to gum arabic, other ingredients, or the combination.
• Hypercholesterolemia. It is unclear if oral gum arabic helps to reduce high cholesterol levels. Details: One small clinical study in patients with hypercholesterolemia shows that taking gum arabic 5 grams twice daily for 4 weeks does not seem to affect plasma lipid levels when compared with baseline (8072).
• Irritable bowel syndrome (IBS). Although there is interest in using oral gum arabic for IBS, there is insufficient reliable information about the clinical effects of gum arabic for this condition.
• Kidney failure. Although there is interest in using oral gum arabic for kidney failure, there is insufficient reliable information about the clinical effects of gum arabic for this condition.
• Metabolic syndrome. It is unclear if oral gum arabic is beneficial for preventing metabolic syndrome. Details: One small clinical study in healthy adults at risk for metabolic syndrome shows that taking gum arabic 20 grams daily for 12 weeks modestly reduces blood pressure and increases fat-free mass when compared with baseline, but not when compared with taking pectin 1 gram. There were no changes in weight, glycated hemoglobin, or cholesterol levels (105039).
• Obesity. It is unclear if oral gum arabic is beneficial for promoting weight loss. Details: One small clinical study in healthy adults shows that taking powdered gum arabic 18 grams in the morning and 12 grams in the evening for 6 weeks reduces body mass index by 0.32 kg/m2 and body fat percentage by about 2% when compared with placebo. Body weight was also reduced by 1.2%, but this was not significant when compared with placebo (18237). It is unclear if gum arabic is beneficial in individuals with obesity.
• Peristomal lesions. It is unclear if topical gum arabic is beneficial for preventing peristomal lesions in patients with a colostomy bag. Details: Preliminary clinical research in infants shows that applying a thick layer of gum arabic gel to peristomal skin before attaching a colostomy bag twice daily for 4 weeks decreases the incidence of postoperative peristomal dermatitis by about 78% when compared with zinc sulfate ointment (92886).
• Sickle cell disease. It is unclear if oral gum arabic is beneficial in patients with sickle cell disease. Details: Preliminary clinical research in patients with sickle cell disease shows that taking gum arabic powder 30 grams daily for 12 weeks does not improve most markers of liver and kidney function in these patients. While an improvement in direct bilirubin levels was observed when compared to baseline, no significant changes in serum levels of total bilirubin, albumin, protein, liver enzymes, urea, or creatinine were reported (102087). However, in this same group of patients, gum arabic did reduce levels of total cholesterol by 8 mg/dL, low-density lipoprotein (LDL) cholesterol by 5 mg/dL, and triglycerides by 12 mg/dL when compared with baseline. Significant improvements in high-density lipoprotein (HDL) cholesterol were lacking (102088). This research is limited by the lack of a control group, Also, it is unclear whether gum arabic can improve clinical outcomes in patients with sickle cell disease. More evidence is needed to rate the effectiveness of gum arabic for these uses.

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POSSIBLY SAFE ...when used orally and appropriately, short-term. Ashwagandha has been used with apparent safety in doses of up to 1250 mg daily for up to 6 months (3710,11301,19271,90649,90652,90653,97292,101816,102682,102683) (102684,102685,102687,103476,105824,109586,109588,109589,109590). ...when used topically. Ashwagandha lotion has been used with apparent safety in concentrations up to 8% for up to 2 months (111538).

PREGNANCY: LIKELY UNSAFE
when used orally. Ashwagandha has abortifacient effects (12).

LACTATION:
Insufficient reliable information available; avoid using.

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POSSIBLY SAFE ...when taken orally and appropriately. Bacillus coagulans spores in doses up to 6 billion colony-forming units (CFUs) daily have been used with apparent safety in clinical studies for up to 3 months (92726,92730,92734,92735,92736,92739,92740,104231,105169)(107611,107612,107614). Lower doses of B. coagulans up to 100 million CFUs daily have been used with apparent safety in clinical studies for up to one year (92738). There is insufficient reliable information available about the safety of non-viable, heat-killed B. coagulans formulations when used orally.

CHILDREN: POSSIBLY SAFE
when taken orally and appropriately. Bacillus coagulans spores in doses up to 100 million colony-forming units (CFUs) daily have been used with apparent safety in clinical studies in infants of most ages for up to one year (92729,92733,92738) and in doses of one billion CFUs in children aged 6-8 years for 3 months (107615). There is insufficient reliable information available about the safety of Bacillus coagulans in preterm infants with a birth weight under 1000 grams. Cases of bacteremia have occurred rarely in preterm infants given other probiotics (102416,111610,111612,111613,111850,111852,111853). The US Food and Drug Administration (FDA) has issued a warning about cases of serious infections caused by probiotics reported in very preterm or very low birth weight infants under 1000 grams (111610). Similarly, the American Academy of Pediatrics does not support the routine administration of probiotics to these infants due to conflicting data on safety and efficacy (111608).

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

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LIKELY SAFE ...when used orally or intravenously and appropriately. Calcium is safe when used in appropriate doses (7555,12928,12946,95817). However, excessive doses should be avoided. The Institute of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: Age 0-6 months, 1000 mg; 6-12 months, 1500 mg; 1-8 years, 2500 mg; 9-18 years, 3000 mg; 19-50 years, 2500 mg; 51+ years, 2000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stone, hypercalciuria, hypercalcemia, and milk-alkali syndrome. There has also been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these studies, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Many of these trials also only included postmenopausal females. Other analyses report conflicting results, and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Advise patients not to consume more than the recommended daily intake of 1000-1200 mg per day and to consider total calcium intake from both dietary and supplemental sources (17484). Also, advise patients taking calcium supplements to take calcium along with vitamin D (93533).

POSSIBLY UNSAFE ...when used orally in excessive doses. The National Academy of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: 19-50 years, 2500 mg; 51 years and older, 2000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stones, hypercalciuria, hypercalcemia, and milk-alkali syndrome. There has also been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these studies, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Many of these trials also only included postmenopausal females. Other analyses report conflicting results, and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Advise patients to not consume more than the recommended daily intake of 1000-1200 mg per day and to consider total calcium intake from both dietary and supplemental sources (17484). Also, advise patients taking calcium supplements to take calcium along with vitamin D (93533).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Calcium is safe when used in appropriate doses (17506).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses. The Institute of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: 0-6 months, 1000 mg; 6-12 months, 1500 mg; 1-8 years, 2500 mg; 9-18 years, 3000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stones, hypercalciuria, hypercalcemia, and milk-alkali syndrome.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately (945,1586,3263,3264,17506). The World Health Organization (WHO) recommends prescribing oral calcium supplementation 1.5-2 grams daily during pregnancy to those with low dietary calcium intake to prevent pre-eclampsia (97347).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses. The Institute of Medicine sets the same daily tolerable upper intake level (UL) for calcium according to age independent of pregnancy status: 9-18 years, 3000 mg; 19-50 years, 2500 mg (17506). Doses over these amounts might increase the risk of neonatal hypocalcemia-induced seizures possibly caused by transient neonatal hypoparathyroidism in the setting of excessive calcium supplementation during pregnancy, especially during the third trimester. Neonatal hypocalcemia is a risk factor for neonatal seizures (97345).

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LIKELY SAFE ...when used orally and appropriately in amounts commonly found in foods. Gum arabic has Generally Recognized As Safe (GRAS) status for use in foods in the US. It is also considered to be safe for use as a food additive by the European Food Safety Authority (4912,105040).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts (8072). Up to 30 grams daily of powdered gum arabic has been used with apparent safety for 3 months (18237,99098,105040).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using in amounts greater than those found in foods (4912,105040).

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking ashwagandha with antidiabetes drugs might increase the risk of hypoglycemia.  Details There is preliminary clinical evidence suggesting that ashwagandha might lower blood glucose levels. Theoretically, ashwagandha might have additive effects when used with antidiabetes drugs and increase the risk of hypoglycemia (19274,90649,102685).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking ashwagandha with antihypertensive drugs might increase the risk of hypotension.  Details Animal research suggests that ashwagandha might lower systolic and diastolic blood pressure (19279). Theoretically, ashwagandha might have additive effects when used with antihypertensive drugs and increase the risk of hypotension.

BENZODIAZEPINES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking ashwagandha might increase the sedative effects of benzodiazepines.  Details There is preliminary evidence that ashwagandha might have an additive effect with diazepam (Valium) and clonazepam (Klonopin) (3710). This may also occur with other benzodiazepines.

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking ashwagandha might increase the sedative effects of CNS depressants.  Details Ashwagandha seems to have sedative effects. Theoretically, this may potentiate the effects of barbiturates, other sedatives, and anxiolytics (3710).

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

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, ashwagandha might decrease the levels and clinical effects of CYP3A4 substrates.  Details In vitro research shows that ashwagandha extract induces CYP3A4 enzymes (111404).

HEPATOTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking ashwagandha with hepatotoxic drugs might increase the risk of liver damage.  Details Ashwagandha has been linked to cases of acute hepatitis, liver failure, hepatic encephalopathy, autoimmune hepatitis, the need for liver transplantation, and death due to liver failure (102686,107372,110490,110491,111533,111535,112111,113610).

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking ashwagandha might decrease the effects of immunosuppressants.  Details Ashwagandha has demonstrated immunostimulant effects in humans (3710,3711,4114,11301,106786). Animal research has shown that ashwagandha can attenuate the immunosuppression caused by cyclophosphamide (3711,4114).

THYROID HORMONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Ashwagandha might increase the effects and adverse effects of thyroid hormone.  Details Concomitant use of ashwagandha with thyroid hormones may cause additive therapeutic and adverse effects. Preliminary clinical research and animal studies suggest that ashwagandha boosts thyroid hormone synthesis and secretion (19281,19282,97292). In one clinical study, ashwagandha increased triiodothyronine (T3) and thyroxine (T4) levels by 41.5% and 19.6%, respectively, and reduced serum TSH levels by 17.4% from baseline in adults with subclinical hypothyroidism (97292).

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ANTIBIOTIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Theoretically, taking antibiotics with Bacillus coagulans might decrease the effectiveness of B. coagulans.  Details B. coagulans preparations usually contain live and active organisms. Therefore, simultaneously taking antibiotics might kill a significant number of the organisms. Tell patients to separate administration of antibiotics and B. coagulans preparations by at least two hours.

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ALUMINUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Calcium citrate might increase aluminum absorption and toxicity. Other types of calcium do not increase aluminum absorption.  Details Calcium citrate can increase the absorption of aluminum when taken with aluminum hydroxide. The increase in aluminum levels may become toxic, particularly in individuals with kidney disease (21631). However, the effect of calcium citrate on aluminum absorption is due to the citrate anion rather than calcium cation. Calcium acetate does not appear to increase aluminum absorption (93006).

BISPHOSPHONATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Calcium reduces the absorption of bisphosphonates.  Details Advise patients to take bisphosphonates at least 30 minutes before calcium, but preferably at a different time of day. Calcium supplements decrease absorption of bisphosphonates (12937).

CALCIPOTRIENE (Dovonex) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Taking calcipotriene with calcium might increase the risk for hypercalcemia.  Details Calcipotriene is a vitamin D analog used topically for psoriasis. It can be absorbed in sufficient amounts to cause systemic effects, including hypercalcemia (12938). Theoretically, combining calcipotriene with calcium supplements might increase the risk of hypercalcemia.

CALCIUM CHANNEL BLOCKERS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Intravenous calcium may decrease the effects of calcium channel blockers; oral calcium is unlikely to have this effect.  Details Intravenous calcium is used to decrease the effects of calcium channel blockers in the management of overdose. Intravenous calcium gluconate has been used before intravenous verapamil (Isoptin) to prevent or reduce the hypotensive effects without affecting the antiarrhythmic effects (6124). But there is no evidence that dietary or supplemental calcium when taken orally interacts with calcium channel blockers (12939,12947).

CEFTRIAXONE (Rocephin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Co-administration of intravenous calcium and ceftriaxone can result in precipitation of a ceftriaxone-calcium salt in the lungs and kidneys.  Details Avoid administering intravenous calcium in any form, such as parenteral nutrition or Lactated Ringers, within 48 hours of intravenous ceftriaxone. Case reports in neonates show that administering intravenous ceftriaxone and calcium can result in precipitation of a ceftriaxone-calcium salt in the lungs and kidneys. In several cases, neonates have died as a result of this interaction (15794,21632). So far there are no reports in adults; however, there is still concern that this interaction might occur in adults.

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Using intravenous calcium with digoxin might increase the risk of fatal cardiac arrhythmias.  Details Hypercalcemia increases the risk of fatal cardiac arrhythmias with digoxin (12940). However, one retrospective analysis of clinical data suggests that intravenous calcium does not increase the risk of dysrhythmias or mortality in patients receiving digoxin (38960).

DILTIAZEM (Cardizem, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, calcium may reduce the therapeutic effects of diltiazem.  Details Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically, calcium might increase this risk of hypercalcemia and reduce the effectiveness of diltiazem.

DOLUTEGRAVIR (Tivicay) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce levels of dolutegravir.  Details Advise patients to take dolutegravir either 2 hours before or 6 hours after taking calcium supplements. Pharmacokinetic research suggests that taking calcium carbonate 1200 mg concomitantly with dolutegravir 50 mg reduces plasma levels of dolutegravir by almost 40%. Calcium appears to decrease levels of dolutegravir through chelation (93578).

ELVITEGRAVIR (Vitekta) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce levels of elvitegravir.  Details Advise patients to take elvitegravir either 2 hours before or 2 hours after taking calcium supplements. Pharmacokinetic research suggests that taking calcium along with elvitegravir can reduce blood levels of elvitegravir through chelation (94166).

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce the absorption and effectiveness of levothyroxine.  Details Advise patients to take levothyroxine and calcium supplements at least 4 hours apart. Calcium reduces levothyroxine absorption, probably by forming insoluble complexes (5082). Calcium carbonate supplements reduce effectiveness of levothyroxine in patients with hypothyroidism (5081,5082,6137).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of calcium and lithium may increase this risk of hypercalcemia.  Details Clinical research suggests that long-term use of lithium may cause hypercalcemia in 10% to 60% of patients (38953). Theoretically, concomitant use of lithium and calcium supplements may further increase this risk.

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce the absorption of quinolone antibiotics.  Details Advise patients to take oral quinolones at least 2 hours before or 4-6 hours after calcium supplements or calcium-fortified foods. Taking calcium at the same time as oral quinolones can reduce quinolone absorption. Calcium binds to quinolones in the gut (4412,10339,21638,38570).

RALTEGRAVIR (Isentress) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Calcium may reduce levels of raltegravir.  Details Pharmacokinetic research shows that taking a single dose of calcium carbonate 3000 mg along with raltegravir 400 mg twice daily modestly decreases the mean area under the curve of raltegravir, but the decrease does not necessitate a dose adjustment of raltegravir (94164). However, a case of elevated HIV-1 RNA levels and documented resistance to raltegravir has been reported for a patient taking calcium carbonate 1 gram three times daily plus vitamin D3 (cholecalciferol) 400 IU three times daily in combination with raltegravir 400 mg twice daily for 11 months. It is thought that calcium reduced raltegravir levels by chelation, leading to treatment failure (94165).

SOTALOL (Betapace) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Calcium seems to reduce the absorption of sotalol.  Details Advise patients to separate doses by at least 2 hours before or 4-6 hours after calcium. Calcium appears to reduce the absorption of sotalol, probably by forming insoluble complexes (10018).

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Calcium seems to reduce the absorption of tetracycline antibiotics.  Details Advise patients to take oral tetracyclines at least 2 hours before, or 4-6 hours after calcium supplements. Taking calcium at the same time as oral tetracyclines can reduce tetracycline absorption. Calcium binds to tetracyclines in the gut (1843).

THIAZIDE DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Taking calcium along with thiazides might increase the risk of hypercalcemia and renal failure.  Details Thiazides reduce calcium excretion by the kidneys (1902). Using thiazides along with moderately large amounts of calcium carbonate increases the risk of milk-alkali syndrome (hypercalcemia, metabolic alkalosis, renal failure). Patients may need to have their serum calcium levels and/or parathyroid function monitored regularly.

VERAPAMIL (Calan, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, calcium may reduce the therapeutic effects of verapamil.  Details Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically, use of calcium supplements may increase this risk of hypercalcemia and reduce the effectiveness of verapamil.

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AMOXICILLIN (Amoxil, Trimox) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Gum arabic can reduce the absorption of amoxicillin.  Details A small study in healthy volunteers shows that taking amoxicillin and gum arabic concurrently significantly reduces the absorption of amoxicillin. Separate doses of amoxicillin from gum arabic by at least 2 hours (12654).

ORAL DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, gum arabic can alter the absorption of oral drugs due to its fiber content.  Details Gum arabic has been used as a suspending osmotic agent in drug formulations. It might improve bioavailability of water-insoluble drugs like naproxen, but reduce absorption of polar drugs like amoxicillin (12654,104058). To avoid changes in absorption, take gum arabic 30-60 minutes after oral medications.

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General ...Orally, ashwagandha seems to be well-tolerated. Topically, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Diarrhea, gastrointestinal upset, nausea, and vomiting. However, these adverse effects do not commonly occur with typical doses.
Serious Adverse Effects (Rare):
Orally: Some case reports raise concerns about acute hepatitis, acute liver failure, hepatic encephalopathy, the need for liver transplantation, and death due to liver failure with ashwagandha treatment.

Dermatologic ...Orally, dermatitis has been reported in three of 42 patients in a clinical trial (19276).

Endocrine ...A case report describes a 73-year-old female who had taken an ashwagandha root extract (unspecified dose) for 2 years to treat hypothyroidism which had been previously managed with levothyroxine. The patient was diagnosed with hyperthyroidism after presenting with supraventricular tachycardia, chest pain, tremor, dizziness, fatigue, irritability, hair thinning, and low thyroid stimulating hormone (TSH) levels. Hyperthyroidism resolved after discontinuing ashwagandha (108745). Additionally, an otherwise healthy adult who was taking ashwagandha extract orally for 2 months experienced clinical and laboratory-confirmed thyrotoxicosis. Thyrotoxicosis resolved 50 days after discontinuing ashwagandha, without other treatment (114111). Another case report describes a 37-year-old female who presented with moderate symptomatic hyponatremia secondary to adrenal insufficiency after chronic consumption of ashwagandha for 2 years. This subject was effectively managed with oral hydrocortisone (114790).

Gastrointestinal ...Orally, large doses may cause gastrointestinal upset, diarrhea, and vomiting secondary to irritation of the mucous and serous membranes (3710). When taken orally, nausea and abdominal pain (19276,110490,113609) and gastritis and flatulence (90651) have been reported.

Genitourinary ...In one case report, a 28-year-old male with a decrease in libido who was taking ashwagandha 5 grams daily over 10 days subsequently experienced burning, itching, and skin and mucous membrane discoloration of the penis, as well as an oval, dusky, eroded plaque (3 cm) with erythema on the glans penis and prepuce (32537).

Hepatic ...Orally, ashwagandha in doses of 154 mg to 20 grams daily has played a role in several case reports of cholestatic, hepatocellular, and mixed liver injuries. In most of these cases, other causes of liver injury were excluded, and liver failure did not occur. Symptoms included jaundice, pruritus, malaise, fatigue, lethargy, weight loss, nausea, diarrhea, abdominal pain and distension, stool discoloration, and dark urine. Symptom onset was typically 5-180 days from first intake, although in some cases onset occurred after more than 12 months of use (102686,107372,110490,110491,111533,111535,112111,113610,114113). Laboratory findings include elevated aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, serum bilirubin, and international normalized ratio (INR) (112111,113610,114113). In most cases, liver enzymes normalized within 1-5 months after discontinuation of ashwagandha (102686,107372,110491,111535,112111,114113). However, treatment with corticosteroids, lactulose, ornithine, ursodeoxycholic acid, and plasmapheresis, among other interventions, was required in one case (111533). Rarely, use of oral ashwagandha has been reported to cause hepatic encephalopathy, liver failure requiring liver transplantation, and acute-on-chronic liver failure resulting in death (110490,113610).

Neurologic/CNS ...Orally, ashwagandha has been reported to cause drowsiness (110492,113609). Headache, neck pain, and blurry vision have been reported in a 47-year-old female taking ashwagandha, cannabis, and venlafaxine. Imaging over the course of multiple years and hospital admissions indicated numerous instances of intracranial hemorrhage and multifocal stenosis of intracranial arteries, likely secondary to reversible cerebral vasoconstriction syndrome (RCVS) (112113). It is unclear whether the RCVS and subsequent intracranial hemorrhages were precipitated by ashwagandha, cannabis, or venlafaxine.

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General ...Orally, Bacillus coagulans is well tolerated.
Serious Adverse Effects (Rare):
Orally: There is concern that probiotics may cause infections in some people.

Immunologic ...Since many probiotic preparations contain live and active microorganisms, there is some concern that they might cause pathogenic infection in some patients. Bacteremia and sepsis have been reported in patients with indwelling or central venous catheters or patients who are severely ill and/or immunocompromised, including preterm infants, that were using probiotic products (4380,8561,13008,13070,90298,102416,103444,105138,105140,105141)(107543,107597,107599,111610,111612,111613,111850,111852,111853). However, reports of pathogenic colonization in relatively healthy patients with intact immune systems who do not have indwelling or central venous catheters are extremely rare (4380,4389,4390,4391,4393,4398,105139,107543,107545,107546,107547).

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General ...Orally and intravenously, calcium is well-tolerated when used appropriately.
Most Common Adverse Effects:
Orally: Belching, constipation, diarrhea, flatulence, and stomach upset.
Serious Adverse Effects (Rare):
Orally: Case reports have raised concerns about calciphylaxis and kidney stones.

Cardiovascular ...There has been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these results, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Many of these trials also only included postmenopausal females. Other analyses report conflicting results, and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). 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 CVD, CHD, or MI (93533,107231). Also, the association between calcium supplementation and CVD, CHD, or 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). To minimize the possible risk of CVD, CHD, or MI, advise patients not to consume more than the recommended daily intake of 1000-1200 mg and to consider total calcium intake from both dietary and supplemental sources (17484). While dietary intake of calcium is preferred over supplemental intake, advise patients who require calcium supplements to take calcium along with vitamin D, as this combination does not appear to be associated with an increased risk of MI (93533).
Rarely, calcium intake can increase the risk of calciphylaxis, which usually occurs in patients with kidney failure. Calciphylaxis is the deposition of calcium phosphate in arterioles, which causes skin ulcers and skin necrosis. In a case report, a 64-year-old female with a history of neck fracture, sepsis, and ischemic colitis presented with painful leg ulcers due to calciphylaxis. She discontinued calcium and vitamin D supplementation and was treated with sodium thiosulfate and supportive care (95816).

Gastrointestinal ...Orally, calcium can cause belching, flatulence, nausea, gastrointestinal discomfort, and diarrhea (1824,1843,12950,38803). Although constipation is frequently cited as an adverse effect of calcium, there is no scientific substantiation of this side effect (1824,1843,1844,1845,12950,38978). Calcium carbonate has been reported to cause acid rebound, but this is controversial (12935,12936).

Oncologic ...There is some concern that very high doses of calcium might increase the risk of prostate cancer. Some epidemiological evidence suggests that consuming over 2000 mg/day of dietary calcium might increase the risk for prostate cancer (4825,12949). Additional research suggests that calcium intake over 1500 mg/day might increase the risk of advanced prostate cancer and prostate cancer mortality (14132). Consumption of dairy products has also been weakly linked to a small increase in prostate cancer risk (98894). However, contradictory research suggests no association between dietary intake of calcium and overall prostate cancer risk (14131,14132,104630). More evidence is needed to determine the effect of calcium, if any, on prostate cancer risk.

Renal ...Kidney stones have been reported in individuals taking calcium carbonate 1500 mg daily in combination with vitamin D 2000 IU daily for 4 years (93943).

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General ...Orally, gum arabic seems to be generally well tolerated.
Most Common Adverse Effects:
Orally: Abdominal bloating, flatulence, mild diarrhea, nausea, and vomiting.

Gastrointestinal ...Orally, gum arabic can cause minor gastrointestinal disturbances such as abdominal bloating, flatulence, nausea, vomiting, cramping, and mild diarrhea (8072,18237,99098,105038,105040,108051). These effects occurred in 15%, 82%, and 90% of subjects respectively in one study (18237). They may subside with continued use within 2 weeks (8072,18237,99098,105038).

Immunologic ...Gum arabic might cause allergic reactions. In one case report, a patient had an immunoglobulin E response after exposure to gum arabic. However, there have been no identified case reports of allergic reactions after oral exposure to gum arabic (19636,105040).

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