DIMension 3 [Discontinued] by XYMOGEN

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral black pepper for allergic rhinitis, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Asthma. Although there has been interest in using oral black pepper for asthma, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Athletic performance. Oral black pepper has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical trial in untrained males shows that taking a supplement containing black pepper extract 10 mg, caffeine 400 mg, capsicum extract 66.7 mg, and niacin 40 mg as a single dose prior to exercise does not improve strength, time to exhaustion, or maximal oxygen consumption when compared with placebo (37873).
• Depression. Although there has been interest in using oral black pepper for depression, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Diarrhea. Although there has been interest in using oral black pepper for diarrhea, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Dysmenorrhea. Although there has been interest in using oral black pepper for dysmenorrhea, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Dyspepsia. Although there has been interest in using oral black pepper for dyspepsia, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Fall prevention. It is unclear if inhaling black pepper oil as aromatherapy is beneficial for fall prevention in older adults. Details: One small clinical study in older adults shows that applying black pepper oil near the right side of the nose as an olfactory stimulant improves stability while the eyes are closed during a one-minute trial when compared with the application of water. The improvement with black pepper oil is comparable to the improvement seen with the application of lavender oil (29160). It is unclear if any benefit persists after inhalation of black pepper oil.
• Fatigue. It is unclear if oral black pepper is beneficial in patients with fatigue. Details: One small clinical trial in adults with below-average energy levels shows that taking black pepper 2 grams as a single dose does not improve sustained attention, motivation to perform cognitive tasks, or feelings of mental energy and mental fatigue when compared with placebo (91731).
• Flatulence. Although there has been interest in using oral black pepper for flatulence, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Headache. Although there has been interest in using oral black pepper for headache, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Insect bite. Topical black pepper has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical trial shows that applying a specific product (Trikatu) containing black pepper, long pepper, and ginger, as well as camphor, eucalyptus oil, and menthol, directly to mosquito bites does not reduce papule size, erythema, edema, or pruritis when compared with a control compound containing the same base ingredients but without the pepper and ginger components (89893).
• Obesity. Although there has been interest in using oral black pepper for obesity, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Pain (chronic). Although there has been interest in using topical black pepper for chronic pain related to various etiologies, including osteoarthritis, postherpetic neuralgia, and peripheral neuropathy, there is insufficient reliable information about the clinical effects of black pepper for these conditions.
• Rhinosinusitis. Although there has been interest in using oral black pepper for rhinosinusitis, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Sexual desire. Although there has been interest in using oral black pepper for increasing sexual desire, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Smoking cessation. It is unclear if inhaling black pepper essential oil as aromatherapy is effective for smoking cessation. Details: One small clinical trial in adult male smokers who were deprived from smoking overnight shows that inhaling a vapor from the essential oil of black pepper, as needed over a 3-hour period, reduces cigarette cravings, negative feelings, and anxiety when compared with a placebo vapor (29159). Another small clinical study in patients addicted to dipping, chewing, or smoking tobacco shows that placing a drop of black pepper essential oil on tissue paper and inhaling for 2 minutes at least three times a day for 3 days reduces nicotine cravings when compared to baseline (90502).
• Swallowing dysfunction. It is unclear if inhaling black pepper oil as aromatherapy is beneficial in patients with swallowing dysfunction. Details: One small clinical study in post-stroke residents of nursing homes shows that one minute of olfactory stimulation with black pepper oil before each meal for 30 days decreases swallowing reflex latency by 11 seconds and increases the number of swallowing movements by 3.3 when compared to baseline (29161). A small clinical trial in children with neurological disorders who were on long-term enteral nutrition shows that applying black pepper oil to the nostrils or nasal cavity for one minute improves the amount of oral intake and swallowing movement in 63% of patients. Although oral intake increased, the need for enteral nutrition was not eliminated (29162).
• Vitiligo. It is unclear if topical piperine oil, a constituent of black pepper, is beneficial in patients with vitiligo. Details: A small clinical study in patients with vitiligo shows that applying piperine oil 1% daily in addition to receiving narrowband ultraviolet B (NB-UVB) light therapy every other day for 3 months improves repigmentation more rapidly when compared with using NB-UVB alone (103820). More evidence is needed to rate black pepper for these uses.

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EFFECTIVE

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

LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about CALCIUM)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Benign prostatic hyperplasia (BPH). Although there is interest in using oral diindolylmethane for BPH, there is insufficient reliable information about the clinical effects of diindolylmethane for this condition.
• Breast cancer. It is unclear if oral diindolylmethane is beneficial in patients at high risk for developing breast cancer. Details: Preliminary clinical research in healthy pre- and post-menopausal patients at high risk for breast cancer due to the BRCA mutation shows that taking diindolylmethane (DIM-Evail, Designs for Health Inc) 100 mg daily for 1 year is associated with a 5% decrease in breast density, as measured by the amount of fibroglandular tissue, when compared with baseline (103830). It is unclear whether this reduces the risk of developing breast cancer. Also, the validity of this finding is limited by the lack of a control group.
• Cervical dysplasia. It is unclear if oral diindolylmethane is beneficial in patients with cervical dysplasia. Details: Clinical research in patients with mild cervical abnormalities shows that taking a specific product (BioResponse-DIM, BioResponse) as 150 mg, providing 45 mg diindolylmethane, daily for 6 months does not improve colposcopy or biopsy results when compared with placebo (93836). Additionally, clinical research in patients with grade 2 or 3 cervical neoplasia shows that taking this same product as 2 mg/kg diindolylmethane daily for 12 weeks does not affect Pap smear, colposcopy, or histology results when compared with placebo; however, both groups showed significant improvements when compared with baseline (47709).
• Colorectal cancer. Although there is interest in using oral diindolylmethane for colorectal cancer, there is insufficient reliable information about the clinical effects of diindolylmethane for this condition.
• Mastalgia. Although there is interest in using oral diindolylmethane for mastalgia, there is insufficient reliable information about the clinical effects of diindolylmethane for this condition.
• Obesity. Although there is interest in using oral diindolylmethane for obesity, there is insufficient reliable information about the clinical effects of diindolylmethane for this condition.
• Premenstrual syndrome (PMS). Although there is interest in using oral diindolylmethane for PMS, there is insufficient reliable information about the clinical effects of diindolylmethane for this condition.
• Prostate cancer. Although there is interest in using oral diindolylmethane for prostate cancer, there is insufficient reliable information about the clinical effects of diindolylmethane for this condition.
• Uterine cancer. Although there is interest in using oral diindolylmethane for uterine cancer, there is insufficient reliable information about the clinical effects of diindolylmethane for this condition. More evidence is needed to rate diindolylmethane for these uses.

(Read more about DIINDOLYLMETHANE)

POSSIBLY EFFECTIVE

• Allergic rhinitis (hay fever). Oral turmeric seems to improve symptoms in people with allergic rhinitis. Details: A large clinical study in people with allergic rhinitis shows that taking a specific curcumin product (Organika Health Products) 500 mg daily for 2 months reduces nasal symptoms, including sneezing, itching, runny nose, and congestion, when compared with placebo (96138).
• Depression. Most research shows that oral curcumin, a constituent of turmeric, when used at doses of at least 1 gram daily for at least 6 weeks improves symptoms of depression when taken alone or in combination with antidepressant medications. Details: Curcumin appears to be most beneficial for depression in middle aged patients compared to older patients, when taken for at least 6 weeks, and when used at a dose of at least 1 gram daily. In adults with major depressive disorder, a meta-analysis of data from 6 clinical studies, as well as individual studies not included in this analysis, show that taking curcumin 1 gram daily along with an antidepressant moderately improves depression symptoms when compared with placebo (96131,96139). Another meta-analysis of 10 studies shows symptom reductions in patients with major depression when combined with conventional antidepressants, but not when used alone in patients with milder depressive symptoms. However, the quality of the evidence is low (104971). Additionally, a large clinical study in adults with mild-moderate symptoms of depression shows that taking curcumin 750 mg twice daily for 12 months modestly reduces depression symptoms when compared with placebo (114898). When used alone, one clinical study shows that curcumin 1 gram daily for 6 weeks may be similarly effective to fluoxetine 20 mg daily. Taking both products together seems to be more effective than either product alone, increasing the response rate from 65% to 78% (89728). Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that curcumin extract at doses of 500-1000 mg daily is provisionally recommended for monotherapy or adjunctive use in mild to moderate depression (110318).
• Dyspepsia. Oral turmeric may be modestly beneficial for some patients with dyspepsia. In patients with functional dyspepsia, small clinical studies show that oral curcumin, a constituent of turmeric, is similarly effective when compared with the proton-pump inhibitor omeprazole. Details: Clinical research shows that taking turmeric 500 mg four times daily for 7 days can relieve overall symptoms of dyspepsia in 64% more patients than taking placebo (11144). A small, unblinded clinical study in patients with a type of dyspepsia called postprandial distress syndrome shows that taking turmeric 250 mg or 500 mg orally three times daily after meals for 4 weeks is associated with reductions in symptom scores which are similar to those seen with simethicone 60 mg three times daily for 4 weeks. However, the recurrence rate upon stopping therapy was about 14% with simethicone, compared with 43% to 46% with turmeric (104963). In patients with functional dyspepsia, taking the constituent curcumin appears similarly effective when compared with omeprazole, but might not provide further symptom reduction in those also taking famotidine or omeprazole (106063,106801,111599). One small clinical study in Iran shows that taking curcuminoids (C3 Complex, Sami Labs) 500 mg with piperine (Bioperine) 5 mg daily in addition to famotidine 40 mg daily for 30 days is no more effective for reducing overall symptoms of dyspepsia, such as abdominal pain, heartburn, bloating, and nausea, when compared with famotidine alone (106063). Another small clinical study in Thailand shows that taking curcumin 500 mg four times daily for 4 weeks is similarly effective for reducing dyspepsia severity and improving satisfaction when compared with an unspecified dose of omeprazole and more effective when compared with placebo (106801). Similarly, a moderate-size clinical study in Thailand shows that taking curcumin 500 mg four times daily for 4 weeks is similarly effective for reducing dyspepsia severity when compared with omeprazole 20 mg daily. However, taking curcumin and omeprazole in combination did not provide further symptom reduction (111599). The validity of these results is limited by the high rate of study dropouts.
• Hyperlipidemia. Research is conflicting on whether oral turmeric, curcumin, or curcuminoids can reduce serum lipids. Any improvement in lipids is likely to be small. Reasons for the conflicting findings may relate to turmeric formulation, duration of treatment, and/or the baseline cholesterol status of the included patients. Details: Results from meta-analyses of clinical research show inconsistent and conflicting results. One large meta-analysis of over 50 clinical studies in healthy adults and those with a variety of conditions shows that supplementation with turmeric or curcumin 80-4000 mg daily for 4-24 weeks reduces total cholesterol by 4 mg/dL, low-density lipoprotein (LDL) cholesterol by 5 mg/dL, and triglycerides by 7 mg/dL and increases high-density lipoprotein (HDL) cholesterol by 2 mg/dL when compared with placebo (112119). Two other meta-analyses of 27 clinical studies agree that taking turmeric, curcumin, or curcuminoids moderately reduce triglyceride levels but suggest that turmeric does not improve total cholesterol when compared with placebo. However, the meta-analyses contradict one another on whether turmeric and its constituents reduce LDL cholesterol or increase HDL cholesterol. (96128,96135). Additionally, a third meta-analysis of 10 clinical trials shows that taking up to 2400 mg daily of curcumin or curcuminoids, from turmeric or isolated sources, for up to 12 weeks, does not significantly improve triglycerides, LDL cholesterol, HDL cholesterol, or total cholesterol (110220).
• Nonalcoholic fatty liver disease (NAFLD). Oral curcumin, a constituent of turmeric, seems to attenuate fat deposition and improve some metabolic parameters in adults with NAFLD. Details: Clinical research shows that taking curcumin daily reduces NAFLD severity in 30% to 79% of patients, compared to 5% to 27.5% of patients receiving placebo. Curcumin also reduces the quantity of additional fat deposition in the liver to 0% to 4.5%, compared to 17.5% to 26% in those taking placebo. Most research shows that taking curcumin also reduces liver enzyme levels, body mass index (BMI), blood glucose levels, glycated hemoglobin (HbA1c), and total cholesterol when compared with placebo. Although some clinical research shows that taking curcumin improves levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides, a meta-analysis of clinical research shows that these lipid levels are not improved in patients with NAFLD, specifically (97430,97431,100258,102350,106062,107120,109279,111349,114901). However, another meta-analysis of 14 small, heterogeneous clinical studies in adults with NAFLD, that included some of these studies, shows that taking various doses and forms of turmeric or curcumin modestly reduces liver enzyme levels, improves measures of insulin resistance, reduces waist circumference, and improves LDL, HDL, and triglyceride levels when compared with placebo (111348). A small clinical trial in patients with NAFLD given specific lifestyle recommendations shows that taking curcumin modestly reduces the frequency of metabolic syndrome and fatty liver but does not have beneficial effects on fatty liver-associated indices, adiposity, or the atherogenic index, when compared with placebo (109285). Findings for specific endpoints are mixed between individual studies and may depend on the dose and formulation of curcumin used or the duration of treatment. These studies have used various doses and formulations. In one study, 500 mg of a dispersion formulation equivalent to 70 mg of curcumin daily for 8 weeks was used (97430). Also, 250 mg once daily or 500 mg twice daily of a specific phytosomal formulation (Meriva, Indena) containing curcumin and soy phosphatidylcholine in a 1:2 ratio and standardized to an overall curcuminoid content of 20% was taken for 8 weeks (97431,106062). Another study used 1 gram of powdered turmeric rhizome taken three times daily with meals for 12 weeks (102350). One study used a curcumin-piperine complex (Curcumin C3 complex 500 mg plus Bioperine 5 mg) daily for 8 weeks (107120). One study used curcumin (Arjuna Natural Extract) 500 mg three times daily for 12 weeks (109285). Despite positive results with curcumin in several small clinical studies of patients with NAFLD, there is some concern that curcumin might cause hepatotoxicity in rare cases, especially when highly bioavailable formulations are used in high doses (103633). There is also evidence that the risk for hepatotoxicity with curcumin may be increased in individuals with the HLAB*35:01 allele (109288). Curcumin-induced hepatotoxicity has not been reported in clinical trials of patients with NAFLD, and its potential mechanism is unclear. However, patients seeking to take curcumin for NAFLD should be advised to monitor for symptoms of hepatotoxicity, including abdominal pain, dark urine, fatigue, jaundice, nausea, and pruritus.
• Oral mucositis. Oral curcumin or curcumin-containing mouthwash seem to reduce the development of severe oral mucositis, as well as reduce the severity and pain of oral mucositis, associated with cancer treatment. Details: Clinical research in patients receiving radiotherapy following recent radical surgery for oral cancer shows that taking turmeric (BCM-95, Arjuna Natural Pvt. Ltd., India) during radiotherapy reduces the incidence of severe oral mucositis to 25% or 20% in those taking turmeric 500 mg two or three times daily, respectively, compared with 65% in those taking placebo. The incidences of severe oral pain, dysphagia, and dermatitis were also reduced by at least 50% (105398). A small clinical study in patients receiving chemotherapy with or without head and neck radiotherapy shows that taking a specific nanoparticle formulation of curcumin (SinaCurcumin, ExirNanoSina) 80 mg twice daily for 7 weeks improves severity of oral mucositis at weeks 1, 4, and 7 and reduces pain at week 7 when compared with placebo. Effects were more pronounced in those with chemotherapy-induced oral mucositis than radiotherapy-induced oral mucositis (106800). In patients with head and neck cancer receiving radiotherapy, preliminary clinical research shows that swishing with 10 mL of turmeric solution (prepared by dissolving turmeric 400 mg in 80 mL of water) six times daily for 6 weeks delays mucositis and reduces the number of cases of intolerable mucositis by 49% when compared to swishing with 10 mL of povidone-iodine solution twice daily for 6 weeks (89726). Another small clinical study shows that swishing with 10 mL of nanoparticulate curcumin 0.1% mouthwash three times daily for 6 weeks is associated with a 50% lower risk of developing oral mucositis, and a delay of 2 weeks in the onset of mucositis, when compared with benzydamine 0.15% mouthwash (104969). A small clinical study in patients with mucositis due to head and neck radiotherapy shows that taking curcumin nanoparticles (SinaCurcumin, ExirNanoSina) 40 mg daily or using 10 mL of a curcumin 0.1% mouthwash three times daily for up to 21 days improves scores related to pain, burning, ulceration, and erythema when compared with placebo. Results with either oral or topical curcumin were similar (111350).
• Osteoarthritis. Some oral turmeric extracts and combination products containing turmeric seem to improve certain symptoms of knee osteoarthritis. However, it is unclear how turmeric compares to the use of non-steroidal anti-inflammatory drugs (NSAIDs). Details: Several meta-analyses of clinical studies show that turmeric extracts and/or curcuminoid products reduce knee pain and stiffness, improve physical function, and reduce the need for rescue medication when compared with placebo (104970,106792,109280,110222). However, a reduced effect was noted in patients with increasing age or body mass index (104790). The studies evaluated in these meta-analyses are heterogeneous, of low- to moderate-quality, and utilized a variety of products and/or dosing strategies (104970,106792,109280,110222). Small to moderate-sized clinical studies show that specific products (Meriva, Indena; Theracurmin, Theravalues Corp) containing curcumin 90-100 mg twice daily for up to 6 months, or specific turmeric extracts (Turmacin, Natural Remedies Pvt. Ltd.; Curcugen, DolCas Biotech, LLC) 500 mg twice daily for 6-12 weeks, reduce pain and analgesic use and improve functionality when compared with placebo (17953,80988,89721,97424,104148,107118). A specific turmeric extract (CuraMed, EuroPharma USA) 1500 mg daily for 12 weeks improves functionality, but not pain, when compared with placebo (96127). Also, a specific nanoparticle formulation of curcumin (SinaCurcumin, ExirNanoSina), 40 mg twice daily for 6 weeks, improves pain, stiffness, and physical activity scores and reduces intake of rescue acetaminophen by about 60% when compared with placebo (102349). However, not all turmeric products seem to be effective for improving symptoms of osteoarthritis. One small clinical study shows that taking a specific turmeric extract (B-Turmactive, PLAMECA S.A.) 500 mg daily for one week does not reduce knee pain when compared with placebo (104147). Also, a meta-analysis of clinical research shows that benefits are limited to bio-optimized forms of curcuminoids, and benefits related to pure extracts are lacking (110222). Turmeric has also been compared with conventional treatments for knee osteoarthritis in small meta-analyses, a network meta-analysis, and individual clinical studies. However, the evidence is mixed as to whether turmeric is as effective or more effective than NSAIDs, such as ibuprofen 400 mg taken 2-3 times daily, diclofenac 25-100 mg daily, or chondroprotective drugs (17952,89720,89722,106792,109280,110222,113607). A network meta-analysis comparing 6 interventions in adults with knee osteoarthritis suggests that curcumin monotherapy, curcumin with chondroprotective agents, or curcumin with NSAIDs improves scores related to pain, function, and stiffness while reducing the need for rescue medication and the incidence of adverse events (113607). Individual studies are heterogenous with respect to comparator medication and dosing schedule. Doses included a non-commercial turmeric extract 500 mg 3-4 times daily for 4-6 weeks (17952,89720) or turmeric extract 500 mg twice daily for 3 months (89722). Topical turmeric has also been evaluated. One clinical study shows that applying curcumin topically as a 5% ointment in Vaseline twice daily for 6 weeks reduces pain associated with knee osteoarthritis by a mean of about 11 on a 100-point visual analog scale when compared with placebo (104964). Another clinical study in patients with knee osteoarthritis shows that applying curcumin in a self-nano-emulsifying polyethylene glycol organogel 1.5 grams to the knee twice daily for 8 weeks reduces pain, stiffness, and difficulty with physical function scores by 72%, 62%, and 46%, respectively, when compared to baseline, with improvements superior to placebo for all outcomes (113357). Research also shows that taking specific combination products containing turmeric and other ingredients can improve pain and functionality in patients with osteoarthritis. These combination products have combined turmeric with chondroitin sulfate and glucosamine hydrochloride (CartiJoint Forte, Fidia Farmaceutici SpA); boswellic acid (Curamin, EuroPharma USA; Rhulief); Boswellia serrata (Rhulief); ashwagandha, Boswellia serrata, and zinc (Articulin-F, Eisen Pharmaceutical Co. Pvt. Ltd.); devil's claw and bromelain (AINAT, Laboratoire de Rhumatologie Appliquée); Boswellia serrata, guggul, and valerian (Phytoproflex, OPTM Healthcare); Boswellia serrata and terminalia (LI73014F2, Laila Nutraceuticals); ashwagandha, Boswellia serrata, and ginger (Artrex, Mendar); or extracts of ginger rhizome, devil's claw tuber, Boswellia serrata resin, and celery seed (Tregocel, Max Biocare) (19276,51950,81466,89717,89719,96127,97419,97421,97428,106078)(109280).
• Pruritus. Oral turmeric has been evaluated for the management of pruritus of various etiologies, with promising results. Details: Clinical research in patients with kidney failure shows that taking turmeric 500 mg orally three times daily for 8 weeks decreases symptoms of uremic pruritus by 1.9-fold when compared with placebo (89724). Also, a small clinical study in patients with sulfur mustard-induced chronic pruritus shows that taking a specific combination product (C3 Complex, Sami Labs LTD) containing curcumin 1 gram plus extract from black pepper or long pepper (Bioperine) daily for 4 weeks reduces pruritus severity and improves quality of life when compared with placebo (81120,81176).

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there has been interest in using topical turmeric for acne, there is insufficient reliable information about the clinical effects of turmeric for this purpose.
• Age-related cognitive decline. Some small clinical studies suggest that oral curcumin, a constituent of turmeric, may modestly improve cognition in elderly patients experiencing cognitive decline. Details: A meta-analysis of three small clinical trials shows that curcumin modestly improves cognition in the elderly (100261). One of these clinical trials shows that taking a specific brand of curcumin (Theracurmin, Theravalues Corp.) 90 mg twice daily for 18 months improves long-term memory and attention when compared with placebo in middle-aged and older adults with or without mild cognitive impairment (96161).
• Amenorrhea. Although there has been interest in using oral turmeric for amenorrhea, there is insufficient reliable information about the clinical effects of turmeric for this purpose.
• Ankylosing spondylitis. Although there has been interest in using oral turmeric for ankylosing spondylitis, there is insufficient reliable information about the clinical effects of turmeric for this purpose.
• Anxiety. Some clinical research show that oral curcumin reduces symptoms of anxiety. Details: A meta-analysis of 8 mostly low-quality clinical studies in adults with anxiety symptoms or an anxiety disorder diagnosis shows that taking curcumin 500-1000 mg daily for up to 12 weeks modestly reduces symptoms of anxiety when compared with placebo (114902). The validity of the meta-analysis is limited by the heterogeneity of the included studies, including differences in the patient populations, form and doses curcumin, treatment durations, and types of anxiety scales used. Additionally, all studies were conducted in either Iran or Australia which may limit generalizability of results to other populations.
• Aromatase inhibitor-induced arthralgia. It is unclear if oral curcumin, a constituent of turmeric, is beneficial for aromatase inhibitor-induced arthralgia. Details: A small clinical trial in patients experiencing aromatase inhibitor-induced arthralgia shows that taking curcuminoids as a nanoemulsion (Curcumin C3 Complex, Sabinsa Corporation) 200 mg daily for 3 months does not improve grip strength or joint symptoms when compared with placebo (113345). However, this study may have been underpowered to detect a difference between groups.
• Asthma. Some small clinical studies suggest that oral turmeric, as an adjunct to conventional asthma treatment, does not improve lung function or symptoms in adults and children with asthma. Details: One small clinical study in adults with mild to moderate asthma shows that adjuvant therapy with turmeric as curcumin 500 mg twice daily for 30 days does not improve lung function based on FEV1, or improve symptoms such as dyspnea, wheezing, cough, or tightness, when compared to standard treatment alone (99349). A small clinical trial in children 7-18 years of age with moderate to severe asthma shows that adding turmeric 500-1000 mg (containing 20-40 mg curcuminoids) daily for 6 months to standard therapy does not improve overall asthma symptoms when compared with placebo and standard therapy, although it may decrease the frequency of nighttime awakenings and the use of rescue inhalers (99348). Due to their small sizes and high drop-out rates, these studies may have been underpowered to detect a difference between groups.
• Athletic performance. It is unclear if oral curcumin, a constituent of turmeric, is beneficial for athletic performance. Details: Preliminary clinical research in middle-aged male long-distance runners shows that taking a turmeric extract providing 2 grams of curcumin 95% and piperine 5% daily for 6 weeks does not improve aerobic capacity when compared with placebo (109286).
• Benign prostatic hyperplasia (BPH). It is unclear if oral curcumin, a constituent of turmeric, is beneficial in BPH. Details: A clinical study in patients with BPH shows that taking curcumin 2250 mg once daily along with tamsulosin and finasteride for 6 months improves lower urinary tract symptoms related to storage, but not overall symptoms or symptoms related to voiding, by about 35%, compared with 25% in those receiving tamsulosin and finasteride alone. Periprostatic fat thickness, quality of life, and erectile function also were improved (106799).
• Beta-thalassemia. It is unclear if oral turmeric is beneficial for iron overload in patients with beta-thalassemia. Details: A small clinical study in patients with beta-thalassemia major and iron overload shows that taking turmeric extract containing curcumin 500 mg twice daily for 12 weeks modestly reduces non-transferrin bound iron (NTBI) by 0.6 micromol/L, but not hemoglobin, transferrin saturation, total iron binding capacity, ferritin, or hepcidin, when compared with placebo (99306). Another small clinical study in adult males with beta-thalassemia intermedia and iron overload shows that taking a higher dose of curcumin 500 mg three times daily for 12 weeks modestly reduces serum iron and ferritin turmeric levels and transferrin saturation when compared with placebo (108871).
• Bruises. Although there has been interest in using topical turmeric to alleviate bruising, there is insufficient reliable information about the clinical effects of turmeric for this purpose.
• Cachexia. It is unclear if oral curcumin, a constituent of turmeric, is beneficial for cancer cachexia. Details: A small clinical trial in patients with cancer anorexia-cachexia syndrome shows that taking curcumin 800 mg twice daily for 8 weeks does not reduce weight loss or improve body composition or handgrip strength when compared with placebo (109283).
• Canker sores. Some preliminary research suggests that topical curcumin, a constituent of turmeric, is beneficial for minor canker sores. Details: Preliminary clinical research in young adults with minor canker sores shows that applying a 2% curcumin oral gel for 6 months reduces ulcer size, pain, and recurrence rate and increases healing rate similarly to 0.1% triamcinolone oral paste (104962). The validity of the study is limited by a lack of investigator blinding and the lack of an intention to treat analysis. Another small clinical study shows that applying a 1% curcumin nanomicelle gel (SinaCurcumin Pharmaceuticals) on lesions three times daily for one week is modestly more effective than applying a 2% curcumin gel for reducing pain and ulcer size (109282). The validity of this finding is limited by the lack of a non-curcumin comparator group.
• Carpal tunnel syndrome. Oral turmeric has only been evaluated in combination with other ingredients; its effect when used alone is unclear. It is unclear if topical curcumin, a constituent of turmeric, is beneficial for carpal tunnel syndrome. Details: A moderate-sized clinical study in adults with mild to moderate carpal tunnel syndrome shows that taking a combination product containing turmeric, alpha-lipoic acid, acetyl-L-carnitine, phosphatidylserine, and vitamins C, E, B1, B2, B6, and B12 twice daily for 60 days reduces symptom severity and pain but does not improve measures of hand and wrist function when compared with control (111702). The validity of these effects is limited by a lack of blinding. The study may also be inadequately powered to detect a difference between groups. Additionally, it is unclear if the effects are due to turmeric, other ingredients, or the combination. Topical turmeric has also been investigated. A small clinical study in patients with mild to moderate carpal tunnel syndrome shows that applying a 1% curcuminoid gel (Sinanomin) to the wrists twice daily for 8 weeks modestly decreases symptom severity and improves function when compared with a placebo gel. However, there was no change in electrodiagnostic testing of the injury. All patients also used a night splint (113356).
• Chemotherapy-induced acral erythema. It is unclear if oral or topical turmeric reduces the risk for acral erythema from capecitabine. Details: A small clinical trial in adults with cancer shows that taking turmeric 4 grams daily for 6 weeks starting at the beginning of treatment with capecitabine does not reduce the incidence of acral erythema overall; however, it does seem to reduce acral erythema grade 2 or higher when compared with expected incidence rates (99309). Topical turmeric has also been evaluated. A clinical study in patients with colorectal, gastric, pancreatic, or breast cancer receiving capecitabine shows that applying a specific ointment (Alpha) standardized to contain curcumin extract 0.5% and henna extract 10% to the soles and palms twice daily, beginning on day 1 of chemotherapy and continued for 4 cycles, does not prevent acral erythema or improve World Health Organization severity scores when compared with placebo. A post-hoc analysis suggests that there may have been a trend toward delayed onset and progression; however, this study was not structured to assess these outcomes (108874).
• Chemotherapy-induced constipation. It is unclear if oral curcumin reduces symptoms of chemotherapy-induced constipation. Details: A small clinical study in patients with various forms of cancer receiving standard chemotherapy for that cancer type shows that taking curcuminoids (C3 Complex, Sami Labs) 500 mg with piperine (Bioperine) 5 mg twice daily for 9 weeks does not reduce symptoms of constipation when compared with placebo (107111).
• Chemotherapy-induced diarrhea. It is unclear if oral curcumin reduces symptoms of chemotherapy-induced diarrhea. Details: A small clinical study in patients with various forms of cancer receiving standard chemotherapy for that cancer type shows that taking curcuminoids (C3 Complex, Sami Labs) 500 mg with piperine (Bioperine) 5 mg twice daily for 9 weeks does not reduce symptoms of diarrhea when compared with placebo (107111).
• Chemotherapy-induced nausea and vomiting (CINV). It is unclear if oral curcumin reduces CINV. Details: A small clinical study in patients with various forms of cancer receiving standard chemotherapy for that cancer type shows that taking curcuminoids (C3 Complex, Sami Labs) 500 mg with piperine (Bioperine) 5 mg twice daily for 9 weeks modestly reduces symptoms of nausea, but not vomiting, in the second and third months after the start of treatment when compared with placebo (107111).
• Chemotherapy-induced peripheral neuropathy. It is unclear if oral curcumin reduces symptoms of chemotherapy-induced peripheral neuropathy. Details: A small clinical study in patients with various forms of cancer receiving standard chemotherapy for that cancer type shows that taking curcuminoids (C3 Complex, Sami Labs) 500 mg with piperine (Bioperine) 5 mg twice daily for 9 weeks modestly reduces symptoms of chemotherapy-induced peripheral neuropathy over a three-month period when compared with placebo (107111).
• Chronic kidney disease (CKD). It is unclear if oral turmeric is beneficial for CKD. Details: A meta-analysis of four small clinical trials in patients with CKD related to diabetic nephropathy or lupus nephritis shows that taking curcumin or turmeric for 0.5-4 months moderately reduces proteinuria when compared with placebo (109276). Also, a small clinical trial in children and young adults ages 6-25 years with vascular dysfunction related to autosomal dominant polycystic disease (PKD) shows that curcumin powder 25 mg/kg daily for 12 months does not improve vascular function or kidney function when compared with placebo (107117).
• Colorectal adenoma. It is unclear if oral turmeric is beneficial for managing colorectal adenoma. Details: Preliminary clinical research in adults with familial adenomatous polyposis shows that taking curcumin 1500 mg twice daily for 12 months does not reduce the quantity or size of lower intestinal adenomatous polyps when compared with placebo (97427). A very small clinical trial in patients with familial adenomatous polyposis shows that taking 8 capsules daily of a turmeric extract, in a formulation also containing pepper fruit, spirulina, seaweed, and ginger root, for 6 months does not affect total polyp number or burden when compared with placebo. However, both number and burden were modestly reduced in the left colon. Each capsule provided curcuminoids 123.65 mg and turmerones 26.79 mg (110223).
• Colorectal cancer. It is unclear if oral turmeric is beneficial for the prevention or treatment of colorectal cancer. Details: A small clinical trial in patients undergoing chemotherapy following colorectal cancer surgery shows that taking curcuminoids (C3 Complex, Sami Labs) 500 mg with piperine (Bioperine) 5 mg daily for 8 weeks modestly improves some measures of quality of life when compared with placebo (107109). In addition, a small clinical study in people at high risk for colorectal cancer, such as those who smoke, shows that taking the turmeric constituent, curcumin, 4 grams daily for 30 days can reduce the number of precancerous rectal aberrant crypt foci (18204). It is not clear if this results in a reduced risk for colorectal cancer.
• Coronary artery bypass graft (CABG) surgery. One small study suggests that oral turmeric may reduce the risk for myocardial infarction after CABG surgery. Details: Preliminary clinical research shows that taking the turmeric constituent, curcuminoids, 4 grams daily in four divided doses, beginning 3 days prior to surgery and continuing for 5 days post-surgery, decreases the relative risk of myocardial infarction following CABG by approximately 56% when compared with placebo (81143).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral turmeric or its constituent, curcumin, is beneficial for reducing symptoms of COVID-19. Details: Small studies have evaluated curcumin as an adjunctive therapy in adults hospitalized with confirmed COVID-19. Patients in these studies also received treatments such as antimicrobials, anti-inflammatory medications, anticoagulants, antiretrovirals, and immunosuppressants (104966,105393,107119). One study shows that adding curcumin reduces the duration of shortness of breath by 6-9 days when compared with patients who received other treatments in combination with probiotics. However, there were no differences in the duration of other symptoms, including fever, cough, or sore throat. Subgroup analyses suggest that taking curcumin may improve oxygenation and reduce the need for supplemental oxygen or ventilation (105393). Another study shows that adding curcumin modestly reduces the time to resolution of COVID-19 symptoms, the length of supplemental oxygen use, and the likelihood for deterioration in the patients' condition when compared with patients who received other treatments alone (104966). A third study shows some benefit of curcumin on fever and cough when compared with baseline; however, it is unclear if any changes were significant when compared with placebo (107119). Doses of curcumin used in these studies include curcumin 525 mg with piperine 2.5 mg (C3 Complex, SamiDirect) twice daily, starting at admission and continuing for 14 days (105393), or a specific nanocurcumin product (SinaCurcumin, ExirNanoSina) 80 mg twice daily for 2 weeks or 240 mg daily in divided doses for 7 days (104966,107119). Limitations of these studies include the small number of patients with severe symptoms, the large number of outcomes evaluated, the inconsistencies in other treatments used, the lack of clarity related to presentation of some results, and, in most cases, a lack of blinding. Turmeric has also been evaluated in adults in the outpatient setting with suspected or confirmed mild to moderate COVID-19. One small clinical study shows that taking curcumin (SinaCurcumin, ExirNanoSina) 80 mg twice daily for 14 days in addition to other COVID-19 treatments (mainly hydroxychloroquine and azithromycin) reduces the duration of cough, chills, myalgia, and smell and taste disturbance, but not dyspnea, fever, sore throat, or others, by 1-2 days when compared with placebo with other treatments (106802). The validity of this study is limited by the lack of confirmatory diagnosis at baseline and lack of consistency with other treatments, as well as the unclear reporting of symptom duration in relation to the initiation of treatment. Another small clinical study in outpatients confirmed to have COVID-19 shows that taking curcumin 1000 mg plus piperine 10 mg (Sami Labs Limited) daily for 14 days modestly improves weakness, but not cough, pain, headache, difficulty breathing, or biochemical indices, when compared with placebo (109278). However, a clinical study in adults with confirmed asymptomatic or mild COVID-19 shows that taking curcumin (curcuRouge®, TheraBioPharma) 360 mg twice daily for 7 days within 5 days of COVID-19 diagnosis does not reduce the risk of fever or oxygen saturation below 96% when compared with placebo (114905). Some research has also examined the effect of turmeric as part of a polyherbal combination. Clinical research in patients hospitalized for moderate COVID-19 symptoms shows that using an Ayurvedic formulation 1776 mg twice daily containing turmeric, ashwagandha, ginger, and Boswellia serrata (BV-4051) for 14 days modestly reduces the duration of illness and reduces the severity of fever, cough, and smell and taste dysfunction when compared to placebo. There was no beneficial effect on other symptoms, including nasal congestion, breathing difficulty, headache, and gastrointestinal symptoms. More than half of the patients were also treated with remdesivir which did not impact the majority of these findings (109899).
• Crohn disease. It is unclear if oral turmeric is beneficial for improving symptoms of active Crohn disease. Details: Some clinical research shows that taking the turmeric constituent, curcumin, 1.08 grams daily for one month, then 1.44 grams daily for one month, can reduce bowel movements, diarrhea, and abdominal pain when compared to baseline in patients with Crohn disease (79730). The validity of these findings is limited by the lack of a comparator group.
• Denture stomatitis. Topical turmeric may be beneficial for treating denture stomatitis. Details: A small clinical study in patients with denture stomatitis shows that applying topical curcumin gel (Curenext, Abbott Laboratories) three times daily for 2 weeks resolves denture stomatitis lesions similarly to clotrimazole ointment (106797).
• Diabetes. Lower quality clinical studies suggest that oral curcumin, a constituent of turmeric, may modestly improve glycemic control in patients with diabetes. Details: A meta-analysis of small clinical trials in patients with diabetic kidney disease shows that curcumin reduces levels of fasting glucose by approximately 8.3 mg/dL when compared with placebo. Curcumin was used in doses of 66.3-1670 mg daily for 2-6 months (107114). Preliminary clinical research included in the analysis shows that taking a specific nanoparticle formulation of curcumin (SinaCurcumin, ExirNanoSina) 80 mg daily for 12 weeks reduces fasting blood glucose by about 20 mg/dL (104149). Other meta-analyses of low- to moderate-quality clinical studies in patients with a variety of conditions including type 2 diabetes show that taking turmeric extract, curcumin, or curcuminoids for 4-36 weeks improves glycated hemoglobin (HbA1c) by 0.4-0.7% and reduces fasting glucose by approximately 13 mg/dL when compared with placebo or conventional treatment (106806,108877,113604). The validity of these findings is limited by the heterogeneity of the included studies and broad curcuminoid doses ranging from 46-1500 mg daily. Conversely, other meta-analyses in patients with type 2 diabetes show that curcumin does not reduce HbA1c or insulin levels when compared with placebo (104965,108877,113604).
• Diabetic foot ulcers. It is unclear if oral curcumin is beneficial in patients with diabetic foot ulcers. Details: Preliminary clinical research in patients with grade 3 diabetic foot ulcers shows that taking nanocurcumin 80 mg orally daily for 12 weeks does not improve glycated hemoglobin (HbA1c) or change the rate of ulcer healing when compared with placebo. Taking turmeric did result in modest decreases in fasting blood glucose, insulin levels, and insulin resistance (104972).
• Diabetic nephropathy. It is unclear if oral curcumin is beneficial in patients with diabetic nephropathy. Details: Meta-analyses of two to four small clinical trials in patients with diabetic kidney disease show that curcumin modestly improves serum levels of creatinine, total cholesterol, and fasting glucose, and reduces systolic blood pressure by 4 mmHg, when compared with placebo. However, there was no effect on diastolic blood pressure, proteinuria, or serum levels of other plasma lipids or blood urea nitrogen. Curcumin was used in doses of 66.3-1670 mg daily for 2-6 months (107114). One small study included in this analysis, which evaluated patients receiving hemodialysis, shows that taking a specific nanoparticle formulation of curcumin (SinaCurcumin, ExirNanoSina) 80 mg daily for 12 weeks reduces fasting blood glucose by about 20 mg/dL when compared with placebo (104149).
• Dysmenorrhea. Oral turmeric has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in university students aged 18 to 24 in Iran with mild to severe primary dysmenorrhea and premenstrual syndrome (PMS) shows that taking a specific combination product containing curcumin 500 mg plus extract from black pepper 5 mg (C3 Complex, Sami Labs) daily, starting 7 days prior to menstruation and continuing for 3 days after menstruation for 3 consecutive menstrual cycles, does not improve the severity of symptoms when compared with placebo (106805). Conversely, a small clinical study in adults with moderately painful dysmenorrhea shows that taking a single dose of a combination product containing turmeric, Boswellia serrata, and sesame (Rhuleave-K, Arjuna Natural Private Ltd.) 1000 mg at the start of menstruation relieves menstrual cramp pain and reduces pain intensity for up to 6 hours when compared with placebo (112806). However, it is unclear if these effects are due to turmeric, other ingredients, or the combinations.
• Endometriosis. It is unclear if oral turmeric is beneficial for reducing pain due to endometriosis. Details: A small clinical study in adults with endometriosis shows that taking the turmeric constituent, curcumin, 500 mg twice daily for 8 weeks does not affect pain associated with endometriosis or quality of life when compared with placebo (113603).
• Erythema. Although there has been interest in using topical turmeric for reducing erythema, there is insufficient reliable information about the clinical effects of turmeric for this purpose.
• Exercise-induced muscle damage. It is unclear if oral curcumin, a constituent of turmeric, is beneficial for reducing muscle damage from exercise. Details: A meta-analysis of 12 small, lower-quality clinical studies in adults shows that taking curcumin 150-500 mg as a single dose before or after exercise or 180-5000 mg daily for up to 56 days reduces markers of muscle damage (i.e. serum creatine kinase levels) when compared with placebo. Curcumin seems most beneficial for this effect in untrained adults and when administered as a single dose. Additionally, a meta-analysis of 3 of these clinical studies shows that curcumin improves range of motion (114897). The interpretation of these findings is limited by significant heterogeneity.
• Exercise-induced muscle soreness. It is unclear if oral turmeric or its constituent, curcumin, is beneficial for reducing muscle soreness from exercise. Details: A meta-analysis of 12 small, lower-quality clinical studies in trained and untrained adults shows that taking curcumin 150-500 mg as a single dose before or after exercise or 180-5000 mg daily for up to 56 days time reduces muscle soreness when compared with placebo. Subgroup analysis indicated that the largest effect size is observed at 96 hours post-exercise with progressively smaller effect sizes at earlier time points (114897). The interpretation of these findings is limited by significant heterogeneity. Turmeric has also been examined in combination with other ingredients. Clinical research in healthy active adults with moderate to severe exercise-induced muscle pain shows that taking a single, 1000-mg dose of turmeric and Boswellia serrata extracts in black sesame oil (Rhuleave-K; Arjuna Natural Private Ltd.) improves pain relief when compared with placebo, with maximal benefits within about 3 hours. The number of people needed to treat to obtain pain relief of at least 50% over a 6-hour period was 1.1 (109277).
• Gingivitis. Small clinical studies suggest that oral turmeric and turmeric mouthwash may reduce the severity of gingivitis. Turmeric mouthwash appears to be similarly effective to chlorhexidine mouthwash. Details: A meta-analysis of generally preliminary clinical research shows that rinsing with a mouthwash containing curcumin for 3-4 weeks is as effective as rinsing with chlorhexidine for reducing the severity of gingivitis or plaque (106059). Mouthwashes in these studies contained 0.05% to 20% curcumin and were usually used twice daily for 3-4 weeks (81127,89723,106059). One mouthwash contained 0.05% turmeric extract and 0.005% eugenol (89723). Another small clinical trial shows that taking a specific nanoparticle formulation of curcumin (SinaCurcumin, ExirNanoSina) 80 mg daily by mouth after breakfast for 4 weeks reduces the severity of gingivitis and gingival bleeding, but not plaque, when compared with placebo in patients with gingivitis and mild periodontitis (104146).
• Gout. Although there is interest in using oral turmeric for gout, there is insufficient reliable information about the clinical effects of turmeric for this condition.
• Gulf war syndrome. It is unclear if oral curcumin is beneficial in patients with Gulf war syndrome. Details: A small preliminary clinical trial in patients with Gulf war syndrome shows that taking curcumin (Meriva, Indena, S.p.A.) 500 mg twice daily for 30 days reduces overall symptoms, including pain, fatigue, gastrointestinal distress, and others, by 19% when compared with baseline. Taking a higher dose of 2000 mg twice daily for an additional 30 days appears to be no more effective than the lower dose (105395).
• Hearing loss. It is unclear if oral turmeric is beneficial for treating hearing loss. Details: A small clinical study in adults with mild to moderate hearing impairment shows that taking curcumin 500 mg daily for 12 weeks improves some measures of auditory function, such as auditory brain stem response threshold, when compared with placebo (114906).
• Helicobacter pylori. Small clinical studies suggest that oral turmeric is not beneficial for eradicating H. pylori when used alone or in combination with standard triple therapy or famotidine. Details: One small clinical study in patients with H. pylori gastritis shows that taking turmeric 2.1 grams daily for 4 weeks is less effective for eradicating H. pylori than taking an omeprazole-based triple regimen for one week (80957). Another small study in adults with peptic ulcers shows that taking a specific curcumin product (C3 Complex, Sami Labs LTD) 500 mg daily for 7 days, in conjunction with standard triple therapy, does not improve H. pylori eradication rates when compared with standard triple therapy alone. The addition of curcumin increased the resolution of dyspepsia symptoms by an additional 21%, but the clinical significance of this outcome is unclear (97420). In patients with dyspepsia, most of whom tested positive for fecal H. pylori antigen, clinical research shows that taking curcuminoids (C3 Complex, Sami Labs) 500 mg with piperine (Bioperine) 5 mg daily in addition to famotidine 40 mg daily for 30 days is no more effective for reducing fecal H. pylori antigen levels than taking famotidine alone (106063).
• Hypertension. It is unclear if oral curcumin is beneficial in patients with hypertension. Details: A meta-analysis of approximately 30 clinical studies in healthy adults or patients with a variety of conditions shows that taking turmeric, curcumin, curcuminoids, or nano-curcumin for 4 to 24 weeks reduces systolic blood pressure by about 2 mmHg and diastolic blood pressure by about 0.8 mmHg when compared with placebo (113602). However, these blood pressure reductions may not be clinically meaningful. In addition, most of the included studies were small and utilized heterogeneous dosing regimens.
• Impaired glucose tolerance (prediabetes). Oral turmeric may modestly improve glucose control in some patients with prediabetes. Details: In overweight or obese individuals with prediabetes, clinical research shows that taking a turmeric extract (BCM95 or Cucugreen; M/s Arjuna Natural Pvt Ltd.) 500 mg daily, providing 95% curcuminoids and at least 65% curcumin, for 90 days, either alone or in combination with zinc 30 mg as zinc gluconate, results in a small reduction in fasting glucose and glycated hemoglobin (HbA1c) when compared with placebo. There was also a small benefit in insulin sensitivity (105391). Other preliminary clinical research in adults with prediabetes shows that taking 500 mg of a combination of turmeric extract and Indian gooseberry extract in a 1:2 ratio along with phosphatidylcholine (EmbliQur) twice daily for 6 months modestly reduces fasting glucose and improves insulin resistance, when compared with placebo. However, changes in most other endpoints were not significantly different from placebo. Each 500 mg capsule contained turmeric extracts 29.86% and turmeric oil 1.27% (113355). The effect of turmeric on progression to type 2 diabetes in patients with prediabetes has also been investigated. Preliminary clinical research shows that taking a turmeric extract containing curcumin 750 mg twice daily for 9 months reduces the percentage of patients with prediabetes who develop type 2 diabetes when compared with placebo (81163).
• Irritable bowel syndrome (IBS). It is unclear if oral turmeric is beneficial for improving symptoms of IBS. Details: Preliminary clinical research in otherwise healthy adults with IBS shows that taking a turmeric extract (Cynara Turmeric, Lichtwer Pharma) 72-144 mg daily for 8 weeks reduces IBS symptoms by about 40% to 60% when compared to baseline (79565). The validity of this finding is limited by the lack of a comparator group. Taking a combination product (CU-FEO, Alfa Wasserman S.p.A.) containing curcumin 42 mg and fennel essential oil 25 mg per capsule twice daily for 60 days improves overall ratings of abdominal pain, abdominal distention, and quality of life by 24% when compared with placebo (97422). It is unclear if these effects are due to turmeric, fennel, or the combination. Observational research suggests that adding a supplement (Enterofytol PLUS) providing curcumin 42 mg and berberine 200 mg twice daily for 2 months to conventional IBS treatment is associated with improvements in symptoms, such as abdominal discomfort, distension, and stool status, by up to 48% when compared with conventional treatment alone. Use of the supplement was also associated with a 64% reduced need for conventional treatments (113354).
• Joint pain. Oral turmeric has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking capsules of a specific combination product (Instaflex Joint Support, Direct Digital) containing glucosamine sulfate 1500 mg, methylsulfonylmethane 500 mg, white willow bark extract 250 mg, ginger root concentrate 50 mg, Boswellia extract 125 mg, turmeric root extract 50 mg, cayenne 40 m H.U. 50 mg, and hyaluronic acid 4 mg in three divided doses daily for 8 weeks reduces joint pain severity by 37% compared to only 16% with placebo. However, it does not improve joint stiffness or function when compared with placebo (89560). It is unclear if these effects are due to turmeric, other ingredients, or the combination.
• Juvenile idiopathic arthritis (JIA). Although there is interest in using oral turmeric for JIA, there is insufficient reliable information about the clinical effects of turmeric for this condition.
• Knee pain. It is unclear if oral turmeric is beneficial for knee pain. Details: Clinical research in individuals with knee pain not related to existing arthritis shows that taking turmeric extract (TurmXTRA 60N; Inventia Healthcare Ltd. and Laila Nutraceuticals) 250 mg, providing 60% curcuminoids, once daily for 90 days modestly reduces pain associated with walking 80 meters when compared with placebo. The time taken to walk 80 meters and to climb nine steps was reduced by 4-5 seconds (105396).
• Lichen planus. Evidence is conflicting on whether turmeric is beneficial for lichen planus. Details: A meta-analysis of several small, heterogeneous, mostly low-quality clinical and observational studies in adults with oral lichen planus shows that oral or topical curcumin with or without corticosteroids for 2-12 weeks does not improve erythema, lesion size, or pain when compared with control (113605). Similarly, a network meta-analysis of small clinical trials in patients with oral lichen planus shows that applying topical turmeric gel does not improve symptoms, clinical resolution, clinical scores, or reduce pain when compared with other available interventions (111640). However, small individual clinical studies have shown some benefit in using turmeric for lichen planus. A small clinical study shows that taking a specific turmeric extract (Curcumin C3 Complex, Sabinsa Corporation) containing curcuminoids 6000 mg daily in three divided doses for 12 days can reduce erythema and ulceration associated with lichen planus when compared with placebo (81109). Another small clinical study shows that taking a nanocurcumin product (SinaCurcumin, ExirNanoSina) 80 mg orally once daily for 1 month reduces oral lichen planus lesion size, pain, and burning similarly to prednisolone 10 mg taken orally once daily for 1 month (104961).
• Metabolic syndrome. It is unclear if oral turmeric is beneficial for metabolic syndrome. Details: Research is conflicting on how turmeric, curcumin, and other formulations affect various measures of metabolic syndrome. Some clinical research and a meta-analysis of 13 clinical studies in patients with metabolic syndrome show that taking turmeric or curcumin decreases low-density lipoprotein (LDL) cholesterol, waist circumference by 2 cm, fasting blood glucose by 9 mg/dL, and diastolic blood pressure by 3 mmHg and increases high-density lipoprotein (HDL) cholesterol by 5 mg/dL when compared with placebo. However, other research shows that turmeric or curcumin have no effect on body weight, lipids, blood pressure, or blood glucose when compared with placebo (98999,99311,105400,109284,111347,112118). The validity of these effects is limited by high heterogeneity within the included studies and incomplete information about randomization and blinding. Studies have used turmeric, curcumin, and curcumin extract 80-2400 mg, in divided doses, daily for 4-12 weeks, nano-curcumin 80 mg daily for 12 weeks, or calebin A (CurCousin, Sabinsa), which is a constituent of turmeric, 25 mg twice daily for 3 months (98999,99311,105400,109284,111347,112118). Also, taking crude or phosphorylated curcuminoids 1 gram daily for 6 weeks does not improve sleep or reduce weight in these patients (105397).
• Migraine headache. It is unclear if oral curcumin is beneficial for migraine headache. Details: A small clinical trial in females with regular migraines shows that taking curcumin 500 mg twice daily for 8 weeks reduces the severity and duration, but not the frequency, of migraine headaches when compared with placebo. In individuals taking curcumin, the duration of headache per month was reduced by approximately 10.3 hours from baseline (107116).
• Myocardial infarction (MI). It is unclear if oral curcumin is beneficial for reducing myocardial injury following a MI. Details: Clinical research in patients with an acute MI shows that taking curcuminoids 500 mg plus piperine (Bioperine) 5 mg daily (Sami Labs) for 8 weeks does not improve ejection fraction, serum levels of cardiac troponin 1, blood pressure, levels of fasting blood glucose, or kidney function parameters when compared to placebo. However, there were some modest benefits on levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, glycated hemoglobin, and certain liver enzymes such as aspartate aminotransferase (AST) and alkaline phosphatase (ALP) (107115). The validity of this study is limited by its short duration and relatively small sample size.
• Obesity. Oral turmeric might modestly improve weight loss, although any effect is unlikely to be clinically significant. Details: Multiple meta-analyses of small, mostly low-quality clinical studies in adults with a variety of comorbid conditions show that taking various forms and doses of turmeric or curcumin results in an average weight loss of about 0.6-1 kg, a decrease in body mass index (BMI) of about 0.2-0.5 kg/m2, and a decrease in waist circumference of about 1.3 cm when compared with control (102345,111351,111352). A sub-analysis of dose and duration shows that a reduction in waist circumference only occurs with curcumin daily doses above 1000 mg, and duration of treatment longer than 8 weeks (102345).
• Oral submucous fibrosis. Small studies suggest that topical or oral curcumin might be beneficial for oral submucous fibrosis. However, the research is heterogenous with respect to outcomes, comparators, and the turmeric preparations, doses, and routes of administration utilized. Details: A meta-analysis of 3 small clinical trials shows that turmeric modestly improves mouth opening when compared with control. In addition, a systematic review of 11 studies shows that turmeric improves overall symptoms, including mouth opening, tongue protrusion, burning sensation, and cheek flexibility. However, studies were small with short duration and used variable dosing strategies. Most trials have studied oral turmeric 300-400 mg, either alone or with black pepper 100 mg or piperine 5 mg, for 3-6 months. Less commonly, turmeric was provided in lozenge form (105399). Also, a network meta-analysis suggests that the turmeric constituent curcumin with or without piperine is most the effective for reducing tongue protrusion when compared indirectly with various medical and antioxidant therapies; however, this analysis suggests that curcumin does not rank among the most effective interventions for improving mouth opening, burning sensation, or cheek flexibility (113514). Other preliminary clinical research shows that taking a specific oral product containing curcumin 300 mg and piperine 5 mg (Turmix tablets, Sanat Products), three times daily for 12 weeks, improves mouth opening, burning sensation, and tongue protrusion when compared with baseline, but not when compared with an antioxidant product containing alpha-lipoic acid, beta-carotene, copper, lycopene, selenium, and zinc. Mouth opening is further improved by concurrent use of a mouthwash (Turmix mouthwash, Sanat Products), containing 0.1% w/v turmeric extract (standardized to 95% curcumin), with thymol, eucalyptol, clove oil, mentha oil, and tea tree oil, twice daily for 12 weeks (102347). A small clinical study shows that applying topical curcumin gel (Curenext, Abbott Laboratories) 5 mg daily in 3-4 divided doses for 6 weeks, in combination with oral physical therapy, improves mouth opening similarly to using an aloe vera gel in combination with oral physical therapy. However, decreases in burning sensation are greater with aloe gel than curcumin gel (104967). It is not clear whether the gels, oral physical therapy, or the combination of both is responsible for the outcome. Finally, clinical research shows that applying a paste providing turmeric and holy basil 10 grams each, mixed in 10 mL of honey, to the oral mucosa 4 times daily for 3 months modestly improves mouth opening, tongue protrusion, and burning sensation and reduces the presence of fibrous bands when compared with taking a vitamin B supplement. There was no effect on the shape of the uvula (113325).
• Pain (acute). Oral turmeric has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with acute musculoskeletal pain shows that taking a specific combination product containing turmeric and Boswellia serrata extracts in black sesame oil (Rhuleave-K; Arjuna Natural Private Ltd.) 1000 mg daily for 7 days is as effective as acetaminophen 1000 mg daily for pain relief, onset of pain relief, and onset of maximal pain relief (109287). This study is limited by its lack of blinding and placebo control. Additionally, the dose of acetaminophen used in this study is below the standard recommended daily dose.
• Periodontitis. There is limited evidence on the oral or topical use of turmeric or its constituent curcumin in patients with periodontitis. Details: A meta-analysis of heterogenous clinical studies in patients with chronic periodontitis suggests that use of local delivery gel products, usually turmeric 2% or a specific product containing curcumin (Curenext), modestly reduces pocket depth when compared with routine products, such as chlorhexidine. However, limited research suggests that curcumin products do not affect plaque or gingivitis measures, and curcumin irrigation does not affect pocket depth based on limited research (107108). A small preliminary clinical study in patients with severe chronic periodontitis shows that placing curcumin gel 2 mg on one side of the mouth along with scaling and root planing (SRP) reduces plaque and probing pocket depth, but not gingival index, when compared with SRP alone (101339). The use of oral curcumin has also been investigated. A small clinical trial in patients with gingivitis and mild periodontitis shows that taking a specific nanoparticle formulation of curcumin (SinaCurcumin, ExirNanoSina) 80 mg daily after breakfast for 4 weeks reduces the severity of gingivitis and gingival bleeding, but not plaque, when compared with placebo (104146).
• Physical performance. It is unclear if oral turmeric may be beneficial for improving physical performance in older adults. Details: A very small clinical study in moderately functioning, sedentary adults over age 65 with low-grade chronic inflammation shows that that taking a specific turmeric extract (Curcumin C3 Complex, Sabinsa Corporation) 500 mg twice daily for 12 weeks does not improve measures of physical function, walking speed, or muscle strength when compared with placebo (111357). However, this study may have been inadequately powered to detect any possible differences between groups.
• Polycystic ovary syndrome (PCOS). Small clinical studies suggest that oral curcumin may improve some metabolic parameters in patients with PCOS, but these improvements may not be considered clinically significant. Details: Clinical research in patients with PCOS shows that taking curcumin 500 mg one to three times daily for 6-12 weeks improves some metabolic parameters (104968,105394,106795). Conversely, a small clinical study in patients aged 18 to 45 with PCOS in Iran shows that taking curcumin 1000 mg daily for 12 weeks modestly reduces fasting glucose but does not improve other metabolic parameters when compared with placebo. Taking curcumin also did not improve testosterone levels or hirsutism scores (111355). Meta-analyses show that taking curcumin modestly decreases body mass index (BMI) and improves measures of glycemic control, including fasting glucose and insulin resistance, and levels of total cholesterol when compared with placebo or metformin alone. However, effects on high-density lipoprotein (HDL) cholesterol levels were mixed and there was no effect on low-density lipoprotein (LDL) cholesterol or triglyceride levels (105394,106795,110219). Other preliminary clinical research shows that taking curcumin decreases plasma dehydroepiandrosterone and fasting plasma glucose levels when compared with placebo (104968). Some clinical research also shows that taking nano-curcumin (SinaCurcumin, ExirNanoSina) 80 mg daily for 3 months is beneficial in patients already taking metformin 1500 mg daily. Taking curcumin had modest beneficial effects on fasting insulin and insulin resistance, as well as levels of testosterone, LDL cholesterol, HDL cholesterol, and triglycerides, when compared with metformin alone. There was no effect of curcumin on body weight, fasting blood glucose, or other hormones (106060).
• Postoperative pain. Small clinical studies suggest that oral curcumin, a constituent of turmeric, may modestly reduce pain in various postoperative recovery settings. Details: One small clinical study in patients undergoing laparoscopic cholecystectomy shows that taking curcumin 2 grams daily reduces postoperative pain, fatigue, and the need for analgesics by the second postoperative week when compared with placebo (81099). In patients undergoing surgery for inguinal hernia and/or hydrocele, taking curcumin 1.2 grams daily for 5 days reduces inflammation and tenderness by the sixth postoperative day when compared with placebo (81206). Curcumin was taken in 3-4 divided doses daily in these studies. Finally, taking a single dose of curcumin 200 mg after surgical removal of impacted third molars modestly reduces acute postoperative pain when compared with taking mefenamic acid 500 mg (99305).
• Premenstrual syndrome (PMS). It is unclear if oral turmeric may be beneficial for improving symptoms of PMS. Details: Some preliminary clinical research in patients with PMS shows that taking curcumin 100 mg twice daily, starting 7 days prior to menstruation and continuing for 3 days after menstruation, improves physical, behavioral, and mood symptoms, as well as overall severity of symptoms, when compared with placebo (97433). Conversely, in university students aged 18 to 24 in Iran with mild to severe PMS and primary dysmenorrhea, a clinical study shows that taking a specific combination product containing curcumin 500 mg plus extract from black pepper 5 mg (C3 Complex, Sami Labs) daily, starting 7 days prior to menstruation and continuing for 3 days after menstruation for 3 consecutive menstrual cycles, does not improve the severity of symptoms when compared with placebo (106805).
• Prostate cancer. It is unclear if oral turmeric is beneficial for the prevention or treatment of prostate cancer. Details: One small clinical study shows that taking curcumin 1.8 grams orally three times daily for 7 days, starting 4 days prior to docetaxel and prednisone treatment and continuing for up to 6 cycles, reduces PSA levels by at least half in 59% of patients when compared to baseline. Also, all patients with measurable lesions showed at least stable disease after treatment, and 40% of patients showed partial response when compared with baseline (96132). It is unclear if the addition of turmeric is beneficial when compared with docetaxel and prednisone alone. In contrast, an additional small clinical trial shows that taking curcumin 6 grams daily for 7 days every 3 weeks, starting four days before docetaxel, does not improve PSA levels or progression-free or overall survival when compared with docetaxel alone (105392).
• Psoriasis. Evidence is limited to one small study of topical use in patients with scalp psoriasis. Details: Preliminary clinical research in adults with scalp psoriasis shows that applying a tonic of turmeric to the scalp twice daily for 9 weeks modestly improves overall symptoms and quality of life when compared with a placebo tonic (97429).
• Quality of life. Some preliminary clinical research suggests that oral curcumin might improve quality of life in patients with various chronic conditions. Details: Small or low-quality clinical trials in various patient populations show that taking curcumin improves at least some measures of quality of life when compared with placebo. Research has been conducted in patients with cancer, sulfur mustard-induced chronic pruritus, benign prostatic hyperplasia (BPH), or irritable bowel syndrome (IBS). Studies have evaluated curcumin 2250 mg once daily for 6 months, a specific combination product (C3 Complex, Sami Labs LTD) containing curcumin 500-1000 mg plus piperine (Bioperine) daily for 4-9 weeks, or a combination product (CU-FEO, Alfa Wasserman S.p.A.) containing curcumin 42 mg and fennel essential oil 25 mg per capsule twice daily for 60 days (81120,81176,97422,106799,107109,107111). Also, in patients with scalp psoriasis, applying a tonic of turmeric to the scalp twice daily for 9 weeks modestly improves quality of life when compared with a placebo tonic (97429).
• Radiation dermatitis. It is unclear if oral or topical turmeric is beneficial for reducing the severity of radiation dermatitis. Details: A meta-analysis of 4 clinical studies in patients with breast cancer shows that taking curcumin 500-2000 mg three times daily for 3-7 weeks or applying curcumin gel 500 mg three times daily for 7 weeks reduces the radiation dermatitis severity score by about 0.5 points (on a 4-point scale) when compared with placebo or other control (111354). The validity of this analysis is limited by the heterogeneity of the included studies. However, a small clinical study in patients with breast cancer shows that taking nanocurcumin 80 mg twice daily during and for up to 2 weeks after treatment does not reduce skin reaction severity overall, but does modestly reduce pain, when compared with taking placebo. Also, there was a small reduction in skin reaction severity near the end of the study. All patients also used aloe vera leaf as part of the hospital protocol (109281). Another small preliminary clinical study in head and neck cancer patients shows that a specific cream (Vicco turmeric cream, Vicco Laboratories) containing turmeric and sandalwood oil, applied 5 times daily during radiation therapy, seems to reduce frequency and severity of radiation dermatitis when compared with baby oil (99307).
• Radiation proctopathy. It is unclear if oral turmeric is beneficial for preventing proctitis or cystitis in patients receiving radiotherapy for prostate cancer. Details: A small clinical study in patients with prostate cancer shows that taking a specific nanocurcumin product (SinaCurcumin, ExirNanoSina) 120 mg daily, for 3 days before and also during a course of radiotherapy, does not reduce the occurrence of proctitis or cystitis when compared with placebo (100259). This study may have been underpowered to detect small treatment effects.
• Respiratory tract infections. Although there is interest in using oral turmeric for various respiratory tract infections, including bronchitis and the common cold, it has not been clinically evaluated.
• Rheumatoid arthritis (RA). Small clinical studies suggest that oral curcumin, a constituent of turmeric, may modestly improve some symptoms of RA. Details: Meta-analyses of small clinical trials in patients with RA show that taking curcumin alone or with other treatments modestly reduces overall RA symptoms, pain, and markers of inflammation when compared with control groups, including placebo or other treatments. However, some research shows that there is no beneficial effect on tender or swollen joint count from the limited available clinical research (109280,111358), while other research shows that there is a benefit (112117). Clinical studies have evaluated curcumin 120-1200 mg daily for 2 weeks to 3 months (11149,18205,96129). The validity of these findings is limited by the small size of the studies, and in some cases, the lack of a comparator group.
• Sarcopenia. Oral turmeric has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in elderly patients with sarcopenia shows that taking a specific slow-release product containing turmeric, protein, carbohydrate, and fiber (Cureit, Aurea Biolabs), 500 mg orally daily for 3 months, increases handgrip strength by about 1% and distance walked before feeling tired by about 6% when compared with placebo. It also increases weightlifting capacity by about 6% from baseline, compared with a 5% decrease from baseline in those taking placebo (104973). It is unclear whether these small changes are clinically meaningful.
• Schizophrenia. Although there is interest in using oral turmeric for improving cognitive function in patients with schizophrenia, there is insufficient reliable information about the clinical effects of turmeric for this use.
• Sepsis. It is unclear if oral curcumin, a constituent of turmeric, is beneficial in patients with sepsis. Details: A small clinical trial in patients admitted to the intensive care unit (ICU) with sepsis shows that a specific nanoparticle formulation of curcumin (SinaCurcumin, ExirNanoSina), 80 mg dissolved in water and administered via gastric tube following lavage twice daily for 10 days does not affect length of ICU stay, Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, blood pressure, or heart rate when compared with placebo (108873).
• Smoking cessation. Oral turmeric has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in adults with a history of smoking 5 or more cigarettes daily for at least 3 years shows that taking a specific combination product containing turmeric 50 mg, ashwagandha, Indian gooseberry, tribulus, bacopa, Albizia lebbeck, licorice, clove, ginger, cowhage, and holy basil (Smotect, Smotect India) daily for 3 months reduces the number of cigarettes smoked by approximately 3 per day when compared with placebo. This product also reduces levels of alveolar carbon monoxide and carboxyhemoglobin but does not improve lung capacity (112115). However, only data from patients who completed treatment were analyzed, which limits the validity of this study. It is unclear if these effects are due to turmeric, other ingredients, or the combination. A moderate-sized clinical study in adults with a history of smoking 5 or more cigarettes daily for at least 3 years shows that taking a specific combination product containing turmeric 100 mg, ashwagandha, Indian gooseberry, tribulus, bacopa, Albizia lebbeck, licorice, clove, ginger, cowhage, and holy basil (Smotect, Smotect India) twice daily for 3 months reduces the number of cigarettes smoked by approximately 3 per day when compared with placebo. This product also reduces levels of alveolar carbon monoxide and carboxyhemoglobin but does not improve lung capacity (112115). However, only data from patients who completed treatment were analyzed, which limits the validity of this study. It is unclear if these effects are due to turmeric, other ingredients, or the combination.
• Stress. It is unclear if oral turmeric is beneficial for reducing occupational stress in healthy adults. Details: A small clinical trial in healthy adults with occupational stress-related anxiety and fatigue shows that taking a specific type of turmeric (CurQfen, Akay Flavours and Aromatics Pvt Ltd.) that contains fenugreek dietary fiber for improved bioavailability at a dose of 500 mg twice daily for 30 days reduces stress and fatigue and improves quality of life when compared with placebo, and also when compared with a standard curcumin supplement with lower bioavailability (99308).
• Stroke. It is unclear if oral turmeric is beneficial for stroke. Details: A small clinical study conducted in Iran in adults with a recent ischemic stroke shows that taking curcumin 500 mg and piperine, a pepper constituent, 5 mg (Sami Lans, India) daily for 12 weeks reduces carotid intima-media thickness, triglycerides, total cholesterol, and systolic and diastolic blood pressure, but does not improve low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or quality-of-life indicators when compared with placebo (113601). The validity of this study is limited by the lack of statistical adjustment for multiple comparisons which can lead studies to erroneously show differences between treatment groups.
• Systemic lupus erythematosus (SLE). There is limited evidence on the oral use of turmeric in adults with lupus nephritis. Details: Preliminary clinical research in adults with lupus nephritis shows that taking turmeric 1.5 grams daily in three divided doses for 3 months reduces systolic blood pressure and improves kidney function when compared to baseline (81104). The validity of this finding is limited by the lack of a comparator group.
• Tuberculosis. It is unclear if oral turmeric is beneficial in patients receiving treatment for tuberculosis. Details: A small clinical study in adults receiving antituberculosis treatment shows that taking a formulation containing turmeric 0.5 grams and Tinospora cordifolia 0.5 grams twice daily for 4 months can reduce levels of Mycobacterium tuberculosis in the sputum and improve lesion healing when compared with antituberculosis treatment alone. Also, liver toxicity associated with the antituberculosis treatment seems to be reduced when administered with this formulation (80424). It is unclear if these effects are due to turmeric, Tinospora cordifolia, or the combination.
• Ulcerative colitis. It is unclear if oral or rectal turmeric, or its constituent, curcumin, is beneficial in adults with ulcerative colitis. Details: Although two small clinical studies in adults with ulcerative colitis show that taking oral turmeric extract 2-3 grams daily for 1-6 months improves the rate of remission and reduces relapse rate (79966,97423), a meta-analysis of these studies and one additional clinical study shows that turmeric does not improve remission rates when compared with placebo (99000). A specific product (Cur-Cure, Bara Herbs Inc) was used in some of these studies. Reasons for the conflicting findings are unclear, but may be due to small patient populations, concerns about blinding, and the inclusion of patients who were also taking immunomodulating drugs. It may also be due to differences in how a study measures remission. A meta-analysis of small clinical studies in patients with mild to moderate ulcerative colitis shows that adding oral curcumin 0.5-3 grams daily to standard treatment for 1-6 months may improve clinical remission rates, but not endoscopic remission rates, when compared with placebo (108872). However, the validity of this finding is limited by the small number of studies that evaluated endoscopic remission. A small clinical study shows that administering an enema form of turmeric extract (NCB-02, Himalaya Drug Company) as 20 mL, containing turmeric extract 140 mg, daily for 8 weeks increases response rate from 50% to about 93% and increases remission rate from about 31% to 71% when compared with placebo in patients with active ulcerative colitis. However, patients using the turmeric extract enema for shorter durations did not improve when compared with placebo (89729). Turmeric has also been investigated in combination with the Mediterranean diet. A small clinical trial shows that taking curcumin (VeNatura Curcumin Supplement) 800 mg twice daily while following the Mediterranean diet for 8 weeks is no more effective for improving ulcerative colitis symptom severity than following the Mediterranean diet without supplemental curcumin (113339).
• Uveitis. It is unclear if oral curcumin is beneficial for uveitis. Details: Observational research in patients with acute non-infectious uveitic macular edema shows that taking a specific hydrophilic curcumin product (Cucrcuwin, Diabec, Alfa Intes) 60 mg twice daily for 6 months, in conjunction with standard corticosteroid treatment, and then alone for an additional 6 months, modestly improves best corrected visual acuity, but not macular thickness or intraocular pressure, when compared with standard treatment alone for 6 months (107110).
• Wound healing. Although there is interest in using topical turmeric for wound healing, there is insufficient reliable information about the clinical effects of turmeric for this condition. More evidence is needed to rate turmeric for these uses.

(Read more about TURMERIC)

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

POSSIBLY SAFE ...when black pepper oil is applied topically. Black pepper oil is nonirritating to the skin and is generally well tolerated (11). ...when black pepper oil is inhaled through the nose or as a vapor through the mouth, short-term. Black pepper oil as a vapor or as an olfactory stimulant has been used with apparent safety in clinical studies for up to 3 days and 30 days, respectively (29159,29160,29161,90502). There is insufficient reliable information available about the safety of black pepper when used orally in medicinal amounts.

CHILDREN: LIKELY SAFE
when used orally in amounts commonly found in foods (11).

CHILDREN: POSSIBLY UNSAFE
when used orally in large amounts. Fatal cases of pepper aspiration have been reported in some patients (5619,5620). There is insufficient reliable information available about the safety of topical pepper oil when used in children.

PREGNANCY: LIKELY SAFE
when used orally in amounts commonly found in foods (11).

PREGNANCY: LIKELY UNSAFE
when used orally in large amounts. Black pepper might have abortifacient effects (11,19); contraindicated. There is insufficient reliable information available about the safety of topical pepper when used during pregnancy.

LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (11). There is insufficient reliable information available about the safety of black pepper when used in medicinal amounts during breast-feeding.

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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). Other clinical studies suggest that, when combined with vitamin D supplementation, calcium supplementation is not associated with an increased risk of CVD, CHD, or MI (93533,107231). 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, to consider total calcium intake from both dietary and supplemental sources (17484), and to combine calcium supplementation with vitamin D supplementation (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). Other clinical studies suggest that, when combined with vitamin D supplementation, calcium supplementation is not associated with an increased risk of CVD, CHD, or MI (93533,107231). 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, to consider total calcium intake from both dietary and supplemental sources (17484), and to combine calcium supplementation with vitamin D supplementation (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).

(Read more about CALCIUM)

LIKELY SAFE ...when used orally in amounts commonly found in foods. The typical diet supplies 2-24 mg of diindolylmethane daily (7170,7176,7664).

POSSIBLY SAFE ...when used orally and appropriately in medicinal doses. Diindolylmethane has been used with apparent safety at a dose of 45 mg daily for up to 6 months or at a higher dose of 100-140 mg daily for up to 3 months (47709,47729,93836,103830).

POSSIBLY UNSAFE ...when used orally in doses of 600 mg daily. In one clinical study, two cases of grade 3 asymptomatic hyponatremia were associated with taking diindolylmethane 600 mg daily (47729).

CHILDREN: LIKELY SAFE
when used orally in amounts commonly found in foods. The typical diet supplies 2-24 mg of diindolylmethane daily (7170,7176,7664).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods. The typical diet supplies 2-24 mg of diindolylmethane daily (7170,7176,7664). There is insufficient reliable information available about the safety of diindolylmethane when used in amounts greater than those found in foods during pregnancy and lactation; avoid using.

(Read more about DIINDOLYLMETHANE)

LIKELY SAFE ...when used orally and appropriately, short-term. Turmeric products providing up to 8 grams of curcumin have been safely used for up to 2 months (10453,11144,11150,17953,79085,89720,89721,89724,89728,101347)(81036,101349,107110,107116,107117,107118,107121,109278,109283,114899) and products providing up to 1500 mg of curcumin daily have been safely used for up to 12 months (114898). Additionally, turmeric in doses up to 3 grams daily has been used with apparent safety for up to 3 months (102350,104146,104148,113357,114906). ...when used topically and appropriately (11148).

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

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

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

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

(Read more about TURMERIC)

AMOXICILLIN (Amoxil, Trimox) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the effects and side effects of amoxicillin.  Details Animal research shows that taking piperine, a constituent of black pepper, with amoxicillin increases plasma levels of amoxicillin (29269). This has not been reported in humans.

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the risk of bleeding when taken with antiplatelet or anticoagulant drugs.  Details In vitro research shows that piperine, a constituent of black pepper, seems to inhibit platelet aggregation (29206). This has not been reported in humans.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Animal research shows that piperine, a constituent of black pepper, can reduce blood glucose levels (29225). Monitor blood glucose levels closely. Dose adjustments might be necessary.

ATORVASTATIN (Lipitor) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase blood levels of atorvastatin.  Details Animal research shows that taking piperine, a constituent of black pepper, 35 mg/kg can increase the maximum serum concentration of atorvastatin three-fold (104188). This has not been reported in humans.

CARBAMAZEPINE (Tegretol) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, black pepper might increase blood levels of carbamazepine, potentially increasing the effects and side effects of carbamazepine.  Details One clinical study in patients taking carbamazepine 300 mg or 500 mg twice daily shows that taking a single 20 mg dose of purified piperine, a constituent of black pepper, increases carbamazepine levels. Piperine may increase carbamazepine absorption by increasing blood flow to the GI tract, increasing the surface area of the small intestine, or inhibiting cytochrome P450 3A4 (CYP3A4) in the gut wall. Absorption was significantly increased by 7-10 mcg/mL/hour. The time to eliminate carbamazepine was also increased by 4-8 hours. Although carbamazepine levels were increased, this did not appear to increase side effects (16833). In vitro research also shows that piperine can increase carbamazepine levels by 11% in a time-dependent manner (103819).

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the effects and side effects of cyclosporine.  Details In vitro research shows that piperine, a constituent of black pepper, increases the bioavailability of cyclosporine (29282). This has not been reported in humans.

CYTOCHROME P450 1A1 (CYP1A1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of drugs metabolized by CYP1A1.  Details In vitro research suggests that piperine, a constituent of black pepper, inhibits CYP1A1 (29213). This has not been reported in humans.

CYTOCHROME P450 2B1 (CYP2B1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of drugs metabolized by CYP2B1.  Details In vitro research suggests that piperine, a constituent of black pepper, inhibits CYP2B1 (29332). This has not been reported in humans.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of drugs metabolized by CYP2D6.  Details In vitro research suggests that some constituents of black pepper inhibit CYP2D6 (29207,29212,38375). This has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of drugs metabolized by CYP3A4.  Details In vitro research shows that piperine, a constituent of black pepper, as well as the pepper fruit seem to inhibit CYP3A4 (14375,29212). This has not been reported in humans.

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, black pepper might increase blood levels of lithium due to its diuretic effects. The dose of lithium might need to be reduced.  Details Black pepper is thought to have diuretic properties (11).

NEVIRAPINE (Viramune) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Black pepper might increase blood levels of nevirapine.  Details Clinical research shows that piperine, a constituent of black pepper, increases the plasma concentration of nevirapine. However, no adverse effects were observed in this study (29209).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of P-glycoprotein substrates.  Details In vitro research shows that piperine, a constituent of black pepper, seems to inhibit P-glycoprotein (14375,29281,29283).

PENTOBARBITAL (Nembutal) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the sedative effects of pentobarbital.  Details Animal research shows that piperine, a constituent of black pepper, increases pentobarbital-induced sleeping time (29214).

PHENYTOIN (Dilantin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Black pepper might increase blood levels of phenytoin.  Details Clinical research shows that piperine, a constituent of black pepper, seems to increase absorption, slow elimination, and increase levels of phenytoin (537,14442). Taking a single dose of black pepper 1 gram along with phenytoin seems to double the serum concentration of phenytoin (14375). Consuming a soup with black pepper providing piperine 44 mg/200 mL of soup along with phenytoin also seems to increase phenytoin levels when compared with consuming the same soup without black pepper (14442).

PROPRANOLOL (Inderal) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Black pepper might increase blood levels of propranolol.  Details Clinical research shows that piperine, a constituent of black pepper, seems to increase absorption and slow elimination of propranolol (538).

RIFAMPIN (Rifadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Black pepper might increase blood levels of rifampin.  Details Clinical research shows that piperine, a constituent of black pepper, seems to increase absorption and serum levels of rifampin (14375,29284).

THEOPHYLLINE Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Black pepper might increase blood levels of theophylline.  Details Clinical research shows that piperine, a constituent of black pepper, seems to increase absorption and slow elimination of theophylline (538).

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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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CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, diindolylmethane might lower serum levels of CYP1A2 substrates.  Details In vitro evidence suggests that diindolylmethane can induce CYP1A2 (7667,47745). Theoretically, it might increase metabolism of CYP1A2 substrates and lower serum concentrations. This interaction has not been reported in humans.

DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, diindolylmethane might increase the risk of hyponatremia if used with sodium-depleting diuretics.  Details Large doses of diindolylmethane (600 mg daily) have been associated with two cases of asymptomatic hyponatremia in clinical research (47729).

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, diindolylmethane might increase or decrease the effects of estrogens.  Details Diindolylmethane might have mild estrogenic or antiestrogenic effects (7664). Theoretically, large amounts of diindolylmethane might interfere with hormone replacement therapy.

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

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

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

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking turmeric with antidiabetes drugs might increase the risk of hypoglycemia.  Details Animal research and case reports suggest that curcumin, a turmeric constituent, can reduce blood glucose levels in patients with diabetes (79692,79984,80155,80313,80315,80476,80553,81048,81219). Furthermore, clinical research in adults with type 2 diabetes shows that taking curcumin 475 mg daily for 10 days prior to taking glyburide 5 mg decreased postprandial glucose levels for up to 24 hours when compared with glyburide alone, despite the lack of a significant pharmacokinetic interaction (96133). Other clinical studies in patients with diabetes show that taking curcumin daily can reduce blood glucose levels when compared with placebo (104149,114898,114900).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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General ...Orally, black pepper seems to be well tolerated when used in the amounts found in food or when taken as a medicine as a single dose. Topically and as aromatherapy, black pepper oil seems to be well tolerated.
Most Common Adverse Effects:
Orally: Burning aftertaste, dyspepsia, and reduced taste perception.
Inhalation: Cough.
Serious Adverse Effects (Rare):
Orally: Allergic reaction in sensitive individuals.

Gastrointestinal ...Orally, black pepper can cause a burning aftertaste (5619) and dyspepsia (38061). Single and repeated application of piperine, the active constituent in black pepper, to the tongue and oral cavity can decrease taste perception (29267). By intragastric route, black pepper 1.5 grams has been reported to cause gastrointestinal microbleeds (29164). It is not clear if such an effect would occur with oral administration.

Immunologic ...In one case report, a 17-month-old male developed hives, red eyes, facial swelling, and a severe cough following consumption of a sauce containing multiple ingredients. Allergen skin tests were positive to both black pepper and cayenne, which were found in the sauce (93947).

Ocular/Otic ...Topically, ground black pepper can cause redness of the eyes and swelling of the eyelids (5619).

Pulmonary/Respiratory ...When inhaled through the nose as an olfactory stimulant, black pepper oil has been reported to cause cough in one clinical trial (29162).

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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, diindolylmethane is generally well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, gas, headache, nausea, rash, and vomiting.
Serious Adverse Effects (Rare):
Orally: Drug rash with eosinophilia and systemic symptoms (DRESS).

Dermatologic ...Orally, diindolylmethane can cause rash (47615,93836). In one case report, a patient developed drug rash with eosinophilia and systemic symptoms (DRESS) after consuming a product containing diindolylmethane, vitamin E, and broccoli powder. An allergen patch test was positive for diindolylmethane (93840).

Endocrine ...Orally, diindolylmethane was associated with grade 3 asymptomatic hyponatremia in 2 of 4 patients taking 600 mg daily for 28 days in one clinical study. Hyponatremia was not seen in the 8 patients taking diindolylmethane 150-450 mg daily (47729).

Gastrointestinal ...Orally, diindolylmethane can cause nausea, vomiting, diarrhea, and gas (47652,47676,47709,47729,93836).

Genitourinary ...Orally, diindolylmethane can cause the urine to darken (93836).

Hematologic ...In one case report, a 65-year-old male developed a deep vein thromboembolism (DVT) and bilateral pulmonary emboli (PE) within a few weeks of initiating treatment with diindolylmethane. It is unclear if diindolylmethane contributed to this event; the patient was at increased risk for emboli due to his age, weight, tobacco use, and possible history of pulmonary embolism (93835).

Hepatic ...In one case report, a patient developed drug rash with eosinophilia and systemic symptoms (DRESS), involving elevated liver transaminases, after consuming a product containing diindolylmethane, vitamin E, and broccoli powder. An allergen patch test was positive for diindolylmethane (93840).

Immunologic ...In one case report, a patient developed drug rash with eosinophilia and systemic symptoms (DRESS) after consuming a product containing diindolylmethane, vitamin E, and broccoli powder. The patient developed fever, activated lymphocytes, and swollen lymph nodes. An allergen patch test was positive for diindolylmethane (93840).

Musculoskeletal ...Orally, diindolylmethane has been reported to cause arthralgias (47615).

Neurologic/CNS ...Orally, diindolylmethane can cause headache (47652,47676,93836). One case has reported ischemic stroke in a 38-year-old female with a history of a patent foramen ovale (PFO), traumatic subdural hematoma, right partial hemicraniectomy, and use of several supplements, including 200 mg of diindolylmethane daily, vitamin D3, vitamin K2, elderberry, caffeine, and possibly cannabis (112895). It is unclear if diindolylmethane contributed to this event; the patient was at increased risk for stroke due to PFO and other factors.

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

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

Dermatologic ...Following occupational and/or topical exposure, turmeric or its constituents curcumin, tetrahydrocurcumin, or turmeric oil, can cause allergic contact dermatitis (11146,79270,79470,79934,81410,81195). Topically, curcumin can also cause rash or contact urticaria (79985,97432,112117). In one case, a 60-year-old female, with no prior reactivity to regular oral consumption of turmeric products, developed urticaria after topical application of turmeric massage oil (97432). A case of pruritus has been reported following topical application of curcumin ointment to the scalp for the treatment of melanoma (11148). Yellow discoloration of the skin has been reported rarely in clinical research (113356). Orally, curcumin may cause pruritus, but this appears to be relatively uncommon (81163,97427,104148,114899). Pitting edema may also occur following oral intake of turmeric extract, but the frequency of this adverse event is less common with turmeric than with ibuprofen (89720). A combination of curcumin plus fluoxetine may cause photosensitivity (89728).

Gastrointestinal ...Orally, turmeric can cause gastrointestinal adverse effects (107110,107112,112118), including constipation (81149,81163,96135,113355), flatulence and yellow, hard stools (81106,96135), nausea and vomiting (10453,17952,89720,89728,96127,96131,96135,97430,112117,112118), diarrhea or loose stool (10453,17952,18204,89720,96135,110223,112117,112118,114898,114899), dyspepsia (17952,89720,89721,96161,112118), gastritis (89728), distension and gastroesophageal reflux disease (18204,89720), abdominal fullness and pain (81036,89720,96161,97430,114898,114899), epigastric burning (81444), and tongue staining (89723).

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

Neurologic/CNS ...Orally, turmeric has been associated with headache and vertigo (81163,114898).

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

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

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

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