Calcium Pyruvate by Natrol, Inc.

EFFECTIVE

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

LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

• Colorectal cancer. Oral calcium seems to be beneficial for preventing colorectal cancer, especially in those with adequate vitamin D levels and normal body mass index (BMI). Details: Population studies have found that increased intake of dietary or supplemental calcium is associated with a reduced risk of colorectal cancer and colorectal adenomas (1047,8820,12120,38951,98898,98899). Clinical trials and meta-analyses of clinical research also show that taking calcium supplements 1.2-2 grams daily for up to 4 years can reduce the risk of colorectal adenoma recurrence by up to 29% (970,12118,12950,15267,34596,38718,39042,95817). However, not all research has been positive. Some meta-analyses of clinical research or observational studies suggest that taking calcium does not reduce the risk of familial adenomatous polyposis or colorectal cancer (34596,39042,39349). Other contradictory research suggests that postmenopausal females who take calcium 1000 mg daily plus vitamin D 400 IU daily do not have a reduced risk of developing colorectal cancer (14290); however, this finding may not be reliable due to the high baseline intake of calcium in study participants. The reason for these conflicting findings is not entirely clear. Vitamin D might be an important factor. People with lower than average vitamin D levels do not seem to get any benefit from calcium supplements (12118). Also, one meta-analysis of previous trials suggests that taking calcium 1200 mg daily reduces the risk of colorectal adenomas in people with a normal BMI, but not in those who are overweight or obese (99715). Despite this conflicting evidence, the US Food and Drug Administration (FDA) approved a qualified health claim in 2005 stating that calcium supplements may reduce the risk of colorectal cancer and colorectal adenomas. However, the FDA has determined that there is little scientific evidence to support this claim (102366).
• Fetal bone mineralization. If calcium intakes are low during pregnancy, oral calcium seems to be beneficial for increasing fetal bone density. Details: With low dietary calcium intake (less than 562 mg elemental calcium daily) during pregnancy, calcium supplementation increases fetal bone mineralization and density. However, calcium supplementation does not offer any additional benefit if calcium intakes are adequate (3263,3264).
• Hypertension. Oral calcium seems to reduce blood pressure by a small amount. However, it is unclear if this reduction is clinically significant. Details: Many clinical trials and observational studies show that intake of calcium supplements or dietary calcium modestly reduces blood pressure in patients with or without hypertension, usually around 1-2 mmHg. Calcium seems to be more effective for certain subpopulations of patients, such as salt-sensitive people and patients with low baseline dietary calcium intake (945,972,974,976,984,1818,1819,1820,1821,6852)(13138,14406,38803,39063,39094,39221). Also, a meta-analysis of clinical research shows that calcium intake during pregnancy reduces systolic blood pressure in offspring by 1-2 mmHg (38852). However, a large-scale clinical trial in postmenopausal females shows that taking vitamin D (cholecalciferol) 400 IU daily in combination with elemental calcium 1000 mg daily does not lower blood pressure or reduce the risk of developing hypertension (16714). Additionally, a meta-analysis of 8 clinical trials shows that taking calcium in combination with vitamin D for up to 7 years has no effect on blood pressure (98861). The validity of this finding is limited by the poor methodological quality of the included studies. Some observational research suggests that calcium can reduce the risk for hypertension. Population research in females aged 45 years and older suggests that higher intake of calcium from both diet and supplement sources is linked to a lower risk of developing hypertension when compared to lower calcium intake (14265). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim stating that calcium supplements may reduce the risk of hypertension. However, the FDA has concluded that this claim is based on supporting, rather than conclusive, evidence (102367).
• Osteomalacia. Oral calcium seems to reverse osteomalacia caused by very low calcium intakes. Details: Osteomalacia is commonly caused by vitamin D deficiency; however, very low calcium intake can also lead to osteomalacia in children and adults. Calcium supplementation can reverse osteomalacia caused by calcium deficiency. Along with appropriate vitamin D supplementation, individuals at risk of osteomalacia need sufficient calcium intake (94819).
• Pre-eclampsia. Oral calcium seems to reduce the risk of pre-eclampsia in high risk pregnancies, especially if calcium intakes are low. Details: Although there is some conflicting evidence (971,38756), most clinical research shows that taking calcium orally 1-2 grams daily reduces pregnancy-related hypertension and pre-eclampsia (973,1833,8828,39043,39319,39426,96480). Calcium appears to reduce the risk of pre-eclampsia by about 50% when compared with placebo. One meta-analysis of 19 controlled trials involving over 29,000 pregnancies found that for every 19 females treated with calcium, one episode of pre-eclampsia would be avoided (96480). Calcium appears to have the greatest effect in individuals at high-risk of pre-eclampsia or with low calcium levels, and when taken at greater than or equal to 20 weeks of gestation (15029,38497,96480,99714). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim regarding the use of calcium supplements to reduce the risk of pregnancy-induced hypertension and pre-eclampsia. However, due to the limited and conflicting research available at that time, the FDA stated that this outcome was highly unlikely. Since then, large, high-quality clinical research has supported this finding. In fact, in 2016 the World Health Organization (WHO) released a recommendation to prescribe oral calcium supplementation 1.5-2 grams daily during pregnancies at high risk of pre-eclampsia if dietary calcium intakes are low, in order to prevent pre-eclampsia (97347).
• Rickets. Oral calcium seems to reverse rickets caused by very low calcium intakes. Details: Rickets is commonly caused be vitamin D deficiency; however, very low calcium intake can also lead to rickets. Calcium supplementation can reverse rickets caused by calcium deficiency (94819). A small clinical study in children with nutritional rickets shows that taking calcium 500-2000 mg daily for 24 weeks improves radiographically measured rickets caused by calcium deficiency. Rickets seems to improve more rapidly with calcium 1000 mg compared to calcium 500 mg. However, increasing the calcium dose to 2000 mg daily is not more beneficial than calcium 1000 mg daily (98904).
• Tooth retention. Oral calcium with vitamin D seems to help with tooth retention in the elderly population. Details: A clinical trial in the elderly population shows that taking calcium citrate malate 500 mg daily along with vitamin D3 (cholecalciferol) 700 IU daily orally for 3 years reduces the risk of tooth loss by about 52% when compared with placebo (8816).

POSSIBLY INEFFECTIVE

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

INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol use disorder. It is unclear if oral calcium is beneficial for alcohol use disorder. Details: Preliminary clinical research shows that taking calcium carbonate 800 mg and vitamin D 200 IU orally daily for 14 days modestly reduces alcohol craving scores and withdrawal scores when compared with placebo in adults with alcohol dependence that are undergoing withdrawal. Taking calcium carbonate did not reduce the need for diazepam; however, the study may have been inadequately powered to detect a difference between groups (107234).
• Atherosclerosis. It is unclear if oral calcium is beneficial for atherosclerosis. Details: A population study has found that taking calcium 1.2 grams daily for 3 years has no effect on carotid intima thickness or carotid atherosclerosis incidence. A total calcium intake (dietary and supplemental) of at least 1794 mg daily in older females may be associated with a decreased risk of carotid atherosclerosis when compared with a total calcium intake below 1010 mg daily (97351).
• Autism spectrum disorder. It is unclear if oral calcium during pregnancy is beneficial for reducing the odds of autism spectrum disorder in the offspring. Details: A small observational study found that calcium supplementation during pregnancy is associated with a 52% reduced odds of an autism spectrum disorder in the offspring (98900).
• Cancer. Oral calcium alone does not seem to prevent cancer. It is unclear if oral calcium with vitamin D is beneficial for preventing cancer. Details: Taking calcium alone does not seem to significantly reduce the risk of cancer (12118,15629). The role of calcium in cancer prevention when taken along with vitamin D is controversial, as conflicting results exist. One clinical trial shows that healthy postmenopausal females who take supplemental calcium 1400-1500 mg daily plus vitamin D3 (cholecalciferol) 1100 IU daily have a 60% lower relative risk for developing cancer of any type. Approximately 25 postmenopausal females would need to take this combination for 4 years to prevent one occurrence of cancer (15629). However, a more recent clinical study shows that healthy postmenopausal females who take supplemental calcium 1500 mg daily plus vitamin D3 (cholecalciferol) 2000 IU daily do not have a reduced risk of cancer at 4 years (93943). Reasons for the disparate results are not entirely clear. The discrepancies do not appear to be related to baseline vitamin D levels or different study populations. It is possible that, given the 10-year time lapse between the two publications, the discrepancies result from differences in cancer detection capability. Also, since cancer risk was a secondary outcome measure in the earlier study and a primary outcome measure in the more recent study, it is possible that the discrepancies result from differences in statistical methodologies. The effect of vitamin D and calcium on cancer risk in males and younger patients is not known. There is also interest in using calcium for reducing the risk of hematological malignancies. An analysis of the Women's Health Initiative study shows that taking calcium 1000 mg daily in combination with vitamin D3 400 IU for up to 10 years is associated with a 20% reduction in the risk of hematologic malignancies when compared with placebo. However, no effect on hematologic malignancy related mortality was seen (97354).
• Depression. It is unclear if oral calcium is beneficial for depression prevention. Details: Population research has found no association between a higher dietary intake of calcium and the risk of depression when compared with a lower dietary intake of calcium (96480).
• Diabetes. It is unclear if oral calcium is beneficial for type 2 diabetes prevention. Details: Some population research has found that a higher intake of calcium from diet or supplements, alone or in combination with vitamin D, is associated with a lower risk of developing type 2 diabetes when compared with lower calcium intake (14265,16713,96473). However, population research is often limited by confounding variables. For example, one analysis found that any beneficial effect might be influenced by concomitant magnesium intake (96473). Furthermore, other population research has found that serum calcium levels higher than 9.6 mg/dL are associated with greater risk of developing diabetes in Chinese adults with osteoporosis. This study is limited because it was not determined whether increased serum calcium was due to increased calcium intake or another factor such as parathyroid function (95815).
• Dysmenorrhea. It is unclear if oral calcium is beneficial for reducing pain associated with dysmenorrhea. Details: Clinical research shows that taking calcium carbonate 1000 mg with vitamin D 5000 IU daily for three menstrual cycles does not reduce pain when compared with placebo in patients with primary dysmenorrhea (95821). However, calcium carbonate 1000 mg taken alone seems to reduce pain when compared with placebo.
• Endometrial cancer. It is unclear if oral calcium is beneficial for endometrial cancer prevention. Details: A meta-analysis of population research suggests that calcium supplements may reduce the risk of endometrial cancer, but dietary calcium does not seem to have any effect (38893).
• Fall prevention. It is unclear if oral calcium with vitamin D is beneficial for preventing falls. Details: Research suggests that calcium in combination with vitamin D, but not calcium alone, might prevent falls by decreasing body sway and normalizing systolic blood pressure (6362,11939,39038). Some experts think the combination of calcium and vitamin D may be important (11916). Preliminary clinical research in adults residing in a health care facility shows that taking vitamin D supplements while increasing dietary calcium and protein for 2 years reduces falls by 11% when compared with standard diets. Intervention diets were supplemented with milk, yogurt, and cheese to provide calcium 1142 mg and protein 69 grams daily (107235). There might also be different effects in females compared to males. In one study, females aged 65 years or older who took vitamin D 700 IU plus calcium citrate 500 mg daily over a 3-year period had a 46% lower risk of falling. However, this combination did not decrease falls in males (14291).
• Fluorosis. Oral calcium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking calcium orally, in combination with ascorbic acid (vitamin C) and vitamin D, seems to be effective for reducing excessive fluoride levels in children and improving symptoms of fluorosis in children aged 6-12 years (990).
• Heart failure. It is unclear if oral calcium in combination with vitamin D is beneficial for preventing heart failure. Details: Based on a secondary analysis of a large-scale clinical trial (Women's Health Initiative), taking calcium 1000 mg with vitamin D 400 IU daily does not reduce the risk of heart failure in the overall population or in individuals at high risk. However, in a subgroup of postmenopausal females without risk factors for heart failure, calcium and vitamin D supplementation might reduce the risk of developing heart failure by about 37% (97307).
• Hypercholesterolemia. It is unclear if oral calcium is beneficial for hypercholesterolemia. Details: Some evidence shows that taking calcium carbonate 400 mg three times daily reduces low-density lipoprotein (LDL) cholesterol levels by 4% and increases high-density lipoprotein (HDL) cholesterol levels by 4% after 6 weeks of treatment when used in combination with a low-fat diet (American Heart Association Step 1) (2557). In contrast, a study in females with dyslipidemia shows that taking calcium 800 mg daily for 2 years might INCREASE total cholesterol levels by about 12 mg/dL when compared with placebo. This same study showed an association between calcium supplementation and an increase in total cholesterol levels and carotid intimal thickness in postmenopausal females, but not premenopausal females (97350). A recent meta-analysis of randomized controlled trials which included both healthy patients and patients with dyslipidemia shows that taking calcium 500-2000 mg daily and vitamin D 200-7142 IU daily modestly improves HDL cholesterol and triglyceride levels, but not LDL cholesterol levels, when compared with placebo. Subgroup analyses suggest that calcium and vitamin D supplementation is more effective in patients with dyslipidemia at baseline. It is unclear if this effect is due to calcium, vitamin D, or the combination (107227). However, other research shows that taking a specific supplement containing calcium 600 mg plus vitamin D 200 IU (Caltrate 600 D, Wyeth Consumer Healthcare Inc.) twice daily in combination with calorie restriction does not reduce total or LDL cholesterol levels when compared with placebo (15601).
• Lead toxicity. It is unclear if oral calcium is beneficial for reducing blood levels of lead. Details: Lead is mobilized along with calcium from bone during pregnancy and lactation, resulting in increased serum concentrations of lead. One clinical study suggests that calcium supplementation does not significantly decrease these elevated lead concentrations (1586). However, another clinical study suggests that taking calcium reduces blood lead levels by 11% when compared with placebo, with greatest effects observed in those with high baseline levels of lead (38957).
• Lyme disease. Although there is interest in using oral calcium for Lyme disease, there is insufficient reliable information about the clinical effects of calcium for this condition.
• Metabolic syndrome. It is unclear if oral calcium alone or with vitamin D is beneficial for metabolic syndrome prevention. Details: Population research has found that a higher intake of calcium from diet and supplements alone, or in combination with vitamin D, is associated with a lower risk of developing metabolic syndrome when compared with lower calcium intake (14265,16713).
• Nephrotic syndrome. It is unclear if oral calcium with vitamin D is beneficial for preventing nephrotic syndrome. Details: Clinical research shows that taking calcium 500-1000 mg daily for 3 months in combination with vitamin D3 60,000 IU daily or weekly for 4 weeks has no effect on bone mineral density or the risk of relapse in children with steroid-sensitive nephrotic syndrome (97355).
• Nonmelanoma skin cancer. It is unclear if oral calcium is beneficial for preventing keratinocyte carcinomas. Details: In middle aged and older adults recently diagnosed with a colorectal adenoma, clinical research shows that taking calcium 1200 mg daily as calcium carbonate for 3-5 years does not reduce the incidence of keratinocyte cancer when compared with placebo over a median of 8 years. A sub-group analysis shows that taking calcium alone or with vitamin D3 1000 IU daily reduced the risk of invasive cutaneous squamous cell carcinoma by a moderate amount, but had no effect on the risk of basal cell carcinoma (104622).
• Oral mucositis. When used in combination with fluoride treatments, a calcium phosphate mouth rinse seems to prevent and reduce mucositis-related pain in patients undergoing hematopoietic stem cell transplantation (HSCT). Details: A small clinical study in patients undergoing HSCT shows that using a particular mouth rinse (Caphosol, EUSA Pharma) containing calcium phosphate, in combination with fluoride treatments, reduces days of mucositis, the duration of pain, and the dose and days of morphine used when compared with placebo and fluoride treatment (38611).
• Ovarian cancer. It is unclear if oral calcium is beneficial for ovarian cancer prevention. Details: An older meta-analysis of 12 cohort studies found that dietary calcium intake is not associated with a reduced risk of ovarian cancer (38792). However, a more recent pooled analysis of 15 cohort and case-control studies has found that the highest intake of dietary or dairy calcium is associated with a 20% lower risk of ovarian cancer when compared to the lowest intake (97349).
• Postpartum depression. It is unclear if oral calcium is beneficial for reducing postpartum depression risk. Details: Preliminary clinical research shows that taking calcium 2 grams daily beginning at 11-21 weeks gestation reduces depression at 12 weeks postpartum when compared with placebo. However, no benefit is seen at 6 weeks postpartum (39447).
• Pregnancy-related leg cramps. It is unclear if oral calcium is beneficial for preventing leg cramps during pregnancy. Details: A small clinical study shows that taking calcium 1 gram twice daily (as a mixture of salts) for 2 weeks can reduce pregnancy-related leg cramps during the second half of pregnancy when compared with no treatment (2567).
• Prostate cancer. It is unclear if oral calcium is beneficial for prostate cancer prevention. Details: Some clinical research shows that taking calcium 1200 mg daily might decrease the risk of developing prostate cancer (14133). However, some epidemiological research suggests that consuming very high doses of calcium, over 2000 mg daily, might actually increase the risk of developing prostate cancer (14134). Some epidemiological research also suggests that doses greater than 1500 mg daily increase the risk of poorly differentiated, clinically advanced, and fatal prostate cancer (14132). Consumption of dairy products has also been weakly linked to a modest increase in risk of prostate cancer (98894). However, contradictory research suggests that there is no association between dietary intake of calcium and overall risk of prostate cancer (14131,14132,104630).
• Stroke. It is unclear if oral calcium is beneficial for stroke prevention. Details: Some population research has found that increasing dietary calcium intake is associated with a decreased risk of ischemic stroke (4822,38678). However, other population research has found that increasing dietary calcium intake is not associated with a decreased risk of stroke (91350). One meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years does not affect the risk of stroke when compared with control. However, the majority of the included research evaluated postmenopausal females, and it is unclear if this finding is applicable to other populations (107233).
• Vertigo. Oral calcium with vitamin D might reduce positional vertigo; the effect of calcium when used alone is unclear. Details: A large clinical study in adults with recurrent benign paroxysmal positional vertigo shows that taking calcium 500 mg and vitamin D 400 IU twice daily for one year reduces annual recurrence of vertigo by 27% when compared with no treatment. The number needed to treat to prevent vertigo was 3.7 (103681). It is unclear if this benefit is due to vitamin D, calcium, or the combination. More evidence is needed to rate calcium for these uses.

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LIKELY EFFECTIVE

• Diabetic neuropathy. Applying a specific prescription patch containing capsaicin 8% or a specific cream containing capsaicin 0.075% can reduce pain in diabetic neuropathy. Details: Clinical research has evaluated the use of a specific patch (Qutenza, NeurogesX Inc.) containing capsaicin 8%, which is approved as a prescription medication by the US Food and Drug Administration (FDA) for the treatment of diabetic peripheral neuropathy. The research in this population shows that a single application of the patch on the painful parts of the feet for 30-90 minutes following pretreatment with topical anesthetics reduces pain for up to 12 weeks when compared with placebo (40719,96453). Patients using the patch experience reduced sleep interference and an average 28% reduction in pain, compared with a 21% reduction with placebo. Additionally, 50% of patients receiving the patch experience pain relief within 19 days, compared to 72 days for those receiving placebo (96453). A meta-analysis of the available clinical research for diabetic peripheral neuropathy found that one-time application of this patch is equally effective to duloxetine 20-120 mg daily, pregabalin 75-600 mg daily, and gabapentin 300-3600 mg daily in producing a 30% or 50% pain reduction. The dose of oral medication used in the evaluated studies did not impact the comparative efficacy of the capsaicin patch (96450). Other clinical research shows that applying cream containing capsaicin 0.075% four times daily for 8 weeks reduces pain intensity when compared with placebo in patients with diabetic peripheral neuropathy (40547,40592,40607). A meta-analysis of clinical research shows that applying cream containing capsaicin 0.075% reduces pain similarly to 5% lidocaine-medicated plaster (40674). Topical cream containing capsaicin 0.075% (Zostrix-HP, Link Medical Products Pty Ltd.) is FDA-approved as an over-the-counter (OTC) medication for this indication (272). However, applying a capsaicin lotion less frequently or with a lower concentration of capsaicin does not seem to be beneficial. A small clinical study in patients with diabetic neuropathy shows that applying a specific lotion (Capsika-75 lotion, Bangkok Drug Company) containing capsaicin 0.075% three times daily for 8 weeks improves pain to a similar degree as a placebo lotion (102277). This study was limited by a high dropout rate, high placebo effect, and poor adherence to therapy. Furthermore, cream or gel (such as Capsika-25 gel, Bangkok Drug Company) containing lower amounts of capsaicin do not appear to be effective for reducing diabetic peripheral neuropathy pain (92984).
• Pain (chronic). Topical cream containing capsaicin can reduce chronic pain associated with various conditions. Topical capsaicin is FDA-approved for this use. Details: Several clinical studies show that topically applying cream containing capsaicin, the active capsicum constituent, 0.05% to 0.075% temporarily relieves chronic pain from rheumatoid arthritis, osteoarthritis, back pain, jaw pain, psoriasis, and neuropathic conditions (12401,17701). Capsaicin, used in topical preparations, is FDA-approved for these uses (272). It can take up to 14 days for the full analgesic effect. For neuropathic pain, the number needed to treat using capsaicin 0.075% for eight weeks is 5.7 (12401). For musculoskeletal pain, for every 8.1 patients treated with capsaicin 0.025%, 1 patient would achieve at least a 50% reduction in pain (12401). Also, applying capsaicin 0.05% (Finalgon CPD Warmecreme) three times daily for 21 days seems to cause a 49% reduction in chronic soft tissue pain when compared with placebo (17701).
• Postherpetic neuralgia. Applying a specific prescription patch containing capsaicin can reduce postherpetic neuralgia pain, especially in patients with the lowest pain scores. Details: Clinical research has evaluated the use of a specific patch (Qutenza, NeurogesX Inc.) containing capsaicin 8%, which is approved as a prescription medication by the US Food and Drug Administration (FDA) for the treatment of postherpetic neuralgia. Research in this population shows that applying a single patch for 60-90 minutes reduces average pain over 24 hours by 27% to 37% for up to 12 weeks, compared to only 4.4% to 26% in patients in the control group (40659,40679,40686,40691,40719,40728,40800,92985,96451,96452). The number needed to treat to achieve at least a 30% or 50% reduction in pain intensity is 10 and 12, respectively; the number needed to treat to achieve an additional beneficial outcome over placebo at 8 weeks and 12 weeks is 9 and 7, respectively (40800,96451). The pain reduction with this patch has an onset of a few days after treatment and the effect lasts for about 5 months (92986). However, some evidence shows that the reduction in pain is only significant for patients who have had postherpetic neuralgia for at least 6 months (40686). Additionally, the reduction in pain and duration of response appears to be greatest for patients with lower pain scores and low sensitivity to light touch at baseline, as well as patients not using concomitant systemic neuropathic pain medications, whereas patients with high pain scores, high sensitivity to touch, or those using systemic neuropathic pain medications experience the smallest and least sustained reduction in pain (40728,96458). Also, other evidence suggests that this patch may be less effective at relieving postherpetic neuralgia when compared with 5% lidocaine-medicated plaster (40688).

POSSIBLY EFFECTIVE

• Back pain. Topical capsicum or capsaicin seems to be beneficial for reducing back pain. Details: A meta-analysis of generally low-quality clinical research, as well as individual studies, show that applying a capsicum-containing plaster providing 11 mg of capsaicin per plaster or 22 mcg of capsaicin per square centimeter of plaster to the back once daily in the morning for 4-8 hours reduces low back pain when compared with placebo (15259,15260,15261). Applying capsaicin 0.05% (Finalgon CPD Warmecreme) three times daily for 21 days seems to cause a 58% reduction in low back pain when compared with placebo (17701). Also, in a mixed group of patients with acute back or neck pain, a large clinical trial shows that four topical applications with a gel containing capsaicin 0.075% with diclofenac 2% every 12 hours modestly reduces pain on motion when compared with diclofenac alone or placebo. The number of patients with at least a 50% reduction in pain from baseline was modestly higher. Capsaicin 0.075% was similarly effective alone and when combined with diclofenac 2% (105202). However, only about half of the patients in this study had back pain.
• Cluster headache. Intranasal capsaicin seems to be beneficial for preventing cluster headaches. Its effect in the treatment of cluster headache is unclear. Details: Some clinical research shows that using the capsicum constituent capsaicin intranasally reduces the frequency of episodic or chronic cluster headache attacks (14323,14351,14352,14358). Capsaicin suspensions of 0.1 mL of a 10 mM suspension, providing 300 mcg/day of capsaicin, has been applied to the ipsilateral nostril. Applications are continued once daily until a burning sensation is no longer experienced (14351,14358). Intranasal application of capsaicin 0.025% (Zostrix, Rodlen Laboratories) might also decrease symptom severity during an acute cluster headache attack. Clinical research shows that daily treatment for 7 days decreases symptom severity over the following week (14353). Ipsilateral, or same side, nostril application of capsaicin appears to be more effective than contralateral application (14351). Due to severe pain associated with intranasal capsaicin administration, pretreatment with intranasal local anesthetic is usually used.
• Nonallergic rhinitis. Intranasal capsaicin in a dose of at least 0.1 mM seems to improve symptoms of nonallergic rhinitis. It is unclear if lower doses of capsaicin are beneficial. Details: Clinical research shows that repeated intranasal in-clinic treatments with capsaicin, the active capsicum constituent, or with capsicum oleoresin, over a period of one to three days, can significantly decrease symptoms of non-allergic, non-infectious perennial rhinitis symptoms (14328,14357,15016,40595,105204,105205). A decrease of symptoms has been observed for up to 6-9 months following these treatments (14328,14357). The following doses have been used: capsaicin 0.15 mg per dose for up to 7 doses over a 14-day period (14328), capsaicin 0.0033 mol once weekly for 5 weeks (14357), capsaicin 15 mcg/0.1 mL applied three times daily for 3 days (15016), and capsaicin 1-4 mcg per puff, applied 3 times in each nostril daily for 3 days (40595). Due to severe pain associated with intranasal capsaicin administration, pretreatment with intranasal local anesthetic is usually used. Personal use of an intranasal spray with a lower dose of capsaicin might also be effective. Clinical research shows that two 0.4 mL puffs with an intranasal spray in each nostril daily for 4 weeks providing capsaicin 0.01 mM, but not 0.001 mM, is more effective than placebo for reducing symptoms of idiopathic rhinitis. This benefit is maintained for an additional 8 weeks. This protocol was at least as effective as receiving five repeated hourly intranasal spray treatments in hospital with capsaicin 0.1 mM (105204).
• Osteoarthritis. The American College of Rheumatology (ACR) conditionally recommends topical capsaicin for knee osteoarthritis, but not for hip or hand osteoarthritis. Details: A meta-analysis of 4 preliminary clinical trials shows that using topical capsaicin 0.025% four times daily has modest benefit for osteoarthritis when compared with placebo. Using capsaicin 0.0125% doesn't seem to be effective (102408). The American College of Rheumatology (ACR) conditionally recommends topical capsaicin for knee osteoarthritis. However, it does not recommend its use for hip osteoarthritis due to the depth of the joint beneath the skin surface, nor for hand osteoarthritis, due to the risk for contamination of the eye (102114).
• Pain (acute). Topical capsicum seems to be beneficial for reducing acute pain due to trauma. Details: Clinical research in patients with trauma-related acute pain shows that topical application with a gel (Sanli Gel) containing capsaicin 0.05% three times daily for 3 days reduces pain by at least 50% in 87% of patients, compared with 63% of those using a piroxicam gel 0.5% (Felden). There was also a significantly greater number of patients with a final pain score of 4 or less. In the capsaicin group, only 12% of patients did not achieve either of these endpoints, compared with 31% in the group receiving piroxicam (105197).
• Postoperative nausea and vomiting (PONV). Applying topical capsicum to acupoints seems to be beneficial for preventing PONV. Details: Clinical research shows that applying a capsicum-containing plaster to acupoints on the hand and forearm 30 minutes prior to anesthesia and leaving in place for 6-8 hours daily for up to 3 days after surgery reduces the incidence of PONV by about 29% to 36% when compared to control (40405,40483,40610). Plasters used in these studies included Sinsin PAS (Sinsin Pharm Co.), which is standardized to contain capsicum 345.8 mg and capsicum tincture 34.58 mg per sheet (40405,40610); and Johnson's Perforated Capsicum Plaster (Johnson & Johnson Ltd.), which is standardized to contain capsicum oleoresin 1% w/w (40483).
• Postoperative pain. Applying topical capsicum-containing plaster to acupoints seems to be beneficial for reducing postoperative pain. It is unclear if a capsicum patch or capsaicin instillation prior to wound closure is beneficial for reducing postoperative pain. Details: Some clinical research shows that applying a capsicum-containing plaster to acupoints on the hands or near the knees of adults or children 30 minutes prior to anesthesia, and leaving in place for 6-8 hours daily for up to 3 days after surgery, reduces the amount of rescue analgesics needed by 29% to 39% within the first 24 hours and by 16% to 19% within the first 48 hours when compared to control (40405,40483,40520,40524,40610). The capsicum-containing plaster used in these studies (Sinsin PAS, Sinsin Pharm Co.) is standardized to contain capsicum 345.8 mg and capsicum tincture 34.58 mg per sheet (40520,40610). Other preliminary clinical research shows that applying a single patch containing the capsicum constituent capsaicin 8% (Qutenza, NeurogesX Inc.) for 30-60 minutes leads to an improvement in overall health status and an average 22% reduction in pain that lasts up to 12 weeks in patients with postoperative and posttraumatic neuropathic pain. Patches were applied to various parts of the body, including the legs, torso, feet, hands, arms, head, and neck, and the reduction in pain continued with the use of a second and third patch application. The validity of these findings is limited by the lack of a control group (96452). Other clinical evidence suggests that instilling capsaicin 15 mg during surgery immediately prior to wound closure reduces the need for pain medication for up to 2 weeks postoperatively when compared with placebo (40741).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). It is unclear if intranasal capsaicin is beneficial for preventing allergic rhinitis symptoms. Details: Preliminary clinical research shows that intranasal treatment with cotton wads soaked in the active capsicum constituent capsaicin 30 mcM, applied for 15 minutes and repeated over two days, reduces the severity of experimentally-induced allergic rhinitis. The severity of symptoms seems to be reduced for up to 2 months after treatment (14324). However, contradictory research shows that patients with allergic rhinitis caused by house dust mites do not have significantly improved symptoms after using a capsaicin solution providing 0.15 mg/dose for up to 7 doses over a 14-day period when compared with placebo (14360).
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). Although there is interest in using oral capsicum for ALS, there is insufficient reliable information about the clinical effects of capsicum for this condition.
• Athletic performance. It is unclear if oral capsaicin is beneficial for improving athletic performance; the available research is limited to small, conflicting studies. Details: Several small clinical studies in physically active young adults show that taking capsaicin might improve some measures of athletic performance, but results are mixed overall (99409,99410,102276,105191,105198,105200). A meta-analysis of these and several other small clinical studies shows that taking the capsicum constituents capsaicin or capsiate 45 minutes before exercise improves measures of muscular endurance but does not improve aerobic endurance when compared with placebo. Doses of the capsicum constituents ranged from 1.2-24 mg, with most studies assessing a single 12 mg dose (111515). The included studies have a number of methodological problems that limit the validity of the findings, such as a small sample size, short study duration, and insufficient blinding. Also, most of the study participants were male. Other small clinical studies not included in the meta-analysis also show conflicting results. One small clinical study in untrained young adults undergoing resistance training shows that taking capsiate, a capsaicin analog, 6 mg orally twice daily for 6 weeks improves upper body, but not lower body, weightlifting performance when compared with placebo (109024). However, another small clinical trial in experienced male athletes shows that taking cayenne (GNC Nature's Fingerprint Cayenne Herbal Supplement) 3 grams, providing capsaicin 25.8 mg, daily for 7 days does not improve sprint time, rate of perceived exertion, or muscle soreness over three days when compared with placebo (105206). Capsicum has also been evaluated in combination with other ingredients. One small clinical study in untrained males shows that taking a supplement containing capsicum extract 66.7 mg, caffeine 400 mg, black pepper extract 10 mg, and niacin 40 mg prior to exercising does not improve strength, time to exhaustion, or maximal oxygen consumption when compared with placebo (37873).
• Burning mouth syndrome. It is unclear if applying topical capsaicin in the mouth is beneficial for burning mouth syndrome. Details: Preliminary clinical studies show that using 15 mL of a mouth rinse containing the active capsicum constituent capsaicin 0.02% for 30 seconds daily for 7-21 days modestly decreases burning discomfort when compared to baseline in patients with burning mouth syndrome (92991,105195). Other preliminary clinical research shows that applying 0.5 mL of a gel containing capsaicin 0.01% or 0.025% to the tongue three times daily for 14 days modestly reduces pain when compared to baseline in patients with burning mouth syndrome. The gel is spread with a cotton swab, and no food or drink is consumed for 30 minutes after application (96456). The validity of these findings is limited by the lack of a control group, the small number of patients, and occasionally unclear statistical comparisons.
• Cancer. It is unclear if eating more chili is beneficial for preventing mortality due to cancer. Details: Population research has found that consuming chili more than four times weekly is not associated with a reduced odds of cancer mortality (105208). Also, other population research has found that any consumption of hot red chili peppers is not associated with a reduced odds of mortality related to cancer (105210).
• Cannabinoid hyperemesis syndrome (CHS). Preliminary clinical research suggests that topical capsaicin might be beneficial for reducing symptoms of CHS. Details: One small clinical study in adults presenting to an emergency department (ED) with CHS shows that applying 5 grams of a cream containing capsaicin 0.1% to the abdomen modestly reduces nausea severity at 60 minutes, but not 30 minutes, when compared with a placebo cream. Nausea was completely resolved in 29% of patients, compared with 0% of those using the placebo cream. However, there was no difference in vomiting at 30 or 120 minutes (105193). This study may not have been adequately powered to detect a difference in some of these outcomes. A meta-analysis of two small, low-quality studies involving the topical use of capsaicin on the abdomen, chest, and possibly back, shows that the mean time to resolution of symptoms was 326 minutes and the mean length of stay in the emergency department was 379 minutes. However, it is unclear how these times compare to the use of placebo or standard antiemetics. This study also conducted a systematic review of the available literature, which indicates that the creams most commonly used in research provide 0.025% to 0.1% capsaicin (105201). Two low-quality, retrospective reviews also suggest that capsaicin cream may be beneficial for CHS. A retrospective review of patients in the ED with CHS has found that applying capsaicin cream 0.025% is associated with a 39% shorter time to discharge when compared with control. Patients treated with capsaicin also required fewer additional rescue treatments when compared with control (109021). Another retrospective review of patients in the ED with CHS also suggests that capsaicin cream 0.025% modestly reduces abdominal pain when compared with baseline. However, 47% and 28% of patients, respectively, received additional antiemetics or an opioid after the use of the cream (105345).
• Cardiovascular disease (CVD). It is unclear if eating more chili is beneficial for preventing mortality due to CVD. Details: Population research has found that consuming chili more than four times weekly is associated with a 34% reduced odds of CVD mortality when compared with never or rarely consuming chili, as well as 44% and 61% reduced odds of ischemic heart disease and cerebrovascular death, respectively (105208). Other population research has found that consumption of hot red chili peppers is not associated with a reduced odds of mortality related to CVD when compared with not eating hot red chili peppers (105210).
• Diabetes. It is unclear if oral capsaicin is beneficial for gestational diabetes. Details: Preliminary clinical research shows that taking chili powder containing capsaicin 5 mg daily for 4 weeks modestly reduces total cholesterol levels and reduces postprandial blood glucose levels by an average of 36 mg/dL and postprandial insulin levels by an average of 14 IU/L in patients with gestational diabetes. Compared to a placebo group, these changes are significant. However, capsaicin intake does not alter fasting plasma glucose or insulin levels (96457).
• Dry skin. It is unclear if oral capsicum is beneficial for dry skin. Details: Preliminary clinical research in adult females with low skin moisture shows that taking paprika oil extract 400 mg, standardized to include 9 mg of xanthophyll, orally daily for 4 weeks improves skin moisture and viscoelasticity scores, but not the number of wrinkles, when compared with control (109026).
• Dyslipidemia. It is unclear if oral capsicum is beneficial for reducing lipid levels. Details: A meta-analysis of three or four mainly small clinical trials in healthy adults shows that taking capsicum does not improve levels of triglycerides, total cholesterol, or high-density lipoprotein (HDL) cholesterol when compared with no treatment or placebo. However, there was a small to moderate effect on levels of low-density lipoprotein (LDL) cholesterol. Freshly chopped chili or fermented red pepper were studied for 4 and 12 weeks, respectively (105194). It is unclear if capsicum can lower lipid levels in patients with dyslipidemia or hyperlipidemia.
• Dyspepsia. It is unclear if oral capsicum is beneficial for dyspepsia. Details: Preliminary clinical research shows that taking red pepper powder 2.5 grams daily in three divided doses for 5 weeks reduces symptoms of functional dyspepsia when compared with placebo. However, in some patients, there seems to be a worsening of symptoms prior to any improvement (12410).
• Fibromyalgia. It is unclear if oral capsicum is beneficial for fibromyalgia. Details: Preliminary clinical research shows that applying cream containing the active capsicum constituent capsaicin 0.025% four times daily to tender points for 4 weeks reduces localized tenderness in patients with fibromyalgia (7038). Other preliminary clinical research shows that applying capsaicin 0.075% cream (Sensedol) three times daily to tender points for 6 weeks in addition to standard therapy increases the pain threshold when compared with standard therapy in patients with severe fibromyalgia (92979). However, capsaicin does not appear to reduce overall pain or improve physical function in patients with fibromyalgia (7038,92979). Also, the long-term effects of capsaicin on fibromyalgia-related pain are unclear.
• Gastroesophageal reflux disease (GERD). Although there is interest in using oral capsicum for GERD, there is insufficient reliable information about the clinical effects of capsicum for this condition.
• HIV/AIDS-related peripheral neuropathy. It is unclear if topical capsaicin is beneficial for this condition. Details: There is conflicting evidence regarding the effects of Qutenza (NeurogesX Inc.), which contains the active constituent of capsicum, capsaicin 8%. Although some research shows it reduces pain in patients with HIV and peripheral neuropathy (22395), other research shows no significant benefit (40746). A meta-analysis of results from both of these studies shows that applying a single capsaicin 8% patch for 30-90 minutes reduces pain intensity by at least 30% in about 30% more patients when compared to control (40800). Additional meta-analyses of the results from these two studies suggests that pain reduction with capsaicin begins a few days after treatment and lasts for about 5 months, with a number needed to treat of 11 to achieve at least a 30% reduction in pain intensity (92986,96451). Reduction in pain and duration of response appears to be greatest for females with lower pain scores at baseline, whereas males with high pain scores at baseline experience the smallest and least sustained reduction in pain (96458). Some research has also evaluated topical capsaicin 0.075%. One small clinical study shows that applying this cream does not relieve symptoms of HIV-associated peripheral neuropathy when compared with placebo (3891).
• Hypertension. It is unclear if oral capsicum is beneficial for lowering blood pressure. Details: Two meta-analyses of small clinical trials show that taking capsicum as freshly chopped chili, fermented red pepper, red pepper capsules, or capsinoid capsules orally daily for 4-12 weeks does not reduce systolic or diastolic blood pressure when compared with control. However, most subjects included in these clinical trials did not have hypertension (105194,109025).
• Intermetatarsal neuroma. It is unclear if injecting capsaicin into the third intermetatarsal space is beneficial for intermetatarsal neuroma. Details: Clinical research in adults with intermetatarsal neuroma shows that a single injection of capsaicin 0.1 mg into the third intermetatarsal space 5 minutes after administration of 2 mL of lidocaine 2% with epinephrine leads to a modest reduction in pain at weeks 1 and 4, but not weeks 2 and 3, when compared with placebo. Capsaicin also reduces the extent to which pain interferes with walking and mood, but not with work, sleep, relationships, or general activity (96454).
• Irritable bowel syndrome (IBS). It is unclear if oral capsicum is beneficial for IBS. Details: Preliminary clinical research shows that taking ground guajillo chili 1 gram, containing capsaicin 0.112%, with each meal for 7 days does not reduce symptoms of IBS (12403). A small clinical study shows that taking chili (Nguan Soon Co., Ltd.) 2.1 grams, providing 2.5 mg capsaicin, daily before meals for 6 weeks does not improve abdominal burning, fecal urgency, or abdominal pain or bloating after a spicy meal. However, there was a modest reduction in abdominal burning after a spicy meal (105207). This study may not have been adequately powered to detect a difference in some of these outcomes.
• Laryngitis. Although there is interest in gargling with capsicum for laryngitis, there is insufficient reliable information about the clinical effects of capsicum for this condition.
• Motion sickness. Although there is interest in oral capsicum for motion sickness, there is insufficient reliable information about the clinical effects of capsicum for this condition.
• Myofascial pain syndrome. It is unclear if topical capsaicin is beneficial for myofascial pain syndrome. Details: Preliminary clinical research shows that applying a specific capsaicin cream (Dipental Cream, Dalim BioTech) containing capsaicin 0.25 mg/gram along with a ketoprofen 30 mg patch (KetotopVRPlaster, Pacific Pharma) to the trapezius does not reduce pain when compared with a ketoprofen patch alone in patients with myofascial pain (92983).
• Neck pain. It is unclear if topical capsaicin is beneficial for neck pain. Details: In a group of patients with acute back or neck pain, a large clinical trial shows that four topical applications with a gel containing capsaicin 0.075% with diclofenac 2% every 12 hours modestly reduces pain on motion when compared with diclofenac alone or placebo. The number of patients with at least a 50% reduction in pain from baseline was modestly higher. Capsaicin 0.075% was similarly effective alone or when combined with diclofenac 2% (105202). However, only about half of the patients in this study had neck pain.
• Neuropathic pain. It is unclear if topical capsicum is beneficial for neuropathic pain. Details: A very small study in adults with neuropathic pain secondary to spinal cord injury shows that applying a patch containing the capsicum constituent capsaicin 8% for 60 minutes daily to the affected area for 12 weeks reduces pain at weeks 2 and 4 and improves mobility, but not quality of life, for up to 12 weeks when compared with placebo (111517). The validity of these findings is limited by insufficient blinding and the small sample size.
• Obesity. It is unclear if oral capsicum is beneficial for obesity. Details: A meta-analysis of 3-5 small clinical trials shows that taking capsicum does not reduce body weight, body fat, or body mass index (BMI) in individuals with a BMI of at least 25 kg/m2 when compared with placebo or no treatment. Freshly chopped chili, fermented red pepper, or capsicum constituents were studied for 4-12 weeks (105194). In one clinical trial included in the analysis, taking capsinoids 3 mg twice daily 30 minutes prior to eating for 12 weeks reduced abdominal fat by about 1%, but did not significantly reduce body weight, when compared with placebo (40599). In overweight individuals, one small clinical trial shows that taking a specific chili extract 200 mg, formulated with fenugreek dietary fiber for sustained release (Capsifen, Akay Natural Ingredients), providing capsaicinoids 4 mg daily for 28 days reduces body weight and BMI by about 2% when compared with placebo. There was no effect on blood pressure (105196). Capsicum has also been evaluated in combination with other ingredients, with some evidence of benefit. One study evaluated a combination product (Prograde Metabolism) containing capsicum extract (Capsimax, OmniActive Health Technologies), raspberry ketone (Razberi K, Integrity Nutraceuticals), caffeine, garlic root extract, ginger root extract, bitter orange fruit (Advantra Z, Nutratech Inc), L-theanine, and black pepper fruit extract (Biperine, Sabinsa Corporation) twice daily for 8 weeks (40802).
• Overall mortality. Eating chili may be beneficial for preventing mortality. It is unclear if taking capsicum supplements is beneficial for preventing overall mortality. Details: Population research has found that consuming chili is associated with a reduced risk of overall mortality. In one study, eating chili more than four times weekly was associated with a 23% reduced odds of overall mortality when compared with never or rarely consuming chili (105208). Other population research has found that any consumption of hot red chili peppers is associated with a 13% reduced odds of mortality when compared with not eating these peppers (105210). Also, eating spicy foods at least once each week, consisting mainly of fresh chili pepper, dried chili pepper, chili sauce, or chili oil, was associated with at least a 10% reduced risk of death when compared with eating these foods less than once a week (105211).
• Peptic ulcers. It is unclear if oral capsicum is beneficial for peptic ulcers. Details: Population research has found that eating capsicum fruit (chili) an average of 24 times per month is associated with a reduced likelihood of having an ulcer when compared with eating chili an average of 8 times per month. This applies to chili in the form of chili powder, chili sauce, curry powder, and other chili-containing foods (12053). However, clinical research shows that consuming chili peppers 1 gram three times daily for 4 weeks does not improve duodenal ulcer healing when compared to control (40828).
• Peripheral neuropathy. Preliminary clinical research suggests that topical capsaicin might be beneficial for reducing peripheral neuropathy pain. Details: Preliminary clinical research shows that applying patches containing the capsicum constituent capsaicin 8% (Qutenza, NeurogesX Inc.) reduces pain in people with non-diabetic peripheral neuropathy (96452,111516). Up to four patches, applied to different painful areas, are used at one time and are left in place for 30 minutes on the feet, or 60 minutes on other parts of the body such as the legs, torso, hands, arms, head, or neck (96452). After an interval of at least 90 days, treatment can be repeated, with new patches applied for 30-60 minutes (99407). There is an average 27% reduction in pain when compared to baseline, lasting up to 12 weeks (96452). Another similar study reported a decrease of 1 point, on a 10-point pain scale, in the typical daily pain intensity (99407). The validity of these findings is limited by methodological problems, including the lack of control groups. Further research shows that using a single application of up to four capsaicin 8% patches for 30-60 minutes, or taking pregabalin orally, 150-600 mg in 2-3 divided doses daily for 8 weeks, reduces the intensity and area of dynamic mechanical allodynia (DMA, pain evoked by light brushing of the skin) in people with non-diabetic peripheral neuropathy. Complete resolution of DMA occurred in 24% of people using the patches, and 12% of those taking pregabalin (99408). The validity of these findings is limited by methodological problems, including a lack of blinding.
• Prurigo nodularis. It is unclear if topical capsaicin is beneficial for prurigo nodularis. Details: Preliminary clinical research shows that applying a cream containing the active capsicum constituent, capsaicin 0.025% to 0.3%, 4-6 times daily improves burning sensations, erythema, pruritus, and healing of skin lesions over a period of 2 weeks to 33 months when compared to baseline. Symptoms may return after discontinuation of therapy (10650).
• Sinonasal polyposis. It is unclear if intranasal capsaicin is beneficial for sinonasal polyposis. Details: Preliminary clinical research in patients with severe sinonasal polyposis shows that intranasal application of 0.5 mL of a 30 mmol/L capsaicin solution to each nostril for 3 days, followed by 0.5 mL of a 100 mmol/L capsaicin solution for 2 days, can cause significant subjective improvement in symptoms as well as objective improvement in nose/sinus air volume and endoscopy scores; however, capsaicin does not seem to significantly affect eosinophil cationic protein levels (14359).
• Swallowing dysfunction. Preliminary research shows that oral capsaicin might be beneficial for improving swallowing ability. Details: Preliminary clinical research shows that elderly patients at risk for aspiration pneumonia due to swallowing dysfunction have improved swallowing reflexes after dissolving a lozenge containing capsaicin 1.5 mcg in the mouth before each meal when compared with using a placebo lozenge (13100). Preliminary clinical research also shows that capsaicin may be beneficial in patients with swallowing dysfunction due to stroke (102278,105192). One study shows that taking 1 mL of nectar containing capsaicin 150 mcM/L with each meal daily for 3 weeks, in addition to thermal tactile stimulation, improves eating and swallowing when compared with using thermal tactile stimulation and placebo nectar (102278). Another study shows that 20 minutes of stimulation with an ice swab containing capsaicin 0.15 mM before lunch and dinner daily for three weeks modestly improves the ability to swallow water when compared with ice stimulation alone. After treatment, approximately 70% of those using the capsaicin ice were able to drink the water without choking, compared with only 33% in those using ice alone (105192). Capsaicin solution has also been administered by nebulizer. A clinical study in patients with swallowing dysfunction secondary to hemorrhagic stroke shows that inhaling capsaicin solution twice daily for one week reduces the incidence of post-swallow residue and pulmonary infection and increases number of coughs in response to capsaicin compared with placebo. However, treatment with nebulized capsaicin does not reduce the number of patients with swallow or cough reflexes compared with control (111518). More evidence is needed to rate capsicum for these uses.

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POSSIBLY EFFECTIVE

• Acne. Application of a topical pyruvic acid skin peel may improve acne severity in some patients. Details: A large clinical trial in females with mild to moderate acne shows that applying a pyruvic acid 50% skin peel every 2 weeks for 10 weeks reduces acne severity when compared to baseline. Pyruvic acid showed similar improvements in acne severity while also improving skin oiliness when compared with an azelaic acid skin peel (108892).
• Obesity. Oral pyruvate may slightly reduce body weight in overweight and obese patients when combined with diet and/or exercise. Details: Several small clinical studies in patients with obesity or hyperlipidemia show that taking pyruvate 6-44 grams daily for up to 6 weeks in place of a portion of dietary carbohydrates and in combination with a low-calorie diet seems to help increase weight loss and decrease body fat (2472,2474,13658). However, a small clinical trial in overweight females shows that taking pyruvate 5 grams twice daily for 30 days while participating in a supervised exercise program does not reduce body weight when compared with placebo (13660). A meta-analysis of these studies shows that taking pyruvate 6-44 grams daily for up to 6 weeks reduces body weight by an average of 1.6 pounds when combined with varying diets and levels of exercise (92511).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol-related liver disease. It is unclear if intravenous sodium pyruvate is beneficial in patients with alcohol-related liver disease. Oral pyruvate has not been evaluated for this condition. Details: A very small clinical study in patients with alcohol-related liver disease shows that infusing sodium pyruvate 54-86.4 grams daily for 10 days and then 50-54 grams daily for 15 days improves markers of liver dysfunction, including aspartate aminotransferase, alanine aminotransferase, and bilirubin levels, when compared to baseline (70256). The validity of these findings is limited by the lack of a comparator group.
• Athletic performance. While research is mixed, most clinical evidence suggests that oral pyruvate does not improve athletic performance when taken alone. Details: A very small clinical study in well-trained cyclists shows that taking pyruvate 7 grams daily for one week does not improve time trial performance or measures of exercise capacity when compared with placebo (70255). Another small clinical study in American football players shows that taking pyruvate 0.22 grams/kg daily for 5 weeks does not improve jump height or peak cycling power when compared with placebo (13661). However, a small crossover trial in male soccer athletes shows that taking sodium pyruvate 0.1 gram/kg daily for one week improves repeated sprint exercise performance when compared with placebo (108893). Pyruvate has also been evaluated in combination with other ingredients. One small clinical study in well-trained cyclists shows that taking a combination of pyruvate and creatine 7 grams daily for one week does not improve endurance capacity or sprint performance when compared with placebo (13772). However, two very small clinical studies in untrained males show that consuming high-dose dihydroxyacetone plus pyruvate 25 grams daily for one week increases arm and leg exercise endurance when compared with placebo (807,808). It is unclear if these findings are due to pyruvate, dihydroxyacetone, or the combination.
• Atrophic acne scars. It is unclear if application of a topical pyruvic acid skin peel improves atrophic acne scars. Details: A small clinical study in adults with atrophic acne scars treated with microneedling shows that applying a pyruvic acid 25% peel once modestly improves acne scarring and patient- and physician-reported scores at 21 weeks when compared to baseline but not when compared with a trichloroacetic acid 15% peel (112174). The interpretation of these findings is limited by the short duration of follow-up, as certain scars may need an extended time for improvement.
• Atrophic acne scars. It is unclear if application of a topical pyruvic acid skin peel improves atrophic acne scars. Details: A small clinical study in adults with atrophic acne scars treated with microneedling shows that applying a pyruvic acid 25% peel once modestly improves acne scarring and patient- and physician-reported scores at 21 weeks when compared to baseline but not when compared with a trichloroacetic acid 15% peel (112174). The interpretation of these findings is limited by the short duration of follow-up, as certain scars may need an extended time for improvement.
• Cataracts. Although there has been interest in using oral pyruvate for cataracts, there is insufficient reliable information about the clinical effects of pyruvate for this purpose.
• Chronic obstructive pulmonary disease (COPD). It is unclear if inhaled sodium pyruvate is beneficial in patients with COPD. Details: A small clinical study in patients with moderate to severe COPD shows that inhaling nebulized sodium pyruvate 275 mcg three times daily for 6 weeks may improve lung function, as measured by forced expiratory volume in one second (FEV1), by up to 11% when compared with placebo (70278).
• Congestive heart failure (CHF). Small clinical studies suggest that intravenous pyruvate may improve measures of cardiac function in patients with CHF. Oral pyruvate has not been evaluated for this purpose. Details: Two very small, open-label clinical studies in patients with CHF show that infusing pyruvate 150-300 mmol/L into the left main coronary artery (for a total dose of 27-41.6 mmol pyruvate) may increase left ventricular ejection fraction (LVEF), increase cardiac index by 23%, increase stroke-volume index by 38%, and decrease pulmonary capillary wedge pressure by 36% when compared to baseline (70253,70262). The validity of these findings is limited by the lack of a comparator group.
• Glaucoma. Oral pyruvate has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with open-angle glaucoma and optic neuropathy shows that taking pyruvate and niacinamide, titrated to 3 grams of each, daily for 3 weeks increases the odds of pointwise improvement in visual function by 3.2-fold when compared with placebo. However, global visual field index and retinal nerve fiber thickness were not improved (107708).
• Hyperlipidemia. It is unclear if oral pyruvate is beneficial in patients with hyperlipidemia. Details: A small clinical study in patients with hyperlipidemia shows that supplementing a high-cholesterol, high-fat diet with pyruvate 36-53 grams daily in three divided doses for 6 weeks decreases total cholesterol by 4% and low-density lipoprotein (LDL) cholesterol by 5% when compared with placebo (70259).
• Ichthyosis. It is unclear if topical pyruvate is beneficial in patients with ichthyosis. Details: A small clinical study in patients with different types of ichthyosis shows that applying a Eucerin skin cream containing pyruvate 5% daily for at least 2 weeks increases shedding of scaly skin when compared with Eucerin alone (70285).
• Wrinkled skin. It is unclear if a topical pyruvic acid skin peel is beneficial in patients with wrinkled skin. Details: A small clinical study in patients with photodamaged facial skin shows that applying a pyruvic acid 50% skin peel once weekly for 4 weeks smooths skin, decreases fine wrinkles, and decreases hyperpigmentation when compared to baseline (12020). The validity of these findings is limited by a lack of control group. More evidence is needed to rate pyruvate for these uses.

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

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

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

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

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

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

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LIKELY SAFE ...when used orally in amounts typically found in food. Capsicum has Generally Recognized as Safe (GRAS) status in the US (4912). ...when used topically and appropriately (7038,10650,105345). The active capsicum constituent capsaicin is an FDA-approved ingredient used in certain over-the-counter, topical preparations (272).

POSSIBLY SAFE ...when used orally and appropriately, short-term in medicinal amounts. A specific sustained-release chili extract (Capsifen) has been used safely in doses of up to 200 mg daily, for up to 28 days (105196). ...when used intranasally and appropriately, short-term. Capsicum-containing nasal sprays, suspensions, and swabs seem to be safe when applied multiple times over 24 hours or when applied daily or every other day for up to 14 days. Although no serious side effects have been reported in clinical trials, intranasal application of capsicum-containing products can be very painful (14322,14324,14328,14329,14351,14352,14353,14356,14357) (14358,14359,14360,15016,105204). POSSIBLY UNSAFE when used orally, long-term or in high doses. There is concern that long-term use or use of excessive doses might be linked to hepatic or kidney damage, as well as hypertensive crisis (12404,40569,40606). There is insufficient reliable information available about the safety of capsicum when injected.

CHILDREN: POSSIBLY UNSAFE
when used topically in children under 2 years old (272). There is insufficient reliable information available about the safety of capsicum when used orally in children.

PREGNANCY: LIKELY SAFE
when used topically and appropriately (272).

PREGNANCY: POSSIBLY SAFE
when used orally and appropriately, short-term. Capsicum 5 mg daily has been used for up to 28 days during the latter half of the second trimester and the third trimester (96457).

LACTATION: LIKELY SAFE
when used topically and appropriately (272).

LACTATION: POSSIBLY UNSAFE
when used orally. Dermatitis can sometimes occur in infants when foods heavily spiced with capsicum peppers are ingested during lactation (739). Also, observational research suggests that intake of raw capsicum peppers during pregnancy is associated with an increased risk of sensitization to inhalant allergens in children by the age of 2 years (41021).

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POSSIBLY SAFE ...when used orally and appropriately, short-term. Pyruvate has been used with apparent safety as 6-40 grams daily, typically given in divided doses, for up to 6 weeks (2472,2474,13658,13660,13661,70255,70259,92512). ...when used topically and appropriately. There is some evidence that skin peels containing up to 50% pyruvic acid can be safely applied by a healthcare professional (12020,70285,108892). ...when nebulized and inhaled in recommended doses for up to 6 weeks (70278).

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

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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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ACE INHIBITORS (ACEIs) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, using topical capsaicin may increase the risk of ACE inhibitor-induced cough.  Details There is one case report of a topically applied capsaicin cream contributing to the cough reflex in a patient using an ACEI (12414). However, it is unclear if this interaction is clinically significant.

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, capsicum may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details In vitro research shows that capsicum might increase the effects of antiplatelet drugs (12406,12407). Also, population research shows that capsicum is associated with an increased risk of self-reported bleeding in patients taking warfarin (12405,20348). However, clinical research shows that taking a single dose of capsaicin (Asian Herbex Ltd.), the active ingredient in capsicum, 400-800 mcg orally in combination with aspirin 500 mg does not decrease platelet aggregation when compared with taking aspirin 500 mg alone. Also, there was no notable effect on measures of platelet aggregation with capsaicin (92990). It is unclear whether capsaicin must be used in more than a single dose to affect platelet aggregation.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking capsicum with antidiabetes drugs might increase the risk of hypoglycemia.  Details Preliminary clinical research shows that consuming capsicum 5 grams along with a glucose drink attenuates the rise in plasma glucose after 30 minutes by 21%, decreases the 2-hour postprandial area under the curve of plasma glucose by 11%, and increases the 2-hour postprandial area under the curve of plasma insulin by 58% in healthy individuals when compared with placebo (40453,40614). Other clinical research shows that taking capsicum 5 mg daily for 28 days significantly reduces postprandial blood glucose and insulin levels, but not fasting blood glucose and insulin levels, in patients with gestational diabetes (96457).

ASPIRIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking capsicum with aspirin might reduce the bioavailability of aspirin.  Details Animal research shows that acute or chronic intake of capsicum pepper reduces oral aspirin bioavailability (22617). This has not been shown in humans.

CIPROFLOXACIN (Cipro) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking capsicum with ciprofloxacin might increase levels and adverse effects of ciprofloxacin.  Details Animal research shows that concomitant use of capsaicin, the active constituent of capsicum, and ciprofloxacin increases the bioavailability of ciprofloxacin by up to 70% (22613).

THEOPHYLLINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking capsicum with theophylline might increase the levels and adverse effects of theophylline.  Details In animal research, oral administration of capsicum reduced excretion of theophylline (12405). However, capsicum does not seem to affect the pharmacokinetics of theophylline when administered intravenously (22616).

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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, capsicum is generally well tolerated in amounts typically found in food or when the extract is used in doses of up to 200 mg daily. Topically and intranasally, capsaicin, a constituent of capsicum, is generally well tolerated.
Most Common Adverse Effects:
Orally: Belching, bloating, burning, diarrhea, dyspepsia, gas, headache, mild constipation, nausea, rhinorrhea, skin flushing, and sweating.
Serious Adverse Effects (Rare):
Orally: Cases of myocardial infarction and hypertensive crisis have been reported.

Cardiovascular ...Orally, palpitation was reported in one clinical trial (105196).
One case of myocardial infarction has been reported in a 41-year-old male without cardiovascular risk factors; the event was attributed to the use of an oral capsicum pepper pill that the patient had been taking for weight loss (40768). Another case of coronary vasospasm and acute myocardial infarction has been reported for a healthy 29-year-old male; the event was attributed to the use of a topical capsicum-containing patch that the patient had been applying to the middle of the back for 6 days (40658). Two cases of arterial hypertensive crisis have been reported for individuals who ingested a large amount of peppers and chili peppers the day before. One of the patients also had an acute myocardial infarction, and the other had high levels of thyroid stimulating hormone (40569,40606).

Dermatologic ...Orally, capsicum or its constituent capsaicin may cause urticaria and skin wheals in rare cases (96457,105203).
Topically, capsicum can cause a prickling sensation, itching, pain, burning, edema, stinging, irritation, rash, and erythema. About 1 in 10 patients who use capsaicin topically discontinue treatment because of adverse effects. These effects seem to occur more often with topical formulations containing higher concentrations of capsaicin, the active constituent of capsicum. Side effects tend to diminish with continued use (12401,15260,15261,40358,40439,40483,40547,40676,40682,40719)(40784,40847,92979,92983,92984,96453,105193,105197,105202,111514). In one case, application of a capsaicin 8% patch (Qutenza) for 60 minutes caused a second-degree burn, characterized by burning, erythema, severe pain, and blistering at the administration site. The burn was treated with topical corticosteroids, but 9 months later neuropathic pain persisted, resulting in limited mobility. It is unclear whether the mobility sequalae were caused by topical capsaicin or the patient's pre-existing neurological disorders (111514). Skin contact with fresh capsicum fruit can also cause irritation or contact dermatitis (12408).
Intranasally, capsaicin can cause nasal burning and pain in most patients. It also often causes lacrimation, sneezing, and excessive nasal secretion; however, these side effects appear to diminish with repeat applications (14323,14329,14358). In some cases, the burning sensation disappears after 5-8 applications (14351,14358). In some cases, patients are pretreated with intranasal lidocaine to decrease the pain of intranasal capsaicin treatment. However, even with lidocaine pretreatment, patients seem to experience significant pain (14324).

Gastrointestinal ...Orally, capsicum can cause upper abdominal discomfort, including irritation, fullness, dyspepsia, gas, bloating, nausea, epigastric pain and burning, anal burning, diarrhea, mild constipation, and belching (12403,12410,40338,40427,40456,40503,40560,40584,40605,40665)(40718,40725,40745,40808,40828,96456,96457,105194,105196). There is a case report of a 3-year-old female who experienced a burning and swollen mouth and lips after touching the arm of a parent that had been treated with a capsaicin patch and then placing the fingers in the mouth (105199). Excessive amounts of capsaicin can lead to gastroenteritis and hepatic necrosis (12404). In a case report, a 40-year-old male with diabetes consumed white wine daily and chewed cayenne which was thought to result in black teeth stains and loss of enamel (40809). Some preliminary research links ingestion of capsaicin with stomach and gallbladder cancer; however the link may be due to contamination of capsaicin products with carcinogens (40771).
Topically, capsaicin can cause diarrhea and vomiting (105202).

Immunologic ...In a case report, a 34-year-old female had anaphylaxis involving difficulty breathing and stupor and also urticaria after consuming a red bell pepper, which is in the capsicum genus. The causal chemical was theorized to be 1,3-beta-glucanase (92978). In another case report, a 33-year-old female experienced angioedema, difficulty breathing and swallowing, and urticaria after ingesting raw green and red peppers (92982).

Neurologic/CNS ...Orally, capsicum can cause sweating and flushing of the head and neck, lacrimation, headache, faintness, and rhinorrhea (7005,12410,105196,105203). Topically, applying capsaicin can cause headache (96450,105202). Injection of capsaicin into the intermetatarsal space has also been associated with headache (96454).

Ocular/Otic ...Topically, capsicum can be extremely irritating to the eyes and mucous membranes. Capsicum oleoresin, an oily extract in pepper self-defense sprays, causes intense eye pain. It can also cause erythema, blepharospasm, tearing, shortness of breath, and blurred vision. In rare cases, corneal abrasions have occurred (12408,12409,40345,40348,40383,40720,40857).
Inhalation of capsicum can cause eye irritation, and allergic alveolitis (5885). In a case report, a 38-year-old female had acute anterior uveitis that developed about 12 hours after using a specific patch (Isola Capsicum N Plus) that contained capsaicin 1.5 mg per patch and methyl salicylate 132 mg per patch for neck pain. The uveitis was controlled with topical steroids and did not recur (92977).

Oncologic ...Population research suggests that moderate to high intake of capsaicin, the active constituent of capsicum, is associated with an increased risk of gastric cancer, while low intake is associated with a decreased risk. It is not clear from the study what amount of capsaicin is considered high versus low intake (92988). Additionally, some research suggests that any link may be due to contamination of capsaicin products with carcinogens (40771).

Pulmonary/Respiratory ...Orally, difficulty breathing was reported in a clinical trial (105196).
Topically, nasopharyngitis related to the use of a cream containing capsaicin has been reported (105202).
Inhalation of capsicum and exposure to capsicum oleoresin spray can cause cough, dyspnea, pain in the nasal passages, sneezing, rhinitis, and nasal congestion (5885,15016,40522,40546,40647). In rare cases, inhalation of the capsicum oleoresin or pepper spray has caused cyanosis, apnea, respiratory arrest and death in people. Death was caused by asphyxiation probably due to acute laryngeal edema and bronchoconstriction from inhalation of the capsicum oleoresin spray (40546,40672,40837,40879).
In a case report, a 47-year-old female who was exposed to capsaicin gas for more than 20 minutes experienced acute cough, shortness of breath, short-term chest pain, wheezing, and difficulty breathing for months afterwards (92980). In rare cases, exposure to capsicum oleoresin spray resulted in apnea, pulmonary injury, cyanosis, and even respiratory arrest (40383,40546).

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General ...Orally and topically, pyruvate seems to be well tolerated.
Most Common Adverse Effects:
Orally: Bloating, diarrhea, and flatulence.
Topically: Burning sensation at high concentrations.

Cardiovascular ...Orally, pyruvate may increase triglyceride levels. In a clinical trial, pyruvate 5 grams twice daily for 30 days before exercise caused a 28% increase in plasma triglycerides when compared with placebo. It is unknown if the increase was temporary or sustained (13660).
Intravenously, pyruvate has been associated with one death following a pyruvate-loading test in a child with restrictive cardiomyopathy (2473).

Dermatologic ...Topically, application of a facial peel containing pyruvic acid 50% can cause an intense burning sensation on the skin and should only be applied over small areas (12020).

Gastrointestinal ...Orally, pyruvate may cause bloating, diarrhea, flatulence, and loose stools. In a clinical trial, pyruvate 22-44 grams daily was associated with gas and bloating in 19% more subjects than placebo and loose stools or diarrhea in 12% and 35% more subjects than placebo, respectively (2474). In another clinical trial, diarrhea, flatulence, and loose stool occurred in 58% of subjects taking pyruvate and 28% of subjects taking placebo (70259).

Pulmonary/Respiratory ...Topically, application of a facial peel containing pyruvic acid 50% can release vapors that are irritating to the respiratory tract. The application should be conducted in a room with adequate ventilation (12020).

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