Red Clover Plus by Kordel's

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Calcium Hydrogen Phosphate Soya Bean extract • Red Clover extract • Wild Yam extract • Dong Quai extract • Agnus castus extract. Other Ingredients: Vegetable Cellulose Capsule, Vegetable Magnesium Stearate, Silicon Dioxide.

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Effectiveness view details

Below is general information about the effectiveness of the known ingredients contained in the product Red Clover Plus. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

CALCIUM (Calcium Hydrogen Phosphate)

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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DONG QUAI

INSUFFICIENT RELIABLE EVIDENCE to RATE

Atopic dermatitis (eczema). Although there is interest in using oral dong quai for atopic dermatitis, there is insufficient reliable information about the clinical effects of dong quai for this condition.
Chronic kidney disease (CKD). There is limited evidence on the use of dong quai in patients with CKD. Details: A large propensity score-matched observational study over 15 years in Taiwanese adults with CKD suggests that taking dong quai is associated with a 5.1% risk of end-stage renal disease (ESRD) and 38% risk of overall mortality when compared with 7% and 56%, respectively, in controls. Higher cumulative doses (i.e., 15 grams or more) and longer duration of exposure (i.e., > 60 days) are also associated with fewer ESRD events (112362). However, the interpretation of these findings is limited by the lack of exact dosage information and retrospective study design.
Coronary heart disease (CHD). Intravenous dong quai has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with CHD shows that injecting 20 mL of an intravenous solution containing dong quai, ginseng, and astragalus (Yi-qi Huo-xue Injection) daily for 2 weeks reduces the frequency and severity of angina episodes when compared with placebo. It also seems to increase exercise tolerance and improve left ventricular function when compared with placebo (33046). It is unclear if these benefits are due to dong quai, other ingredients, or the combination.
Dysmenorrhea. Although there is interest in using oral dong quai for dysmenorrhea, there is insufficient reliable information about the clinical effects of dong quai for this condition.
Hypertension. Although there is interest in using oral dong quai for hypertension, there is insufficient reliable information about the clinical effects of dong quai for this purpose.
Idiopathic interstitial pneumonia. Oral dong quai has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of 17 studies conducted in China in patients with idiopathic interstitial pneumonia concludes that adding traditional Chinese medicine combinations containing dong quai root and astragalus root to treatment with conventional medicines improves pulmonary function index, six-minute walking distance, and the Borg scale of perceived exertion when compared with conventional treatment alone (103618). The included studies are of low quality, include a range of treatment durations from 1-12 months, and vary in the conventional medicines and Chinese herb combinations used. The doses of dong quai used were not stated.
Infertility. Although there is interest in using oral dong quai for infertility, there is insufficient reliable information about the clinical effects of dong quai for this condition.
Iron deficiency anemia. Although there is interest in using oral dong quai for iron deficiency anemia, there is insufficient reliable information about the clinical effects of dong quai for this condition.
Menopausal symptoms. There is inconsistent and contradictory evidence about the effect of dong quai on menopausal symptoms. Benefits have only been seen when it is used in combination with other ingredients; its effect when used alone is unclear. Details: Some clinical research shows that taking dong quai, 1.5 grams three times daily for 24 weeks, does not affect menopausal symptoms (738). Other clinical research shows that dong quai improves menopausal symptoms when used in combination with other constituents. In one clinical trial, taking five chewable tablets of a specific combination of dong quai and chamomile (Climex) daily for 12 weeks reduced the frequency and severity of hot flushes when compared with placebo (48445). In another trial, taking a combination providing dong quai 75 mg, along with American ginseng, black cohosh, milk thistle, red clover, and vitex agnus-castus (Phyto-Female Complex) twice daily for 3 months reduces menopausal symptoms, including the number and intensity of hot flushes, the number of night sweats, and sleep quality (19552). Taking another combination product containing dong quai, burdock root, licorice root, motherwort, and Mexican wild yam root, 500 mg three times daily for 3 months, also reduces menopausal symptoms when compared with placebo (48522). It is unclear if the beneficial effects in these studies were due to dong quai, other ingredients, or a combination of ingredients.
Migraine headache. Oral dong quai has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with menstrual migraine shows that taking a combination of soy isoflavones 60 mg, dong quai 100 mg, and black cohosh 50 mg daily for 24 weeks reduces the frequency of attacks when compared with placebo (35797). It is unclear if this effect is due to dong quai, other ingredients, or the combination.
Osteoporosis. Although there is interest in using oral dong quai for osteoporosis, there is insufficient reliable information about the clinical effects of dong quai for this condition.
Peptic ulcers. Although there is interest in using oral dong quai for peptic ulcers, there is insufficient reliable information about the clinical effects of dong quai for this condition.
Premature ejaculation. Topical dong quai has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In one preliminary clinical trial in patients with premature ejaculation, a multi-ingredient cream preparation (SS Cream) containing dong quai, Panax ginseng root, Cistanches deserticola, Zanthoxyl species, Torlidis seed, clove flower, Asiasari root, cinnamon bark, and toad venom was applied to the glans penis 1 hour prior to intercourse and washed off immediately before intercourse. Patients using the cream had significantly improved ejaculatory latency when compared with placebo cream (2537). It is unclear if this effect is due to dong quai, other ingredients, or the combination.
Premenstrual syndrome (PMS). Although there is interest in using oral dong quai for PMS, there is insufficient reliable information about the clinical effects of dong quai for this condition.
Psoriasis. Although there is interest in using oral dong quai for psoriasis, there is insufficient reliable information about the clinical effects of dong quai for this condition.
Pulmonary hypertension. Preliminary clinical research shows that intravenous dong quai may be effective in patients with pulmonary hypertension. Details: Some preliminary clinical research in patients with chronic obstructive pulmonary disease (COPD) and pulmonary hypertension shows that intravenous administration of 250 mL of a solution containing dong quai 25%, once daily for 5-10 days, reduces pulmonary arterial pressure and pulmonary vascular resistance when compared to baseline (48438,48442,48443). The validity of these findings is limited by the lack of comparator groups.
Rheumatoid arthritis (RA). Although there is interest in using oral dong quai for RA, there is insufficient reliable information about the clinical effects of dong quai for this condition.
Stroke. Preliminary evidence does not support the use of intravenous dong quai for acute ischemic stroke. Details: Preliminary clinical research in patients with acute ischemic stroke shows that administering 200 mL of a solution containing dong quai 25% intravenously daily for 20 days does not improve neurological symptoms when compared with dextran-40 (48483). More evidence is needed to rate dong quai for these uses.

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RED CLOVER

INSUFFICIENT RELIABLE EVIDENCE to RATE

Androgenic alopecia. Topical red clover has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in individuals with androgenic alopecia shows that topical application of a combination of red clover flower extract and acetyl tetrapeptide-3 increases the growth phase of hair production by 13% and decreases the resting phase of hair production by 29% when compared to baseline (19540). The validity of these findings is limited by the lack of a comparator group.
Benign prostatic hyperplasia (BPH). Although there is interest in using oral red clover for BPH, there is insufficient reliable information about the clinical effects of red clover for this condition.
Breast cancer-related hot flashes. It is unclear if oral red clover is beneficial for reducing hot flashes in patients who have had breast cancer. Details: A small clinical study in breast cancer patients with menopausal symptoms due to tamoxifen therapy shows that taking red clover extract (Promensil Forte) 80 mg daily for 24 months does not reduce menopausal symptoms, including hot flashes, sleep disturbance, and fatigue, any more than placebo (102901).
Hyperlipidemia. It is unclear if oral red clover is beneficial in patients with hyperlipidemia; research is conflicting. Details: Most clinical trials in adult females with or without elevated cholesterol levels show that taking red clover extracts providing isoflavones 40-120 mg daily for 3 months to 1 year does not reduce total or low-density lipoprotein (LDL) cholesterol, or increase high-density lipoprotein (HDL) cholesterol, when compared with control (3375,8502,11089,11091,17091,19450,19543). However, a meta-analysis of 10 clinical trials in perimenopausal and postmenopausal patients with or without hyperlipidemia shows that red clover decreases total cholesterol by around 11 mg/dL, but does not affect LDL cholesterol, triglyceride, or HDL cholesterol levels, when compared with placebo (102840). This finding is limited by imprecision and inconsistency of the results and the fact that the benefit seems to be mostly attributed to two trials with a high risk of detection and performance bias. When this meta-analysis was repeated without those two trials, red clover supplementation for at least three months still shows a significant, albeit smaller, reduction in total cholesterol of around 4 mg/dL when compared with placebo among post-menopausal individuals. The meta-analysis also shows a small but statistically significant increase in HDL by approximately 1.5 mg/dL and no change in LDL or triglyceride levels (112145). Included studies were of moderate to high quality and lacked heterogeneity.
Mastalgia. It is unclear if oral red clover is beneficial in patients with mastalgia. Details: One very small study in patients with cyclic mastalgia shows that taking red clover isoflavones (Promensil, Novogen) 40-80 mg daily reduces subjective ratings of breast pain and tenderness. Reductions in pain were 44% with 40 mg and 31% with 80 mg, compared with 13% for placebo (9552).
Menopausal symptoms. It is unclear if oral red clover is beneficial for menopausal symptoms; research is conflicting and has notable methodological issues. Details: The most recent meta-analysis of 8 small clinical trials in patients with menopausal symptoms suggests that red clover reduces hot flash frequency by an average of 1.7 times when compared with control. The benefit tends to be greater in those with a higher frequency of hot flashes at baseline (5 or more) and when higher doses of red clover isoflavones are used (80 mg or more daily) (105694). However, this finding is limited by imprecision and inconsistency, as well as selective reporting bias in some of the included trials. An older meta-analysis of small, low-quality clinical studies in menopausal patients also suggests that red clover might improve psychological symptoms such as anxiety and depression when compared with control (91525). The most extensively studied product is a specific red clover supplement (Promensil or Melbrosin, Novogen). A meta-analysis of 5 small clinical studies assessing only Promensil shows that taking 80 mg daily for 12 weeks reduces hot flash frequency by 30% to 50%, or by about 3-4 hot flashes per day, when compared with placebo (96731). The validity of these findings is limited by imprecision, inconsistency, and publication bias. Notably, this meta-analysis and all included studies were funded by the supplement manufacturer (8925,10976,10991,17103,19545,96731). In contrast, studies with independent funding sources have not found a benefit with red clover isoflavones 40-120 mg daily for up to 12 months when compared with placebo (10975,17091,19549). Some research has also found benefit for menopausal symptoms when red clover is used in combination with other ingredients. Red clover has been used in combination with black cohosh, dong quai, milk thistle, American ginseng, and Vitex agnus-castus (Phyto-Female Complex) twice daily for 3 months (19552). Red clover isoflavones 37.1 mg have also been used in combination with a probiotic-rich liquid daily for 12 weeks (96730).
Osteoarthritis. It is unclear if topical red clover is beneficial in patients with osteoarthritis. Details: Preliminary clinical research shows that applying 20 drops of a standardized extract of red clover aerial parts to the knee twice daily for 4 weeks, in addition to taking meloxicam orally, improves subjective measures of pain and function more than using meloxicam plus placebo. However, radiological and laboratory changes were not evaluated (102839).
Osteoporosis. It is unclear if oral red clover is beneficial in patients with osteoporosis; research is conflicting. Details: One small clinical study in healthy postmenopausal patients shows that taking red clover providing isoflavones 57-85.5 mg daily for 6 months increases bone mineral density (BMD) of the proximal radius and ulna by 3% to 4% (10948). Another clinical study in females ages 49-65 years shows that taking a specific red clover extract (Promensil, Novogen) providing isoflavones 40 mg daily for one year does not increase BMD or bone mineral content (BMC) of the hip, but seems to slightly reduce the loss of lumbar spine BMD and BMC when compared with placebo (6127). However, other research has found no benefit. One clinical study in patients who are at least one year post-menopause and not taking bone preserving medications shows that taking a specific product containing enriched red clover isoflavones (Rimostil [formononetin enriched], Novagen) 50 mg daily for 2 years does not improve BMD of the spine, femoral neck, distal radius, or proximal radius when compared with placebo. However, this study may have been underpowered due to a high drop-out rate (91524). Another small clinical study in perimenopausal and postmenopausal adults shows that taking red clover flowering tops providing isoflavones 120 mg daily for one year does not seem to slow the loss of hip, femoral neck, or lumbar spine BMD when compared with placebo (17091). More evidence is needed to rate red clover for these uses.

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VITEX AGNUS-CASTUS (Agnus castus)

POSSIBLY EFFECTIVE

Mastalgia. Meta-analyses of small clinical studies show that vitex agnus-castus moderately reduces breast pain due to cyclic mastalgia. Details: Two small meta-analyses of low-to-moderate quality clinical studies in patients with cyclic mastalgia show that taking vitex agnus-castus moderately reduces breast pain when compared with placebo (101981,111753). The validity of these findings is limited by the heterogeneity of the included studies. Doses of vitex agnus-castus dried fruit extract range from 3.2-40 mg daily, for 2-6 months (90617,96250,101981,111753). Vitex agnus-castus is commonly used in proprietary products, alone or in combination with other herbs (Agnucaston/Cyclodynon, Bionorica AG, Femicur, Mastodynon, Bionorica AG, Monoselect Agnus, ZE 440) (13395).
Premenstrual syndrome (PMS). Clinical research shows that vitex agnus-castus produces modest improvements in PMS symptoms. Details: Clinical research shows that taking vitex agnus-castus fruit extract orally for 2-6 menstrual cycles seems to reduce symptoms of PMS, especially breast pain or tenderness (mastalgia), edema, constipation, irritability, depressed mood, anxiety, anger, and headache (7055,7076,7078,7079,13394,15065,41483,41489,41490,41494,90619,101981). Doses of fruit extracts have varied from 3.5-40 mg daily, usually for 2-3 menstrual cycles (7055,7076,7078,7079,15065,41483,41489,41490,90619,96435). A meta-analysis of the available clinical research, including 17 studies involving 2,401 patients, shows that taking vitex agnus-castus is comparable to fluoxetine or oral contraceptives, and modestly more effective than placebo, for reducing the symptoms of PMS. A sub-group analysis indicates that efficacy is not impacted by the dose or form used, although the dried powdered berries appear to be ineffective. The low quality of the included studies and the high level of bias and heterogeneity limit the validity of these findings (96435). Another meta-analysis limited to three randomized controlled trials shows that taking vitex agnus-castus increases the likelihood of PMS symptom remission by 2.6-fold over placebo (101979). Some clinical studies have used a specific dried extract of vitex agnus-castus fruit (Agnolyt, Madaus AG) (7076). Other studies used a specific fruit extract known as Ze 440 (Prefemin, Zeller AG), which is standardized to casticin content (7078,90619). Additional studies have used the fruit extract BNO 1095 (Agnucaston/Cyclodynon, Bionorica AG) (15065,41483,41489,41490).

POSSIBLY INEFFECTIVE

Fractures. Limited evidence suggests that vitex agnus-castus does not improve fracture healing rates. Details: Clinical research shows that taking a specific vitex agnus-castus dried fruit extract (Agnugol, Goldaru Pharmacy Company) 4 mg, alone or in combination with magnesium oxide (Nature Made Company) 250 mg, daily for 8 weeks does not improve long bone fracture healing when compared with placebo (90618).

INSUFFICIENT RELIABLE EVIDENCE to RATE

Acne. Although there is interest in using oral vitex agnus-castus for acne, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
Aging skin. Vitex agnus-castus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical trial in postmenopausal adults with wrinkles shows that taking one capsule orally daily of a combination of vitex agnus-castus 400 mg, evening primrose oil 500 mg, soy isoflavones 100 mg, and black cohosh 520 mg (Estosalus, Max Biocare Pty Ltd) for 12 weeks improves skin elasticity, skin smoothness, and wrinkle density scores when compared with placebo (109440).
Amenorrhea. Although there is interest in using oral vitex agnus-castus for amenorrhea, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
Anxiety. Although there is interest in using oral vitex agnus-castus for anxiety, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
Benign prostatic hyperplasia (BPH). Although there is interest in using oral vitex agnus-castus for BPH, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
Dementia. Although there is interest in using oral vitex agnus-castus for dementia, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
Dysmenorrhea. It is unclear if oral vitex agnus-castus is beneficial in patients with dysmenorrhea. Details: Preliminary clinical research in patients with primary dysmenorrhea shows that taking a specific vitex agnus-castus extract (Agnucaston, Bionorica AG) daily for 3 months reduces pain, as measured on a visual analog scale, similarly to ethinyl estradiol 0.03 mg / drospirenone 3 mg (Yasmin) taken daily (104975).
Fibrocystic breast disease. Although there is interest in using oral vitex agnus-castus for fibrocystic breast disease, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
Hyperprolactinemia. Although there is interest in using oral vitex agnus-castus for hyperprolactinemia, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
Infertility. It is unclear if oral vitex agnus-castus is beneficial for female infertility. Details: Preliminary clinical research in infertile females with oligomenorrhea or amenorrhea shows that taking homeopathic vitex agnus-castus (Phyto Hypophyson L, Steierl-Pharma GmbH) 50 drops orally three times daily for 3 months does not increase the chance of getting pregnant (41470). Also, one small clinical study in those with infertility due to secondary amenorrhea or luteal insufficiency shows that taking a vitex agnus-castus preparation (Mastodynon, Bionorica GmbH, Neumarkt/Opf.) 30 drops twice daily for at least 3 months does not increase the chance of pregnancy when compared with placebo, although the study was likely inadequately powered to detect a difference (7077).
Insect repellent. Limited research suggests that topical vitex agnus-castus has insect repellent activity. Details: Preliminary clinical research shows that applying a carbon dioxide extract of vitex agnus-castus seeds seems to repel ticks and fleas for 6 hours, mosquitoes for 3-8 hours, and biting flies for 3 hours (13396). It is unclear how this compares with commonly used insect repellants.
Insomnia. Although there is interest in using oral vitex agnus-castus for insomnia, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
Lactation. Although there is interest in using oral vitex agnus-castus for stimulating lactation, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
Menopausal symptoms. Clinical research suggests that vitex agnus-castus can relieve some menopausal symptoms; however, most research uses vitex agnus-castus in combination with other treatments. Details: Clinical research shows that taking vitex agnus-castus extract 15 mg twice daily for 8 weeks improves some menopausal symptoms, including anxiety and vasomotor dysfunction, by 76% and 88%, respectively, when compared with baseline. However, there was no effect on depression or sexual dysfunction (101980). Vitex agnus-castus has also been studied as a component of combination products. Preliminary clinical research shows that taking a combination of vitex agnus-castus, equivalent to 1000 mg dried fruit, black seed powder 500 mg, and citalopram 20 mg daily for 8 weeks reduces vasomotor, psychosocial, and physical symptoms of menopause when compared with citalopram alone (100325). Other preliminary clinical research shows that taking one capsule orally daily of a combination of vitex agnus-castus 400 mg, evening primrose oil 500 mg, soy isoflavones 100 mg, and black cohosh 520 mg (Estosalus, Max Biocare Pty Ltd) for 12 weeks moderately reduces the severity of hot flashes, sweating, sleep problems, depressed mood, and irritability when compared with placebo. There was no effect on plasma lipids, joint discomfort, anxiety, exhaustion, or sexual problems (105102). It is unclear if these effects are due to vitex agnus-castus, other ingredients, or the combination.
Menorrhagia. It is unclear if oral vitex agnus-castus is beneficial in patients with menorrhagia. Details: A meta-analysis of two moderate quality clinical trials in patients who had heavy menstrual periods shows that taking vitex agnus-castus does not reduce menstrual bleeding over the next 1-2 menstrual cycles when compared with placebo (101982). However, preliminary clinical research in patients using an intrauterine device (IUD) shows that taking vitex agnus-castus three times daily for 8 days, starting on the first day of menstruation, and repeated for four consecutive menstrual cycles, reduces the amount of bleeding by approximately 48% when compared with baseline. This reduction was similar to the effects of mefenamic acid 250 mg daily after 4 months, although treatment with mefenamic acid was superior during the first three months (90620).
Migraine headache. Although there is interest in using oral vitex agnus-castus for migraine headache, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
Polycystic ovary syndrome (PCOS). Vitex agnus-castus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with oligomenorrhea due to PCOS shows that taking a traditional combination product (Aslagh) containing equivalent amounts of essential oils of vitex agnus-castus fruit, fennel, and wild carrot seeds orally daily for 3 months, either alone or in combination with metformin, improves rates of menstrual bleeding and menstrual cyclicity similarly to metformin alone. All three groups experienced a significant improvement from baseline. Aslagh was taken as two, 500-mg capsules twice daily, except during menses; metformin was titrated over one week to a dose of 500 mg three times daily (108974).
Premenstrual dysphoric disorder (PMDD). Limited evidence suggests that vitex agnus-castus might improve symptoms of PMDD. Details: In a clinical trial, vitex agnus-castus 20-40 mg daily for 8 weeks was similar to fluoxetine 20-40 mg daily for relieving symptoms of PMDD. About 58% of patients responded to vitex agnus-castus, compared to about 68% of patients taking fluoxetine. Vitex agnus-castus was more effective for physical symptoms such as breast tenderness, swelling, cramps, and food cravings (12207,41493).
Rheumatoid arthritis (RA). Although there is interest in using oral vitex agnus-castus for RA, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
Sexual dysfunction. It is unclear if oral vitex agnus-castus is beneficial in patients with sexual dysfunction. Details: Preliminary clinical research in healthy females under 44 years of age with sexual dissatisfaction shows that taking a specific vitex agnus-castus product (Agnugol, Goldaru Herbal Pharmaceutical Company) 3.2-4.8 mg orally once daily for 16 weeks modestly improves scores of sexual satisfaction, function, arousal, and desire when compared with placebo (109437). Additionally, a moderate-sized clinical study in females 50-69 years old with sexual dysfunction conducted in Iran shows that taking vitex agnus-castus 40 drops daily for 8 weeks improves sexual dysfunction scores from mild dysfunction to no dysfunction at 6 and 8 weeks when compared with placebo but does not improve scores at 4 weeks (112361). More evidence is needed to rate the effectiveness of vitex agnus-castus for these uses.

WILD YAM

POSSIBLY INEFFECTIVE

Menopausal symptoms. Topical wild yam does not seem to improve menopausal symptoms. Details: Wild yam applied topically as a cream in menopausal patients for 3 months appears to be no better than placebo for relieving vasomotor symptoms, such as hot flashes and night sweats. It also does not appear to change serum follicle stimulating hormone (FSH), estradiol, or progesterone levels (10989).

INSUFFICIENT RELIABLE EVIDENCE to RATE

Cognitive function. It is unclear if oral wild yam is beneficial for improving cognitive function in healthy adults. Details: Preliminary clinical research in healthy adults shows that taking a specific wild yam extract (Diopower 15, Anti-Aging Pro Corporation) orally, 50 mg (containing diosgenin 8 mg) daily for 12 weeks, modestly improves overall measures of cognitive function and semantic fluency when compared with placebo (96724).
Dysmenorrhea. Although there is interest in using oral or topical wild yam for dysmenorrhea, there is insufficient reliable information about the clinical effects of wild yam for this condition.
Gallbladder disease. Although there is interest in using oral wild yam for gallbladder disease, there is insufficient reliable information about the clinical effects of wild yam for this condition.
Infertility. Although there is interest in using oral or topical wild yam for infertility, there is insufficient reliable information about the clinical effects of wild yam for this condition.
Osteoporosis. Although there is interest in using oral wild yam for osteoporosis, there is insufficient reliable information about the clinical effects of wild yam for this condition.
Postmenopausal conditions. Although there is interest in using oral wild yam for postmenopausal conditions, there is insufficient reliable information about the clinical effects of wild yam for these conditions.
Premenstrual syndrome (PMS). Although there is interest in using oral wild yam for PMS, there is insufficient reliable information about the clinical effects of wild yam for this condition.
Rheumatoid arthritis (RA). Although there is interest in using oral wild yam for RA, there is insufficient reliable information about the clinical effects of wild yam for this condition.
Sexual dysfunction. Although there is interest in using oral wild yam for sexual dysfunction, there is insufficient reliable information about the clinical effects of wild yam for this condition. More evidence is needed to rate wild yam for these uses.

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Safety view details

Below is general information about the safety of the known ingredients contained in the product Red Clover Plus. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

CALCIUM (Calcium Hydrogen Phosphate)

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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DONG QUAI

POSSIBLY SAFE ...when used orally and appropriately. Dong quai has been used with apparent safety in a dose of 4.5 grams daily for 24 weeks, or in combination with other ingredients in doses of up to 150 mg daily for up to 6 months (19552,35797). ...when used intravenously as a 25% solution, in a dose of 200-250 mL daily for up to 20 days (48438,48442,48443,48483).

POSSIBLY UNSAFE ...when used orally in large amounts, long-term. Theoretically, long-term use of large amounts of dong quai could be harmful. Dong quai contains several constituents such as bergapten, safrole, and isosafrole that are considered carcinogenic (7162). There is insufficient reliable information available about the safety of dong quai when used topically.

PREGNANCY: POSSIBLY UNSAFE
when used orally. Dong quai has uterine stimulant and relaxant effects (8142); theoretically, it could adversely affect pregnancy. Observational research has found that intake of An-Tai-Yin, an herbal combination product containing dong quai and parsley, during the first trimester is associated with an increased risk of congenital malformations of the musculoskeletal system, connective tissue, and eyes (15129).

LACTATION:
Insufficient reliable information available; avoid use.

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RED CLOVER

LIKELY SAFE ...when used orally in amounts commonly used in foods. Red clover has Generally Recognized As Safe (GRAS) status for use in foods in the US (4912,10372).

POSSIBLY SAFE ...when used orally and appropriately in supplemental amounts. Red clover extracts containing up to 80 mg isoflavones have been used with apparent safety in clinical studies lasting up to 2 years (3375,6127,8925,11089,11091,17091,19540,19556,91524,102901,102840). ...when used topically and appropriately. Red clover extracts have been used topically with apparent safety for up to 4 weeks (102839).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (4912).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in medicinal amounts. Red clover has estrogenic activity (19555); avoid using. There is insufficient reliable information available about the safety of the topical use of red clover during pregnancy and lactation.

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VITEX AGNUS-CASTUS (Agnus castus)

LIKELY SAFE ...when the fruit extract is used orally and appropriately, short-term. Vitex agnus-castus fruit extract has been used safely in studies at doses up to 40 mg daily, for up to 3 months (7055,7076,7077,7078,7079,12207,13393,15065,90617,90618,96435). There is insufficient reliable information available about the safety of vitex agnus-castus seeds when used orally or topically.

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally. Theoretically, the hormonal effects of vitex agnus-castus might adversely affect pregnancy or lactation (10979,11456,13393,109439). Animal research shows that taking vitex agnus-castus fruit extract when planning to become pregnant or during pregnancy may increase the risk of infertility, low fetal body weight, abortion, and stillbirth (109439); avoid using.

WILD YAM

POSSIBLY SAFE ...when used orally. A dose of 50 mg (containing 8 mg diosgenin) has been used with apparent safety for 12 weeks (12,96724). ...when used topically. A wild yam cream has been used with apparent safety for 3 months (10989).

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

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Interactions with Drugs view details

Below is general information about the interactions of the known ingredients contained in the product Red Clover Plus. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

CALCIUM (Calcium Hydrogen Phosphate)

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.

(Read more about CALCIUM)

DONG QUAI

ANTICOAGULANT/ANTIPLATELET DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, dong quai may increase the risk of bleeding when used with anticoagulant or antiplatelet drugs; however, research is conflicting.

Details

Animal studies suggest that dong quai has antithrombin activity and inhibits platelet aggregation due to its coumarin components (6048,10057,96137). Additionally, some case reports in humans suggest that dong quai can increase the anticoagulant effects of warfarin (3526,6048,23310,48439). However, clinical research in healthy adults shows that taking 1 gram of dong quai root daily for 3 weeks does not significantly inhibit platelet aggregation or cause bleeding (96137). Until more is known, use dong quai with caution in patients taking antiplatelet/anticoagulant drugs.

ESTROGENS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, dong quai may reduce the effects of estrogens.

Details

Dong quai has estrogenic effects (6180,7860,15108,15535,48459). Theoretically, concomitant use of large amounts of dong quai might interfere with hormone replacement therapy due to competition for estrogen receptors.

WARFARIN (Coumadin)

Interaction Rating = Major Do not take this combination.

Severity = High • Occurrence = Probable • Level of Evidence = D

Dong quai may increase the risk of bleeding when used with warfarin.

Details

Case reports suggest that concomitant use of dong quai with warfarin can increase the anticoagulant effects of warfarin and increase the risk of bleeding (3526,6048,23310,48439). In one case, after 4 weeks of taking dong quai 565 mg once or twice daily, the international normalized ratio (INR) increased to 4.9. The INR normalized 4 weeks after discontinuation of dong quai (3526).

(Read more about DONG QUAI)

RED CLOVER

ANTICOAGULANT/ANTIPLATELET DRUGS

Interaction Rating = Minor Be watchful with this combination.

Severity = Moderate • Occurrence = Unlikely • Level of Evidence = B

Although some laboratory research suggests that red clover may have anticoagulant and antiplatelet activity, clinical research has not shown this effect.

Details

In vitro research suggests that genistein in red clover has antiplatelet effects, and historically, red clover was thought to have anticoagulant effects due to its coumarin content. However, some experts state that this is unlikely as most natural coumarins have not been shown to have anticoagulant effects, and their content in red clover is low (17091,19557,19558,19559). Additionally, some clinical research in postmenopausal patients found no effect on coagulation or prothrombin time with the use of red clover flowering tops 378 mg daily for 12 months or red clover isoflavone (Rimostil) 50 mg daily for 2 years (17091,91524).

CAFFEINE

Interaction Rating = Minor Be watchful with this combination.

Severity = Moderate • Occurrence = Unlikely • Level of Evidence = D

Theoretically, soy might reduce the clearance of caffeine; however, a small clinical study found no effect.

Details

Red clover contains genistein. Taking genistein 1 gram daily for 14 days seems to inhibit caffeine clearance and metabolism in healthy females (23582). However, this effect does not seem to occur with the lower amounts of genistein found in red clover. A clinical study in healthy postmenopausal individuals shows that taking red clover capsules standardized to contain 60 mg isoflavones twice daily for 14 days does not affect the pharmacokinetics of caffeine (105693).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES

Interaction Rating = Minor Be watchful with this combination.

Severity = Mild • Occurrence = Unlikely • Level of Evidence = D

Theoretically, red clover might increase levels of drugs metabolized by CYP1A2; however, a small clinical study found no effect.

Details

In vitro evidence shows that red clover inhibits CYP1A2 (12479). However, a clinical study in healthy postmenopausal individuals shows that taking red clover capsules standardized to contain 60 mg isoflavones twice daily for 14 days does not affect the pharmacokinetics of caffeine, a CYP1A2 probe substrate (105693).

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES

Interaction Rating = Minor Be watchful with this combination.

Severity = Moderate • Occurrence = Unlikely • Level of Evidence = D

Theoretically, red clover might increase the levels and clinical effects of drugs metabolized by CYP2C19.

Details

In vitro evidence suggests that red clover weakly inhibits CYP2C19 (12479). This interaction has not been reported in humans.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES

Interaction Rating = Minor Be watchful with this combination.

Severity = Mild • Occurrence = Unlikely • Level of Evidence = D

Theoretically, red clover might increase levels of drugs metabolized by CYP2C9; however, a small clinical study found no effect.

Details

In vitro evidence suggests that red clover might inhibit CYP2C9 (12479). However, a clinical study in healthy postmenopausal individuals shows that taking red clover capsules standardized to contain 60 mg isoflavones twice daily for 14 days does not affect the pharmacokinetics of tolbutamide, a CYP2C9 probe substrate (105693).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES

Interaction Rating = Minor Be watchful with this combination.

Severity = Mild • Occurrence = Unlikely • Level of Evidence = B

Theoretically, red clover might increase levels of drugs metabolized by CYP3A4; however, a small clinical study found no effect.

Details

In vitro evidence shows that red clover might inhibit CYP3A4 isoenzymes (6450,12479). However, a clinical study in healthy postmenopausal individuals shows that taking red clover capsules standardized to contain 60 mg isoflavones twice daily for 14 days does not affect the pharmacokinetics of alprazolam, a CYP3A4 probe substrate (105693).

ESTROGENS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = D

Theoretically, concomitant use of large amounts of red clover might interfere with estrogen therapy.

Details

Red clover contains phytoestrogens which might have estrogenic activity in some people. Theoretically, red clover might compete for estrogen receptors and interfere with estrogen-containing drug therapy (4743,19560,19729).

METHOTREXATE (Trexall, others)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, red clover might increase the risk of methotrexate toxicity.

Details

In a case report, a 52-year-old female receiving weekly methotrexate injections for psoriasis developed symptoms of methotrexate toxicity, including severe vomiting and epigastric pain, after three days of taking red clover 430 mg daily. Toxicity resolved after red clover was discontinued. However, no liver function tests or methotrexate levels were reported (91522).

TAMOXIFEN (Nolvadex)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, the phytoestrogens in red clover might interfere with tamoxifen.

Details

In vitro and animal research suggests that genistein, a constituent of red clover, might antagonize the antitumor effects of tamoxifen (8192). However, there is some evidence from an animal study that red clover does not reduce the efficacy of tamoxifen (102901). Until more is known, tell patients taking tamoxifen to avoid red clover.

(Read more about RED CLOVER)

VITEX AGNUS-CASTUS (Agnus castus)

ANTIPSYCHOTIC DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, vitex agnus-castus could interfere with the activity of antipsychotic drugs.

Details

Vitex agnus-castus might interfere with the action of dopamine antagonists such as antipsychotic drugs due to its dopamine agonist effects (7014,7015).

CONTRACEPTIVE DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = B

Theoretically, vitex agnus-castus could interfere with oral contraceptives.

Details

Vitex agnus-castus might interfere with the efficacy of oral contraceptives due to possible hormone modulating activity (10979,11456).

DOPAMINE AGONISTS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, vitex agnus-castus could interfere with dopamine agonists.

Details

Vitex agnus-castus might potentiate the actions of dopaminergic agonists due to possible dopaminergic effects (10122).

ESTROGENS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = D

Theoretically, vitex agnus-castus could interfere with the activity of estrogens.

Details

Vitex agnus-castus has hormone modulating activity that can interfere with the efficacy of hormone replacement therapy (10979,11456).

METOCLOPRAMIDE (Reglan)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, dopaminergic effects of vitex agnus-castus could interfere with metoclopramide.

Details

Vitex agnus-castus might interfere with the action of dopamine antagonists such as metoclopramide due to its possible dopaminergic effects (7014,7015).

WILD YAM

ESTROGENS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, wild yam might increase or decrease the effects of estrogen.

Details

Wild yam root shows estrogenic and anti-estrogenic effects in vitro (6180,70411,96723,96725). Theoretically, wild yam might interfere with hormone therapy.

(Read more about WILD YAM)

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Adverse Effects view details

Report an Adverse Reaction to Red Clover Plus

Below is general information about the adverse effects of the known ingredients contained in the product Red Clover Plus. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

CALCIUM (Calcium Hydrogen Phosphate)

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).

(Read more about CALCIUM)

DONG QUAI

General ...Orally, dong quai is generally well-tolerated.
Most Common Adverse Effects:
Orally: Burping and flatulence.
Intravenously: Headache.

Cardiovascular ...Orally, dong quai might cause hypertension; according to one case report, a parent and breastfed infant experienced hypertension (195/85 mmHg and 115/69 mmHg, respectively) after the parent consumed a soup containing dong quai root (48428).

Dermatologic ...Dong quai contains psoralens that may cause photosensitivity and photodermatitis (10054,10057,48461).

Endocrine ...In a case report, a male developed gynecomastia after ingesting dong quai tablets (48504).

Gastrointestinal ...Orally, burping and gas may occur with dong quai (738).

Hematologic ...In one case report, a 55-year-old female with protein S deficiency and systemic lupus erythematosus (SLE) had temporary vision loss in the left eye from hemiretinal vein thrombosis three days after taking a phytoestrogen preparation containing dong quai 100 mg, black cohosh 250 mg, wild Mexican yam 276 mg, and red clover 250 mg (13155). It is unclear if dong quai contributed to this event.

Neurologic/CNS ...Dong quai given orally or by injection may be associated with headache (738,48438).

Oncologic ...Dong quai contains constituents that are carcinogenic; however, whether these constituents are present in concentrations large enough to cause cancer with long-term or high-dose use is unknown (7162).

Pulmonary/Respiratory ...A pharmacist experienced allergic asthma and rhinitis after occupational exposure to dong quai and other herbs (48435).

(Read more about DONG QUAI)

RED CLOVER

General ...Orally and topically, red clover seems to be well tolerated.
Most Common Adverse Effects:
Orally: Myalgia, nausea, and vaginal spotting.

Dermatologic ...Orally, a specific red clover isoflavone product (Promensil) has been associated with mild cases of psoriasis and thrush, although a direct causal link has not been established (9552).

Gastrointestinal ...Orally, red clover has been reported to cause nausea (8194).

Genitourinary ...In human research, 80 mg, but not 40 mg, of a specific red clover isoflavone product (Promensil) increased the duration of menstrual cycles in patients with mastalgia (9552). Red clover has also been reported to cause vaginal spotting (8194).

Hematologic ...In one case report, a 53-year-old female had a spontaneous subarachnoid hemorrhage associated with the use of an herbal supplement containing red clover, dong quai, and eleuthero. It is not clear if this was due to red clover, another ingredient, the combination of ingredients, or other factors (70419). In another case report, a 55-year-old female with protein S deficiency and systemic lupus erythematosus (SLE) had temporary vision loss in the left eye from hemiretinal vein thrombosis 3 days after taking a combination phytoestrogen product containing red clover 250 mg, wild yam 276 mg, dong quai 100 mg, and black cohosh 250 mg (13155). It is unclear if red clover contributed to this event.

Musculoskeletal ...Orally, red clover has been reported to cause myalgia (8194).

Neurologic/CNS ...Orally, a specific red clover isoflavone product (Medoflavon) has been associated with headache, although with a similar frequency to placebo (19545).

Oncologic ...Due to potential estrogenic effects of red clover isoflavones, there has been some concern that red clover might increase the risk of estrogen-sensitive cancers such as breast cancer or uterine cancer. A meta-analysis of 8 clinical trials suggests that increased intake of red clover- and soy-derived isoflavones may modestly increase mammographic breast density in premenopausal, but not postmenopausal, adults when compared with placebo. However, in a sub-group analysis assessing only isolated red clover isoflavones, there was no change in breast density (70428). Furthermore, a 2015 review by the European Food Safety Authority (EFSA) reported no increase in risk of breast cancer in females taking isoflavone-containing supplements (91725). Similarly, no effect was found on endometrial thickness and histopathological changes in the uterus after up to 36 months of supplementation with 40-120 mg daily of isoflavones from red clover extract (91725).

(Read more about RED CLOVER)

VITEX AGNUS-CASTUS (Agnus castus)

General ...Orally, vitex agnus-castus is generally well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, fatigue, headache, insomnia, irregular menstruation, nausea, skin irritation, stomach pain, vomiting.

Dermatologic ...Orally, skin conditions such as itching, irritation, urticaria, rash, acne, eczema, and hair loss have been reported (7055,7076,7078,7079,12207,13393,15065,90617,90619,101981).

Gastrointestinal ...Orally, gastrointestinal upset or pain, diarrhea, and nausea and vomiting, have been reported (7079,12207,13393,15065,90620,101981,101982). In one clinical trial, a single patient reported persistent gastroenteritis while taking vitex agnus-castus (7076). Orally, development of a bezoar resulting in colonic obstruction is described in a 63-year-old male who consumed an unknown amount of vitex agnus-castus seeds (111752).

Genitourinary ...Orally, irregular or prolonged menstrual bleeding has been reported (7055,7079,12207,13393,15065,41489,41490,95326).

Hematologic ...Orally, nosebleed has been reported in a single patient in a clinical trial (7079).

Immunologic ...Orally, multiple abscesses have been reported in a single patient (7055).

Neurologic/CNS ...Orally, headache, fatigue, and insomnia (7076,7078,12207,13393,13395,15065), confusion (90617), and vertigo (7079) have been reported.

Other ...Orally, weight gain has been reported (12207,13393,15065).

WILD YAM

General ...Orally, wild yam is generally well tolerated.
Most Common Adverse Effects:
Orally: Fever, headache, upset stomach, and vomiting.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis.

Gastrointestinal ...Orally, wild yam can cause upset stomach and vomiting, especially at higher doses (12,86450).

Hematologic ...In one case report, a 55-year-old female with protein S deficiency and systemic lupus erythematosus (SLE) had temporary vision loss in the left eye from hemiretinal vein thrombosis 3 days after taking a combination phytoestrogen product containing wild yam 276 mg, dong quai 100 mg, red clover 250 mg, and black cohosh 250 mg (13155). It is unclear if wild yam contributed to this event.

Immunologic ...There are three case reports of anaphylaxis after ingestion of cooked wild yam (96722).

Neurologic/CNS ...Orally, wild yam can cause headache and fever, especially at higher doses (86450).

(Read more about WILD YAM)

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