L-Carnitine 500 mg [Discontinued] by Indiana Botanic Gardens

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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EFFECTIVE

• L-carnitine deficiency. Oral and intravenous L-carnitine can treat primary and secondary L-carnitine deficiency. Details: Administering L-carnitine orally or intravenously is effective for acute or chronic treatment of primary L-carnitine deficiency or secondary L-carnitine deficiency due to inborn errors of metabolism. This is an FDA-approved indication for L-carnitine (4949,58611,59018). For primary or secondary deficiencies, oral L-carnitine 990 mg 2-3 times daily is used. For inborn errors of metabolism resulting in secondary L-carnitine deficiency, L-carnitine 50 mg/kg given as a slow (2-3 minute) bolus injection or by infusion followed by 50 mg/kg administered in divided doses every 3-4 hours over the next 24 hours is also used. Subsequent daily maintenance doses of intravenous L-carnitine are usually around 50 mg/kg (3616).

POSSIBLY EFFECTIVE

• Angina. Oral and intravenous L-carnitine may improve exercise tolerance and symptoms of angina during exercise in patients with angina. Details: Several small clinical trials in patients with chronic stable angina or cardiac syndrome X show that taking L-carnitine orally or intravenously seems to improve exercise tolerance and time to onset of angina when compared with placebo (3623,3624,58156,59096,59118,59216,59217,59230). Oral doses of L-carnitine have ranged from 900 mg to 2 grams daily in single or divided doses for 2 weeks to 6 months (3623,3624,58156,59096,59118,59217). Intravenous L-carnitine 3 grams in 500 mL of 5% dextrose, administered once daily for 14 days (59230), or intravenous DL-carnitine 40 mg/kg administered 30 minutes prior to exercise (59216) have also been used.
• Congestive heart failure (CHF). Oral and intravenous L-carnitine may improve exercise capacity and symptoms of heart failure in patients with CHF. Details: Several small clinical trials in patients with CHF show that taking L-carnitine 1.5-3 grams daily in single or divided doses for up to 34 months or administering intravenous L-carnitine 5 grams daily for 7 days seems to improve symptoms and increase exercise capacity when compared with placebo (3625,3626,58145,58771,58824). Also, taking a specific combination product containing L-carnitine 2250 mg and coenzyme Q10 270 mg (Carni Q-Gel, Tishcon Corporation) daily for 12 weeks appears to improve symptoms of CHF when compared with no treatment (58392).
• Hyperlipidemia. Oral or intravenous L-carnitine may slightly improve lipid levels. Oral, but not intravenous, L-carnitine may also improve lipoprotein(a) levels in patients with elevated lipoprotein(a). Details: Most meta-analyses of clinical research in patients with or without hyperlipidemia show that L-carnitine, given orally at a dose of 76 mg to 3 grams daily or intravenously at a dose of 15-20 mg/kg three times weekly, appears to reduce total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels by up to 9.5 mg/dL, 8.3 mg/dL, and 11.2 mg/dL, respectively, while increasing high-density lipoprotein (HDL) cholesterol by up to 1.6 mg/dL. Sub-analyses in patients with elevated levels of specific lipids shows that L-carnitine might be most beneficial in these populations (95073,102019,111886). However, clinical research is generally very low to moderate quality. Also, any effects of L-carnitine on these lipids are modest and might not be considered clinically significant. An umbrella meta-analysis of meta-analyses of clinical research shows that taking L-carnitine orally reduces total cholesterol, LDL cholesterol, and triglyceride levels by only 1.1 mg/dL, 4.8 mg/dL, and 2.5 mg/dL, with increases in HDL cholesterol of 0.7 mg/dL (111896). More information is needed on the effects of L-carnitine on lipid levels specifically in patients with hyperlipidemia. Some research has also evaluated the benefits of L-carnitine in people with hyperlipidemia and elevated lipoprotein(a) levels or those undergoing hemodialysis. Preliminary clinical research and a meta-analysis of clinical research in these populations shows that taking L-carnitine 1-2 grams daily for 8-24 weeks reduces levels of lipoprotein(a) by about 9 mg/dL when compared with control (58155,95073). However, giving L-carnitine intravenously 1 gram three times weekly or 4 grams daily does not improve lipoprotein(a) levels in these patients (95073). Also, oral or intravenous L-carnitine does not improve LDL cholesterol, HDL cholesterol, or triglyceride levels in these patients (58155,95073). Whether L-carnitine reduces the risk of cardiovascular events in patients with hyperlipidemia is unknown.
• Kidney failure. Intravenous, but not oral, L-carnitine is FDA-approved for the prevention and treatment of L-carnitine deficiency in patients with kidney failure undergoing hemodialysis. Any other benefits with the use of L-carnitine in patients on hemodialysis are unclear. Details: Patients with kidney failure undergoing maintenance hemodialysis often experience L-carnitine deficiency, which can lead to lipid, red blood cell, cardiac muscle, and skeletal muscle abnormalities (26496). Use of intravenous L-carnitine for the prevention and treatment of L-carnitine deficiency in people with kidney failure who are undergoing hemodialysis is an FDA-approved indication for L-carnitine. L-carnitine 10-20 mg/kg is given as a slow (2-3 minute) bolus injection, with dose adjustments made based on subsequent pre-dialysis L-carnitine concentrations (3616). However, oral L-carnitine is not FDA-approved for this purpose. There is concern that long-term administration of high doses of oral L-carnitine may result in accumulation of toxic metabolites, including trimethylamine and trimethylamine-N-oxide, in patients with kidney failure (3616). Research in other areas are conflicting. Most clinical research shows that taking L-carnitine 0.7-3 grams or 10 mg/kg daily or administering L-carnitine 2-6 grams or 30-60 mg/kg weekly via intravenous infusion can improve cardiac function, intravenous fistula complications, red blood cell count, hemoglobin, and C-reactive protein levels in patients on hemodialysis (9790,26496,58257,58437,58842,59009,59178,111877). A meta-analysis of 18 clinical studies in adults with kidney-related anemia undergoing hemodialysis shows that receiving oral or intravenous L-carnitine reduces erythropoietin responsiveness and erythropoiesis stimulating agent (ESA) requirement, but not hemoglobin level, when compared with placebo or conventional therapy, regardless of treatment duration or route of administration (107406). Despite an earlier meta-analysis suggesting that L-carnitine does not reduce the incidence of dialysis-related hypotension or muscle cramping (58511), a more recent meta-analysis shows that L-carnitine reduces the incidence of dialysis-related hypotension by 74% when compared with placebo (111878). However, sub-analyses suggest that only oral L-carnitine, and doses of over 4.2 grams weekly for at least 12 weeks, are effective for preventing hypotension (111878). A meta-analysis and some preliminary clinical research also show that muscle cramping is reduced by up to 78% when compared with controls (104176,111878). Additionally, observational research has found that administering at least 1 gram of L-carnitine per dialysis session for at least 10 sessions monthly is associated with a 10% to 20% decrease in the number of hospitalization days during the subsequent month (58409). However, L-carnitine may not be beneficial for improving other measures in people with kidney failure receiving dialysis. While some research shows that L-carnitine decreases lipoprotein(a) levels (44187), low-density lipoprotein (LDL) cholesterol levels (26496,91723,107399), and total cholesterol levels (107399), most research shows that it does not improve serum lipid levels (9790,26496,44187,58257,58320,58842,58939,59009,59025,59031)(59036,59059,59080,90633,91723,107399). Additionally, while one small clinical trial shows that taking L-carnitine can improve performance on some exercise tests (104179), most research shows that L-carnitine does not improve respiratory function or exercise performance. The effect on quality of life is unclear (58154,58437,58472,58743,59031,90633,111867,111877).
• Male infertility. Oral L-carnitine, taken alone or in combination with acetyl-L-carnitine, may increase sperm motility in males with infertility, leading to a greater likelihood of pregnancy in female partners. Details: Although some clinical research has yielded conflicting results (58209,58588,59020,90627,111861), most clinical research shows that taking L-carnitine 1-3 grams daily in divided doses for up to 24 weeks, with or without acetyl-L-carnitine 1 gram daily, increases sperm count and motility, and improves sperm morphology, in males with infertility of various etiologies (12352,58167,58182,58194,58334,58469,58831,58849,59129,59189)(59190,101560,107394,111861,111459,111888,111890). However, it is unclear if taking L-carnitine increases the odds of pregnancy. One meta-analysis of randomized controlled trials shows that taking L-carnitine and acetyl-L-carnitine in combination increases the odds of pregnancy by 3.7-fold over placebo. However most clinical research investigating the effect of L-carnitine alone or with acetyl L-carnitine on pregnancy rates disagrees (12352,58182,101560,111861,111459,111888). The number of studies investigating the effect of L-carnitine alone or with acetyl-L-carnitine on pregnancy rate is small and the duration of supplementation may be inadequate. Taking L-carnitine 1 gram and acetyl-L-carnitine 0.5 grams twice daily after taking nonsteroidal anti-inflammatory drugs for 2 months seems to increase sperm count and motility in males with abacterial prostatovesiculoepididymitis, an inflammation of the prostate gland, seminal vesicles, and epididymis (9791). Some studies have also evaluated L-carnitine in combination with other ingredients. One clinical trial in males with asthenospermia shows that taking L-carnitine 150 mg, acetyl-L-carnitine 50 mg, L-arginine 1660 mg, and Panax ginseng 200 mg daily for 3 months increases sperm motility and sexual satisfaction when compared with no treatment (32189). Another small clinical trial shows that taking this combination along with prulifloxacin 600 mg daily for 6 months improves sperm concentration and motility when compared with prulifloxacin alone in patients with chronic prostatitis due to Chlamydia trachomatis infection (59006). Other small and preliminary clinical studies have investigated the effects of a specific combination product providing L-carnitine 1 gram twice daily for 6 months, along with acetyl-L-carnitine, coenzyme Q10, selenium, zinc, vitamin C, folic acid, vitamin B12, and citric acid (Proxeed Plus). Taking this combination product has been shown to improve measures of sperm quality such as sperm count, sperm concentration, total motility, and progressive motility when compared to baseline. The effect on sperm volume and morphology is unclear. Most research has been conducted in patients with oligoasthenozoospermia, although some benefit has also been shown in patients with varicocele-related infertility, especially those with more severe varicocele (102017,107395,111296). The validity of these findings is limited by the lack of comparator group. Also, it is unclear if these effects are due to L-carnitine, other ingredients, or the combination. The effect of L-carnitine in combination with other ingredients on pregnancy rate has also been examined. One meta-analysis of moderate-quality clinical research shows that taking L-carnitine in combination with micronutrients increases the odds of pregnancy by 3.5-fold over placebo or no treatment (111888).
• Myocarditis. Oral DL-carnitine may prevent myocarditis in children with diphtheria. Details: Myocarditis is a complication of diphtheria. Clinical research in children with diphtheria shows that taking DL-carnitine 100 mg/kg daily for 4 days reduces the risk of myocarditis and mortality when compared with no treatment (3620,3621).
• Valproic acid-induced toxicities. Although more well-designed research is needed to confirm these findings, oral and intravenous L-carnitine may improve neurologic and hepatic function and reduce ammonia levels in patients with these valproic acid-induced toxicities. Details: Valproic acid-induced toxicities are often associated with low plasma and tissue levels of L-carnitine. Preliminary clinical research and case reports in patients on valproic acid therapy who have neurologic or hepatic deterioration or hyperammonemia show that taking L-carnitine 50-100 mg/kg daily in divided doses or administering L-carnitine 150-500 mg/kg daily via intravenous infusion seems to improve neurologic and hepatic function and bring plasma ammonia levels within normal limits (1438,1914,1915,1916,1917,4523,5798,5799,95068). There is also some preliminary evidence that intravenous L-carnitine can prevent the development of severe valproic acid-induced hepatotoxicity when given to patients being treated for overdose and accidental ingestion of valproic acid (1438,4528,5798,5799), especially if treatment is initiated early (4528). Despite these results, most evidence consists of anecdotal individuals or small case series. A more recent retrospective cohort study suggests that treatment with an L-carnitine dosing regimen consisting of a 100 mg/kg intravenous loading dose followed by up to 3 grams daily in divided doses for 3 days or until ICU discharge does not enhance valproic acid elimination or prevent organ dysfunction when compared with patients not treated with L-carnitine (111869). Also, taking L-carnitine does not appear to reduce valproic acid-associated weight gain (58295). Well-designed clinical trials are still needed to determine the role of L-carnitine in the treatment or prevention of valproic acid toxicities.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Topical L-carnitine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical trial in patients with mild-to-moderate acne shows that applying a proprietary formulation containing L-carnitine, licochalcone, and 1,2-decanediol to the face twice daily for 8 weeks reduces the number of acne lesions and pustules and improves quality of life when compared to baseline. However, the improvements do not appear to be significant when compared with placebo (26493).
• Age-related fatigue. Small clinical studies suggest that oral L-carnitine may improve physical and mental fatigue associated with aging. Details: Two small clinical trials in elderly patients experiencing fatigue after slight physical activity shows that taking L-carnitine 2-4 grams daily for 1-6 months improves physical and mental fatigue, increases muscle mass, and decreases fat mass when compared with placebo (16109,16111).
• Aluminum phosphide poisoning. It is unclear if intravenous L-carnitine is beneficial in people with aluminum phosphide poisoning. Details: A meta-analysis of preliminary clinical research in patients with aluminum phosphide poisoning shows that intravenous L-carnitine does not reduce the odds of mortality when compared with control groups receiving routine treatments only (111892). However, only 2 studies were included in the analysis and both studies may have been underpowered to detect differences.
• Alzheimer disease. Oral L-carnitine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with mild to moderate Alzheimer disease shows that taking L-carnitine tartrate 3.73 grams, in combination with serine, nicotinamide riboside, and N-acetyl cysteine, daily for 28 days and then twice daily for 56 days does not improve cognitive function when compared with taking placebo. However, in patients with the most severe symptoms, there was some modest improvement (110623). This study may have been underpowered to detect differences. Also, the effect of L-carnitine alone is unclear.
• Androgenic alopecia. It is unclear if topical L-carnitine is beneficial in people with androgenic alopecia. Details: One small clinical trial in individuals with androgenic alopecia shows that applying topical L-carnitine 2% solution to the scalp twice daily for 6 months significantly increases the number of terminal hair shafts on the scalp when compared with placebo (58390).
• Anorexia nervosa. Although there has been interest in using oral L-carnitine for anorexia nervosa, there is insufficient reliable information about the clinical effects of L-carnitine for this purpose.
• Anthracycline cardiotoxicity. Oral and intravenous L-carnitine have only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in patients with breast cancer undergoing doxorubicin treatment shows that taking a combination of L-carnitine and vitamin E over 4 21-day treatment cycles decreases the proportion of patients with cardiac events by 24.2% when compared with chemotherapy treatment only. There were also modest beneficial effects on some enzyme measures of cardiac health. Patients received L-carnitine 3 grams intravenously on the first day of each cycle followed by an oral intake of 300 mg 4 times daily for the remaining 20 days. Vitamin E 1800 mg daily was taken orally in 3 divided doses (111891).
• Athletic performance. Oral L-carnitine has been evaluated for its effect on athletic performance in several small and short-term clinical studies, with mixed results. Details: Maximal exercise in trained athletes has been associated with a decrease in plasma L-carnitine levels (3648,58583). Theoretically, restoring these levels with L-carnitine supplementation might have beneficial effects. However, clinical studies examining the use of L-carnitine for athletic performance have reported conflicting results. Some clinical studies show that taking L-carnitine 2 grams, either before exercise or daily for up to 6 weeks, enhances athletic performance and endurance and reduces post-exercise muscle pain in male athletes and healthy untrained males (58450,59182,59185), but other studies do not support these findings (1947,59128,59134). Additionally, although some studies show that taking L-carnitine 1-2 grams or 40 mg/kg before exercise or 4 grams daily for 2 weeks can decrease lactate accumulation and increase oxygen uptake, power output, and time to anabolic threshold during exercise (3649,3650,59061,59184,59186), other studies show no improvement in these outcomes (58471,58775,59033,59045,59069,59128). These discrepancies may be related to the small study sizes, short treatment durations, and variable dosing regimens.
• Atrial fibrillation. It is unclear if oral L-carnitine is beneficial for preventing postoperative atrial fibrillation in patients undergoing aortic valve surgery. Details: A very small clinical study in patients undergoing aortic valve replacement or valve-sparing aortic root replacement shows that receiving oral L-carnitine (L-Cartin FF, Otsuka Pharmaceutical) 1 gram three times daily, beginning 2 days prior to surgery and continuing for 7 days after surgery, is associated with a postoperative atrial fibrillation rate of 20%, compared with a rate of 60% in a historical age-matched control group not receiving L-carnitine (107408).
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral L-carnitine is beneficial in children with ADHD. Details: One small crossover trial in children with ADHD shows that taking L-carnitine 50 mg/kg twice daily for 6 months improves parent and teacher assessments of behavior when compared with placebo (58166).
• Autism spectrum disorder. Small clinical studies suggest that oral L-carnitine may improve some symptoms of autism spectrum disorder. Details: Small clinical trials in children 3-16 years of age with autism spectrum disorder show that taking L-carnitine 50 mg/kg or 150 mg/kg daily for 8 to 12 weeks modestly improves overall symptoms of autism, especially lethargy, social isolation, hyperactivity, and irritability, when compared with taking placebo. However, there is inconsistency between studies with respect to rating scales used and specific endpoints showing improvement. In one study, children remained on any pre-existing medications; in the other two, all children were also taking risperidone (58981,111887,111900).
• Arrhythmia. Small clinical studies suggest that oral L-carnitine may reduce the incidence of arrhythmias in patients with premature ventricular contractions. Details: Small clinical trials in patients with premature ventricular contractions show that taking L-carnitine 2 grams twice daily for 45 weeks or 2 grams three times daily for 2 weeks might reduce the incidence of arrhythmias when compared to baseline (59043,59120,59143).
• Asthenopia (eye strain). Oral L-carnitine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in videoterminal users with computer vision syndrome and without dry eye shows that taking a product containing L-carnitine 50 mg, along with zinc and extracts of elderberry, black currant, and eleuthero root (Meramirt CM) daily for 1 month modestly reduces severity of eye strain and sensitivity when compared with not taking this product (111295). It is unclear if these findings are due to L-carnitine, other ingredients, or the combination.
• Beta-thalassemia. Small clinical studies suggest that oral L-carnitine may improve symptoms and reduce complications of beta-thalassemia minor, intermedia, and major. Details: Several small clinical trials in children with beta-thalassemia major show that taking L-carnitine 50 mg/kg daily for 3-6 months might reduce pulmonary artery systolic pressure, increase cardiac output during exercise, and improve progression to puberty (58294,58502,58556). Clinical research in adults with beta-thalassemia intermedia shows that taking L-carnitine with hydroxyurea appears to increase hemoglobin and hematocrit and reduce left ventricular end-diastolic diameter, a measure of pulmonary hypertension (58679). In patients with beta-thalassemia major or intermedia aged 6 years and up, taking L-carnitine 50 mg/kg daily for 6 months normalized left ventricular dilatation and hypertrophy in 30% and 37% of patients, respectively, compared with only 10% in those taking placebo. Cardiac output was also improved, but there were no changes in blood parameters (101565). Clinical research in children with beta-thalassemia minor shows that taking L-carnitine 50 mg/kg daily, with or without folic acid 1 mg daily, for 3 months appears to reduce bone pain by 84% to 87% and increase the number of climbable stairs 3.1- to 5.2-fold when compared with baseline (90631).
• Cachexia. Small clinical studies suggest that oral L-carnitine may improve body composition and quality of life in patients with cancer-related cachexia. Details: One small clinical trial in patients with cancer-related cachexia shows that taking L-carnitine 4 grams daily for 12 weeks increases body mass index (BMI) when compared with placebo (59029). Other research shows that taking L-carnitine 4 grams daily with megestrol acetate, eicosapentaenoic acid (EPA), and thalidomide for 5 months is more effective than any single product alone for increasing lean body mass in patients with cancer-related cachexia (23437). Additionally, taking L-carnitine 4 grams daily with megestrol acetate, celecoxib, and antioxidants for 4 months appears more effective than megestrol acetate alone for improving lean body mass, fatigue, and quality of life in these patients (59012).
• Cancer-related fatigue. It is unclear if oral L-carnitine is beneficial for improving fatigue in patients with advanced cancer. Details: Some cancer patients have low blood levels of L-carnitine, which may reduce energy production and lead to fatigue. Some small clinical trials in patients with advanced cancer show that taking L-carnitine 3-4 grams daily for 7 days significantly improves some measures of fatigue when compared to baseline (16106,16110). However, other higher quality clinical research shows that taking L-carnitine 2-4 grams daily for 4-12 weeks is no more effective than placebo for improving fatigue in advanced cancer patients (26498,58523,59029).
• Celiac disease. It is unclear if oral L-carnitine is beneficial in patients with celiac disease. Details: Some research shows that L-carnitine blood levels are low in patients with celiac disease. One small clinical trial in patients with celiac disease shows that taking L-carnitine 2 grams daily for 6 months lowers some measures of fatigue when compared with placebo. However, L-carnitine does not significantly improve measures of depression or quality of life in these patients (16105).
• Chemotherapy-related fatigue. It is unclear if oral L-carnitine is beneficial in patients with fatigue due to sunitinib therapy. Details: A small clinical study in adults with renal cell carcinoma who are experiencing fatigue associated with sunitinib treatment shows that taking L-carnitine 1500 mg daily for 2 weeks modestly improves fatigue severity when compared to baseline (100352). The validity of this finding is limited by the small study size and lack of a comparator group.
• Chronic fatigue syndrome (CFS). It is unclear if oral L-carnitine is beneficial in patients with CFS. Details: One small clinical study in adults with CFS shows that taking L-carnitine 1 gram three times daily for 2 months can improve some symptoms of CFS when compared to baseline (3630). The validity of this finding is limited by the lack of a comparator group.
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral L-carnitine is beneficial in patients with COPD. Details: One small clinical study in adults with moderate to severe COPD shows that taking L-carnitine 2 grams daily for 6 weeks improves exercise performance and walking tolerance when compared with placebo (58213).
• Cirrhosis. Preliminary research suggests that oral L-carnitine may be beneficial in patients with cirrhosis. Details: One small clinical trial in patients with cirrhosis who are receiving branched-chain amino acids supplements to improve nutritional status shows that taking L-carnitine 1 gram orally daily for 6 months, in addition to increasing exercise by 2000 steps per day, does not improve muscle volume, handgrip strength, or leg strength, but does reduce complaints of muscle cramping, when compared to baseline (102124). Another small, uncontrolled clinical trial in patients with cirrhosis shows that taking L-carnitine 1800 mg daily for 6 months does not improve Child-Pugh scores, but may improve quality of life, when compared to baseline (104177). The validity of these studies is limited by the lack of comparator groups. The effect of L-carnitine has also been examined retrospectively in patients with cirrhosis. One retrospective study in matched patients that had been admitted to hospital for cirrhosis suggests that taking L-carnitine for more than 30 days is associated with an increase in survival length by about 21 months compared with not taking L-carnitine. Overall, L-carnitine use was also associated with a 36% to 48% increase in the proportion of patients surviving 1-5 years, with the greatest effect in patients with modest to severe liver dysfunction. The median dose of L-carnitine was 1000 mg daily for at least 6 months is associated with a reduced loss of skeletal muscle compared with not taking L-carnitine (111860). The validity of these studies is limited by their retrospective design.
• Cognitive function. It is unclear if oral L-carnitine is beneficial for improving cognitive function in healthy individuals. Details: Low-quality clinical research shows that taking L-carnitine 500 mg as a single dose or 250 mg twice daily for 3 days does not improve cognitive function or memory in otherwise healthy young adults when compared with placebo (58176,95070).
• Coronary heart disease (CHD). It is unclear if oral L-carnitine is beneficial in patients with CHD. Details: One small clinical trial in patients with CHD shows that taking L-carnitine 2 grams prior to exercise does not improve endurance when compared with placebo (58196). Another small clinical trial in patients with CHD shows that taking L-carnitine 1 gram daily for 12 weeks does not improve low-density lipoprotein (LDL) cholesterol, total cholesterol, or apolipoprotein-B when compared with placebo; however, it does appear to increase high-density lipoprotein (HDL) and apolipoprotein A-1 levels in these patients (95071).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral L-carnitine is beneficial for COVID-19 prevention or treatment. Details: Preliminary clinical research in patients hospitalized with mild to moderate COVID-19 shows that taking L-carnitine 1 gram 3 times daily for 5 days does not reduce the incidence of fever or cough when compared with standard treatments only. However, all patients taking L-carnitine survived compared with 86% of those given standard treatment only. Also, there were improvements in oxygen saturation and inflammatory measures (111874). Other clinical research in patients with confirmed asymptomatic or mild COVID-19 shows that taking L-carnitine tartrate (Carnipure) 1 gram 3 times daily for 21 days does not prevent the development of severe lung symptoms when compared with taking placebo. However, in a sub-group of patients, lung lesion improvement was significantly better between days 7 and 14. In adults without COVID-19 but living with someone with confirmed disease, taking this product does not prevent COVID-19 when compared with taking placebo. However, the total number of confirmed illnesses in the population was low (111898).
• Critical illness (trauma). It is unclear if oral or nasogastric L-carnitine is beneficial for critical illness. Details: One small clinical trial in critically ill patients in the ICU shows that receiving L-carnitine (BSK, Zist Takhmir Co, Tehran-Iran) 3 grams daily via a nasogastric tube for 7 days modestly improves disease severity, organ function, inflammatory and other laboratory measures when compared with receiving placebo. Also, mortality rate was reduced by approximately 50%. There was no effect on the duration of hospital or ICU stay (111883,111884). However, another small clinical trial in critically ill patients following an acute ischemic stroke shows that oral or nasogastric L-carnitine tartrate 500 mg every 8 hours for 6 days does not affect the duration of mechanical ventilation or hospital or ICU stay, the severity of illness, or 28-day mortality rates, when compared with taking placebo. There was a modest beneficial effect on insulin resistance (111881). This study was small and may have been underpowered to detect differences.
• Diabetes. Oral L-carnitine may improve glycemic control in patients with diabetes, but it is unclear if these improvements are clinically meaningful. It is also unclear if L-carnitine can improve lipid profiles or weight loss in these patients. Details: While individual study results are mixed (58169,58189,58514,58793,90632,96922,101561), meta-analyses of available clinical research in mixed populations shows that taking L-carnitine 200 mg to 4 grams daily reduces fasting plasma glucose and glycated hemoglobin (HbA1C) levels, and possibly insulin, and improves insulin resistance, when compared with taking placebo or a control diet, although the clinical significance of these improvements is unclear (102018,111875,111886). One meta-analysis shows that these benefits are generally specific to patients with high levels of fasting glucose, diabetes, or obesity, as well as studies investigating L-carnitine in doses of at least 2 grams daily for 12 weeks. However, a small number of studies included in this analysis investigated the effects of acetyl-L-carnitine (111875). Other research in obese patients with type 2 diabetes shows that, when taken with orlistat or sibutramine, L-carnitine 2 grams daily for 12 months decreases body weight and body mass index and improves glycemic control when compared with orlistat or sibutramine alone (58778,58830,58882). The effect of L-carnitine on lipids in people with diabetes is unclear. Some studies show significant reductions in total cholesterol, low-density lipoprotein cholesterol, triglycerides, and/or lipoprotein(a) (58554,58647,58649,90632,101561,107397), while other studies show no improvement in lipid profiles (58169,58189).
• Dilated cardiomyopathy. Small clinical studies suggest that oral L-carnitine may improve ejection fraction in children with dilated cardiomyopathy and adults with ischemic cardiomyopathy. Details: Primary L-carnitine deficiency is a common cause of pediatric dilated cardiomyopathy. Additionally, patients with dilated cardiomyopathy of unknown etiology have been shown to have low cardiac levels of L-carnitine (59196,100351). Due to these findings, L-carnitine has been evaluated for the treatment of dilated cardiomyopathy in children and adults, but the small sizes of these studies and methodological limitations limit the reliability of the results. One small clinical study in children under 13 years of age with dilated cardiomyopathy shows that taking L-carnitine 50-100 mg/kg daily for 1 year in conjunction with standard care improves ejection fraction and reduces left atrial and ventricular diameters when compared with placebo and standard care (100351). The results of this study are limited by the small sample size, unclear etiology of dilated cardiomyopathy, and potential bias. Another small clinical study in children under 5 years of age with dilated cardiomyopathy and low serum levels of L-carnitine shows that taking L-carnitine 100 mg/kg daily for 3 months improves left ventricular ejection fraction (LVEF), cardiac output, and New York Heart Association (NYHA) classification when compared with baseline (59196). Further research is needed to clarify whether L-carnitine is beneficial for most children with dilated cardiomyopathy, or only those with carnitine deficiency. L-carnitine has also been evaluated in older adults. A meta-analysis of clinical studies in mostly older adults with dilated cardiomyopathy shows that addition of intravenous L-carnitine, alone or followed by oral L-carnitine, 1-6 grams daily to conventional therapy for a total of 10-28 days is associated with a 28% increased likelihood of overall efficacy, with improvements observed in both LVEF and cardiac output, when compared with conventional therapy alone (107405). The validity of these findings is limited by the heterogeneity of the included studies, potential publication bias, and unclear reporting. A small individual clinical study in older adults with ischemic cardiomyopathy shows that taking oral L-carnitine daily for 2 months improves LVEF when compared with baseline (58150). The validity of this finding is limited by the lack of a comparator group.
• Dry eye. Topical L-carnitine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Evidence suggests that chronic use of eye drops containing benzalkonium chloride can cause tear film instability and lead to dry eye (90921). One small clinical trial in patients with glaucoma using eye drops containing benzalkonium chloride shows that using additional eye drops containing L-carnitine (1.017%), eledoisin (0.04%), taurine (0.49%), sodium hyaluronate (0.20 grams/100 mL), and vitamin E acetate (0.20 grams/100 mL) (Carnidrop Plus, Sigma-Tau) three times daily for 15 days reduces dry eye symptoms by approximately 50% when compared to baseline (90625). It is unclear if these findings are due to L-carnitine, other ingredients, or the combination.
• Endometriosis. Although there has been interest in using oral L-carnitine for endometriosis, there is insufficient reliable information about the clinical effects of L-carnitine for this purpose.
• Exercise-induced muscle damage. It is unclear if oral L-carnitine tartrate is beneficial for exercise recovery. Details: A small clinical study in healthy males and females participating in moderate physical activity at least 3 days weekly shows that taking a specific product (Carnipure, Lonza Consumer Health, Inc.) providing elemental L-carnitine 2 grams daily for 5 weeks improves perceived recovery and soreness as well as serum creatine kinase levels by 33% and 28%, respectively, when compared with placebo (107398).
• Exercise-induced muscle soreness. Small clinical studies suggest that oral L-carnitine may slightly reduce exercise-induced muscle soreness. Details: Evidence from mostly small clinical trials, when considered alone or combined via meta-analysis, shows that taking L-carnitine 1-3 grams daily for around 3 weeks modestly reduces exercise-induced muscle soreness, especially in the period of 24-48 hours after exercise. Benefits may last up to 96 hours post-exercise. Levels of creatinine kinase, lactate dehydrogenase, and myoglobin also appear to improve with L-carnitine supplementation, reflecting a reduction in muscle damage (58326,58709,59148,101567).
• Hepatic encephalopathy. Oral or intravenous L-carnitine may improve biochemical markers of disease severity in patients with hepatic encephalopathy, but L-carnitine does not seem to improve clinically important outcomes such as fatigue, quality of life, or overall disease severity. Details: A meta-analysis of nine studies in adults with hepatic encephalopathy shows that taking L-carnitine 1-6 grams daily orally or intravenously for up to 90 days increases albumin levels and decreases plasma levels of ammonia, bilirubin, aspartate aminotransferase (AST), blood urea nitrogen (BUN), and creatinine, but does not improve fatigue or quality of life, when compared with placebo (102122). A more recent clinical trial shows that taking L-carnitine 2 grams daily for 24 weeks modestly improves bilirubin levels and some measures of cognitive and liver health, but not quality of life, when compared with taking placebo (111876). Two of the clinical trials included in this analysis also show that taking L-carnitine 2 grams daily for 60-90 days significantly improves cognitive function when compared with placebo in adults with hepatic encephalopathy (58174,58204). Another small clinical trial in patients with advanced liver cirrhosis shows that L-carnitine improves psychometric response to the ammonia tolerance test, suggesting that L-carnitine might be useful in the prevention of hepatic encephalopathy (58872). L-carnitine has also been evaluated in combination with rifaximin. A small clinical study in patients with overt hepatic encephalopathy shows that taking oral L-carnitine 1500 mg in combination with rifaximin 1200 mg three times daily for 12 weeks has no effect on the modified portal systemic encephalopathy index when compared with rifaximin alone. L-carnitine improved blood ammonia levels at 4 weeks, but not at 8 or 12 weeks (107410).
• Hepatitis-related fatigue. It is unclear if oral L-carnitine is beneficial in patients with hepatitis-related fatigue. Details: One small clinical trial in patients with hepatitis C who are receiving interferon-alpha treatment shows that taking L-carnitine 2 grams daily significantly reduces fatigue when compared with interferon-alpha alone. L-carnitine appears to reduce fatigue within the first 3 months of treatment, but not after 6 months (16104).
• Hepatitis B. Oral L-carnitine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with hepatitis B shows that taking a specific vitamin complex providing L-carnitine 2472 mg (Godex, Celltrion Pharm) in combination with entecavir 0.5 grams daily for 12 months normalizes alanine transaminase (ALT) levels in 95% and 100% of patients after 3 months and 12 months, respectively, compared to 59% and 86% of patients taking entecavir alone. However, the L-carnitine complex does not appear to improve aspartate transaminase (AST) levels or reduce hepatitis B virus titers (91724). It is unclear if these findings are due to L-carnitine, other ingredients, or the combination.
• Hepatitis C. Small clinical studies suggest that oral L-carnitine may improve response to treatment and markers of liver function in patients with hepatitis C. Details: Two small clinical trials in patients with chronic hepatitis C show that taking L-carnitine 2 grams once or twice daily along with interferon-alpha and ribavirin for 12 months modestly improves response to treatment, increases hemoglobin and red blood cell counts, reduces aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, and reduces steatosis when compared with interferon-alpha and ribavirin treatment alone (58405,59010).
• HIV/AIDS. Although there has been interest in using intravenous L-carnitine to increase CD4 counts in patients with HIV/AIDS, there is insufficient reliable information about the clinical effects of L-carnitine for this purpose.
• Hyperthyroidism. It is unclear if oral L-carnitine is beneficial in patients with hyperthyroidism. Details: One small clinical trial in females with hyperthyroidism shows that taking L-carnitine 2-4 grams daily for 2-6 months seems to significantly improve symptoms associated with hyperthyroidism, such as palpitations, nervousness, tremors, and asthenia, when compared with placebo (8047).
• Hypertriglyceridemia. It is unclear if oral L-carnitine is beneficial in patients with hypertriglyceridemia. Details: Small clinical studies in patients with hypertriglyceridemia show that taking L-carnitine 1 gram daily for 12 weeks does not reduce triglyceride levels when compared with placebo (59028,59244).
• Hypothyroidism. It is unclear if oral L-carnitine is beneficial for improving fatigue in patients with hypothyroidism. Details: One small clinical trial in patients with secondary hypothyroidism shows that taking L-carnitine (Ildong Pharmaceutical Co.) 990 mg twice daily for 12 weeks in addition to adequate doses of levothyroxine does not reduce overall fatigue severity when compared with placebo. However, taking L-carnitine might improve physical and mental fatigue in patients with secondary hypothyroidism that are less than 50 years of age. L-carnitine might also improve mental fatigue in patients that underwent thyroidectomy for thyroid cancer (95069).
• Infertility. It is unclear if oral L-carnitine is beneficial for female infertility. Details: One uncontrolled clinical trial in females who had failed to conceive in previous in vitro fertilization (IVF) cycles shows that taking L-carnitine (L-CAR Basic Premium; AA Project Co. ltd.) 1000 mg daily for an average of 82 days does not improve the number of retrieved oocytes or fertilization rates when compared with previous IVF cycles. However, embryo quality at days 3 and 5 of insemination was improved, resulting in an increase in the rate of transferable embryos from 60% in previous cycles to 67%, morphologically good-quality embryos from around 46% to 54%, and blastocysts from around 11% to 21%. The most evidence of benefit was seen in those taking L-carnitine for the shortest time length of 7-44 days (96933).
• Intermittent claudication. Although there has been interest in using oral L-carnitine for intermittent claudication, there is insufficient reliable information about the clinical effects of L-carnitine for this purpose.
• Liver disease. Small clinical studies suggest that oral L-carnitine may modestly improve some, but not all, lipid parameters in adults with liver disease. Details: A meta-analysis of six small, low-quality clinical trials in patients with hepatitis C, nonalcoholic steatohepatitis (NASH), and nonalcoholic fatty liver disease (NAFLD) shows that taking L-carnitine moderately reduces total cholesterol and slightly reduces triglyceride levels, but does not improve low-density lipoprotein (LDL) cholesterol or high-density lipoprotein (HDL) cholesterol levels, when compared with control. Studies evaluating L-carnitine doses of 2 grams daily or less and study durations of 24 months or longer showed the largest effect on lipid levels (104178). Another meta-analysis of preliminary clinical research in patients with hepatitis B or C, hepatic encephalopathy, NASH, or NAFLD shows that taking L-carnitine modestly reduces levels if aspartate aminotransferase (AST) and alanine aminotransferase (AST) when compared with taking placebo or no L-carnitine. Some of the studies included in this analysis used acetyl-L-carnitine. However, a meta-analysis of two studies investigating the effect of carnitine orotate shows that taking this compound increases the proportion of patients with normal ALT levels by 4.6 fold (111871).
• Liver transplant. It is unclear if oral L-carnitine is beneficial in patients awaiting a liver transplant. Details: One small clinical trial shows that taking L-carnitine 500 mg three times daily while awaiting a liver transplant does not reduce the incidence of primary graft dysfunction (PGD) or non-function (PNF) when compared with placebo. However, survival one month after surgery was 97% in those taking L-carnitine, compared with 74% in those taking placebo (101562). This study may have been inadequately powered to detect a difference in the incidences of PGD and PNF between groups.
• Low birth weight. It is unclear if oral or intravenous L-carnitine is effective for increasing body weight in preterm infants. Several small clinical studies show conflicting results. Details: Several very small clinical trials in preterm infants receiving total parenteral nutrition show that administering L-carnitine orally at a dose of 13-60 mcmol/kg or intravenously at a dose of 10 mg/kg or 50-100 mcmol/kg daily can improve fat utilization and weight gain when compared with control (3633,3634,3635,3636,3637,58902,59097). However, other small clinical studies show that supplementation with L-carnitine does not significantly increase body weight in preterm infants (58190,58800,59161). The reasons for the discrepant findings are unclear, but due to small study size, some of the studies may have been underpowered to detect significant differences between groups.
• Lyme disease. Although there has been interest in using oral L-carnitine for Lyme disease, there is insufficient reliable information about the clinical effects of L-carnitine for this purpose.
• Metabolic syndrome. It is unclear if oral or intravenous L-carnitine is beneficial in patients with metabolic syndrome. Details: One very small clinical trial in patients with metabolic syndrome undergoing 2 days of moderate calorie restriction followed by a 5-day modified fasting period shows that intravenous L-carnitine 2 grams twice daily for 7 days increases weight loss by 1.4 kg and decreases waist circumference by 3.3 cm when compared with intravenous saline. Perceived hunger scores, physical fatigue, and insulin levels were also improved. However, there were no effects on blood pressure (90634). Other clinical research in patients with metabolic syndrome and a total carotid plaque volume of at least 50 mm³ shows that taking L-carnitine 2 grams daily for 6 months does not affect the progression of carotid plaque volume when compared with taking placebo. Also, taking L-carnitine increased the progression of carotid plaque stenosis by 9.3%, as well as levels of low-density lipoprotein (LDL) cholesterol, in this population (111879).
• Migraine headache. It is unclear if oral L-carnitine is beneficial in patients with migraine headaches. Details: One small clinical trial in patients with migraines shows that taking L-carnitine 500 mg daily, with or without magnesium oxide, for 12 weeks does not significantly reduce migraine frequency or severity when compared with a control (59030). However, another small preliminary clinical trial in children with episodic migraines shows that taking L-carnitine 25 mg per kg twice daily for 12 weeks prophylactically is as effective as taking propranolol 1 mg/kg once daily for reducing the frequency, severity, and duration of migraine headaches (111870). These studies were small and may have been underpowered to detect differences between groups.
• Muscle cramps. It is unclear if oral L-carnitine is beneficial in patients with muscle cramps. Details: One small, uncontrolled clinical trial in adults with type 2 diabetes shows that taking L-carnitine 300 mg twice daily for 4 months decreases the monthly frequency of muscle cramps from around 4 cramps per month at baseline to around 1 cramp per month after treatment. When compared with baseline, pain was also reduced by about 1 point on a 5-point scale (96922). However, the lack of a placebo control group limits the validity of these findings.
• Multiple sclerosis-related fatigue. It is unclear if oral L-carnitine is beneficial in patients with multiple sclerosis-related fatigue. Details: Some patients with multiple sclerosis have low blood levels of L-carnitine. Additionally, immunosuppressive therapy for multiple sclerosis can cause fatigue. One small, open-label clinical trial in patients with multiple sclerosis receiving immunosuppressive therapy and with low L-carnitine levels shows that taking L-carnitine 3-6 grams daily decreases some measures of fatigue when compared with no treatment (16107).
• Myocardial infarction (MI). It is unclear if oral or intravenous L-carnitine is beneficial in patients who have experienced an MI. Details: Some clinical research shows that taking L-carnitine orally or intravenously after MI reduces premature ventricular beats (58172,59044), improves myocardial viability (59248) and left ventricular function (3628), and reduces mortality (3627,3629,59037). However, other studies show no change in left ventricular functioning (58148) or mortality after taking L-carnitine (3628,58225,90630). The reasons for these discrepant findings are unclear, but may be due to differences in the dosing regimens and length of follow-up. Oral L-carnitine doses have ranged from 2-4 grams daily for up to 12 months (3627,3629,59248). Intravenous L-carnitine has been dosed at 5 grams within the first 36 hours after an MI followed by 3 grams twice daily on days 3-7 (58172), 100 mg/kg every 12 hours for 36 hours (59044), or 9 grams daily for 5 days followed by oral L-carnitine 6 grams daily for 12 months (3628).
• Narcolepsy. It is unclear if oral L-carnitine is beneficial in patients with narcolepsy. Details: One small clinical trial in patients with narcolepsy shows that taking L-carnitine 340 mg in the morning and 170 mg in the evening for 8 weeks reduces dozing off time during the day by about 9 minutes when compared with placebo. However, the number of naps needed, quality of life, and sleepiness are not affected (90624).
• Neonatal apnea. It is unclear if intravenous L-carnitine is beneficial for preventing neonatal apnea in premature infants. Details: One small clinical trial in premature infants shows that adding L-carnitine 30 mg/kg daily to total parenteral nutrition or oral feeds does not affect ventilator requirements or reduce the incidence of apnea when compared with placebo (58163).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral L-carnitine is beneficial in children and adults with NAFLD. Details: One small clinical study in adults with NAFLD shows that taking L-carnitine 600 mg daily for 3 months improves markers of liver function when compared with baseline. No improvements in liver function markers were reported in patients in the control group; however, no statistical comparisons were conducted between groups (58808). A small clinical study in children aged 5-15 years with NAFLD receiving vitamin E shows that taking L-carnitine 25 mg/kg twice daily (maximum of 500 mg twice daily) for 3 months has no effect on aminotransferase concentrations or sonographic grades of fatty liver when compared with placebo (107401).
• Nonalcoholic steatohepatitis (NASH). It is unclear if oral L-carnitine is beneficial in patients with NASH. Details: One small clinical trial in patients with NASH shows that taking L-carnitine 1 gram after breakfast and 1 gram after dinner daily along with following a specific diet improves markers of liver function when compared with diet alone (58715). Another small clinical trial in patients with obesity and nonalcoholic steatohepatitis taking simvastatin 20 mg daily and following a hypocaloric diet shows that taking L-carnitine 10 mL twice daily for 90 days modestly reduces BMI, and improves liver health, lipid, and glycemic indices, when compared with taking a product described as essential phospholipids (111893).
• Obesity. Oral L-carnitine seems to have a small effect on weight loss in overweight or obese individuals when taken for up to 6 months, but some conflicting results exist. Doses of 2 grams daily seem to offer the most benefit. Details: Meta-analyses of clinical trials show that taking L-carnitine 250 mg to 4 grams daily reduces weight and body mass index (BMI) by a small amount when compared with a control group not taking L-carnitine (95074,101563,101564). Subgroup analyses show that L-carnitine only reduces BMI and weight in overweight or obese patients. Taking L-carnitine did not affect weight or BMI in patients with a BMI of up to 25 kg/m2 or in patients undergoing hemodialysis (101563,101564). Another subgroup analysis shows that the largest benefit occurs at a dose of 2 grams daily (101564). In patients with obesity and nonalcoholic steatohepatitis taking simvastatin 20 mg daily and following a hypocaloric diet, one clinical trial shows that taking L-carnitine 10 mL twice daily for 90 days modestly reduces BMI, and improves liver health, lipid, and glycemic indices, when compared with taking a product described as essential phospholipids (111893). However, conflicting results exist. One subgroup analysis in overweight or obese individuals shows that there is no effect on BMI when L-carnitine is taken for 24 weeks or more (101563). One meta-analysis of two small clinical trials in patients with overweight or obesity shows that taking L-carnitine is no more effective than lifestyle modification for reducing body weight (111866). Also, some clinical research shows that taking L-carnitine does not reduce body weight in obese females. Doses used in these studies include L-carnitine 1 gram daily for 12 weeks or 2 grams twice daily for 8 weeks along with exercise (58151,111872). The effect of L-carnitine on cardiovascular risk has also been examined in patients with obesity. One small clinical trial shows that taking L-carnitine 1 gram daily for 12 weeks modestly reduces the lipid accumulation index, based on waist circumference and blood triglyceride levels, when compared with taking placebo. However, there was no effect on other cardiovascular risk indices based on ratios of triglycerides, high-density lipoprotein (HDL) cholesterol, and/or low-density lipoprotein (LDL) cholesterol levels (111872). L-carnitine has also been evaluated in combination with weight loss medications. Clinical research shows that taking L-carnitine 2 grams daily along with orlistat 360 mg daily or sibutramine 10 mg daily for 1 year decreases body weight and BMI when compared with orlistat or sibutramine alone in obese adults with type 2 diabetes (58778,58830,58882).
• Osteoarthritis. It is unclear if oral L-carnitine is beneficial in patients with knee osteoarthritis. Details: A small clinical study in females with knee osteoarthritis and overweight or obesity who are on a low-calorie diet shows that taking L-carnitine 1 gram daily for 12 weeks does not improve pain, stiffness, or physical function when compared with placebo (107403).
• Pemphigus. Although there has been interest in using oral L-carnitine for glucocorticoid-induced muscle wasting in patients with pemphigus, there is insufficient reliable information about the clinical effects of L-carnitine for this purpose.
• Peripheral arterial disease (PAD). It is unclear if oral L-carnitine is beneficial in patients with PAD. Details: One small clinical trial in patients with PAD shows that taking L-carnitine 2 grams twice daily for 3 weeks may improve walking distances in people with PAD (3631). However, another small clinical trial in patients with PAD or coronary heart disease shows that taking L-carnitine 2 grams two hours before exercise does not improve endurance (58196). Also, adding L-carnitine 1 gram twice daily to cilostazol therapy for 180 days does not appear to confer additional benefit in this patient population (59023).
• Polycystic ovary syndrome (PCOS). It is unclear if oral L-carnitine is beneficial for improving pregnancy rates or cardiovascular risk in people with PCOS. The effect of L-carnitine on body composition has promising results. Details: Clinical research shows that adding L-carnitine 3 grams daily for 3 months to standard clomiphene plus metformin therapy improves menstrual regularity by 20%, ovulation rate by 24%, and pregnancy rate by 21% when compared with placebo (102123). Preliminary clinical research in patients with PCOS who are resistant to both clomiphene and human chorionic gonadotropin (HCG) shows that taking L-carnitine 2 grams twice daily from day 3 of clomiphene treatment until HCG injection results in the presence of a dominant follicle in 64% of cycles and pregnancy in 20% of cycles (96936). However, L-carnitine may not be beneficial in combination with assisted reproductive technology (ART), including in vitro fertilization and intracytoplasmic sperm injection. A small clinical study in patients with PCOS receiving ART in combination with a gonadotropin-releasing hormone antagonist protocol shows that adding L-carnitine 3000 mg daily during the induction of ovulation (from the second day of the cycle until the day of oocyte triggering) does not improve pregnancy rates in frozen-thawed embryo transfer cycles when compared with control (107409). The effect of L-carnitine has also been examined on anthropometric and cardiovascular risk indices in patients with PCOS. One small clinical study shows that taking L-carnitine 250 mg daily for 12 weeks reduces body weight by 2.8 kg, body mass index (BMI) by 1.2 kg/m2, waist circumference by 1.7 cm, and hip circumference by 2.2 cm when compared with placebo (96935). A meta-analysis of this and other small studies also shows that L-carnitine modestly reduces BMI when compared with placebo in patients with PCOS (111873). Although several studies also show improvements in markers of glycemic control and insulin sensitivity, most research does not support beneficial effects on lipid levels, cardiovascular risk, or liver fat content (96935,107402,107404).
• Rett syndrome. It is unclear if oral L-carnitine is beneficial in patients with Rett syndrome. Details: Two small clinical studies in children with Rett syndrome show that taking L-carnitine 100 mg/kg daily in two or three divided doses for up to 6 months modestly improves well-being, motor skills, sleep efficiency, and communication skills when compared with control or placebo (1433,58161).
• Sarcopenia. Oral L-carnitine may be beneficial for preventing sarcopenia in adults over 75 years of age, but not in healthy older females. Details: One small clinical trial in healthy, active, older females aged 65-70 years shows that taking L-carnitine, as L-carnitine-l-tartrate 1500 mg, daily for 24 weeks does not improve muscle strength or muscle mass when compared with placebo (96930). An additional preliminary clinical trial in females aged 60-75 years taking part in a twice weekly resistance exercise program shows that taking L-carnitine tartrate 1 gram daily with L-leucine 3 grams daily for 24 weeks does not improve muscle strength or volume when compared with taking L-leucine 4 grams daily or no supplementation (111880). These studies were small and may have been underpowered to detect differences. In contrast, in weaker adults 75 years of age and older, taking L-carnitine 2-4 grams daily for 1-6 months increases muscle mass by approximately 2-4 kg when compared with placebo (16109,16111).
• Sepsis. Small clinical studies suggest that intravenous L-carnitine may not reduce mortality in patients with sepsis, although patients with more severe sepsis may see some benefit. Details: Meta-analyses of generally low-quality small clinical trials in patients with sepsis shows that intravenous administration of L-carnitine, 2-6 grams as a bolus followed by a 4-12 gram infusion, does not reduce the risk of 28-day or 1-year mortality when compared with placebo (104180,111868). However, in a subgroup analysis of patients with more severe sepsis, classified as those with a sequential organ failure assessment score (SOFA) of greater than 12, the risk of 1-year mortality was reduced by 32% when compared with placebo (104180).
• Spinal muscular atrophy. Although there has been interest in using oral L-carnitine for spinal muscular atrophy, there is insufficient reliable information about the clinical effects of L-carnitine for this purpose.
• Theophylline-induced cardiac toxicity. It is unclear if intravenous L-carnitine is beneficial in patients with theophylline-induced cardiac toxicity. Details: One small clinical trial shows that intravenous administration of L-carnitine 100 mg/kg over 30-60 minutes followed by 50 mg/kg every 8 hours along with intravenous propranolol within 24 hours of theophylline intoxication improves symptoms associated with theophylline-induced cardiac toxicity when given along with standard treatment. This combination led to greater improvements than either agent used alone. These included improvements in serum theophylline levels, heart rate, arrhythmia, mean arterial pressure, and duration of hospital stay. When L-carnitine was used without propranolol, only respiratory rate and theophylline levels over 24 hours were improved to a greater extent than with standard treatment alone (101566).
• Toxin-induced liver damage. Small clinical studies have evaluated oral and intravenous L-carnitine for the management of liver damage caused by different classes of drugs, including antimycobacterial antibiotics and asparaginase-based agents, with promising results. Details: The antimycobacterial antibiotics used to treat tuberculosis, including isoniazid, rifampicin, and pyrazinamide, have been associated with hepatotoxicity (90922). Clinical research shows that taking L-carnitine 2 grams in two divided doses daily for 4 weeks along with a standard treatment regimen for tuberculosis reduces the percentage of treatment-naïve patients with drug-induced hepatotoxicity by almost half when compared with placebo (26499). The asparaginase-based medications have also been associated with hepatotoxicity. Two case series of children with hyperbilirubinemia caused by treatment with L-asparaginase or pegaspargase show that administering intravenous L-carnitine 50-100 mg/kg daily improves bilirubin levels (100353,100354). One case series also suggests that taking oral L-carnitine 50-100 mg/kg daily can help to prevent hyperbilirubinemia in patients with a history of asparaginase-induced hepatotoxicity (100353).
• Traumatic brain injury (TBI). Although there has been interest in using oral L-carnitine for TBI, there is insufficient reliable information about the clinical effects of L-carnitine for this purpose.
• Urinary tract infections (UTIs). It is unclear if oral L-carnitine is beneficial in children with UTIs. Details: One small clinical trial in children 6 months to 10 years of age shows that taking L-carnitine 50 mg/kg daily as a syrup along with antibiotics for 7 days prevents renal scarring associated with acute pyelonephritis. Kidney damage was resolved in 50% of children taking L-carnitine, compared with 13% of children taking placebo. There were no differences in urine cultures between groups (101568).
• Venous leg ulcers. Although there has been interest in using oral L-carnitine for venous leg ulcers, there is insufficient reliable information about the clinical effects of L-carnitine for this purpose. More evidence is needed to rate L-carnitine for these uses.

(Read more about L-CARNITINE)

EFFECTIVE

• Bowel preparation. Oral sodium phosphate is effective for cleansing the colon in preparation for colonoscopy; however, it is unclear whether sodium phosphate is as effective as polyethylene glycol (PEG) solution. Some products are approved by the US Food and Drug Administration (FDA) for this use. However, due to the potential for kidney damage, sodium phosphate is not recommended as first-line therapy. Details: Sodium phosphate tablets (OsmoPrep, Salix Pharmaceuticals; Visicol, Salix Pharmaceuticals) are FDA-approved for cleansing the colon in preparation for colonoscopy. Clinical research shows that using the OsmoPrep formulation can achieve an "excellent" or "good" response rate, which is defined as having 90% of the mucosa visible with only some or little suctioning needed, in 94% to 97% of patients (88133). Similarly, using the specific product Visicol has been shown to achieve an excellent or good response rate in 82% to 86% of patients (94674). Non-FDA-approved sodium phosphate products have also been investigated. One such product (Fleet Phospho-soda, C. B. Fleet Co.) has been shown to achieve adequate bowel cleansing in 23% to 89% of patients (93846,94673). Another sodium phosphate tablet preparation (Clicolon tablets, Korea Pharma Co.) has been shown to achieve adequate bowel cleansing in 63% to 93% of patients (93848,93850,93853). Excellent or good bowel cleansing was found in 98.6% of patients using a 32-tablet regimen of other sodium phosphate tablets (Quiklean, Universal Integrated Corporation) (107008). Reasons for the differences in the percentage of patients who achieve adequate bowel cleansing with the same sodium phosphate product may relate to the method used to analyze bowel cleansing, differences in diet followed during bowel cleansing, and demographic factors (93846,93848,93850,93853). Various preparations (OsmoPrep, Salix Pharmaceuticals; Visicol, Salix Pharmaceuticals; Clicolon tablets, Korea Pharma Co.; Quiklean, Universal Integrated Corporation) have been used which contain 1.102 grams of sodium phosphate monobasic monohydrate and 0.398 grams of sodium phosphate dibasic anhydrous. These products have been taken as 3-4 tablets with 8 ounces of water every 15 minutes for a total of 20 tablets the evening before colonoscopy, and 3-4 tablets with 8 ounces of water every 15 minutes for a total of 12-20 tablets the morning of a colonoscopy (88133,93848,93850,94674,107008). Also, sodium phosphate solution (Fleet Phospho-soda, C. B. Fleet Co.) containing sodium hydrogen phosphate 24.4 grams and disodium phosphate dodecahydrate 10.8 grams has also been used the morning and evening before the procedure (93846). Numerous publications have compared the bowel cleansing activity of sodium phosphate with PEG solution. When given as a split-overnight dosage, sodium phosphate is about as effective as PEG solutions in achieving adequate bowel cleansing. However, when day-before dosage is used, PEG is more effective for bowel cleansing than sodium phosphate (93861,93862,107008). Sodium phosphate and PEG may have different effectiveness depending on the colonic site assessed. When only trials assessing descending colon cleansing are considered, sodium phosphate is found to work similarly to PEG solutions. When only studies assessing ascending colon cleansing are considered, PEG is more effective for bowel cleansing than sodium phosphate (93861). Also, a large clinical trial in outpatients scheduled for non-sedated colonoscopy shows that receiving PEG resulted in an easier insertion and a less painful colonoscopy when compared with receiving sodium phosphate (104473). However, in patients with chronic constipation, sodium phosphate seems to be preferable. A meta-analysis of three small clinical studies in adults with chronic constipation shows that using sodium phosphate has an 87% greater chance of a successful bowel preparation when compared with using PEG (104472). Sodium phosphate is not recommended as first-line therapy for bowel preparation prior to colonoscopy due to the potential for kidney damage (93863,94672). In fact, one sodium phosphate preparation (Fleet Phospho-soda, C. B. Fleet Co.) that was previously approved as an over-the-counter supplement for bowel preparation in the US was withdrawn from the market for this indication in December 2008 due to concerns for phosphate-induced kidney disease (94672). Of the sodium phosphate products that are still approved by the FDA, current guidelines recommend that these products not be used for bowel cleansing in patients with kidney disease, pre-existing electrolyte disturbances, congestive heart failure, cirrhosis, ascites, or inflammatory bowel disease. Guidelines also recommend that caution should be used if these products are prescribed for patients who are elderly, hypertensive, or taking certain classes of drugs (94672). For small bowel preparation for endoscopy, a meta-analysis suggests that sodium phosphate is no more effective than fasting alone (93860).
• Hypophosphatemia. Oral or intravenous phosphate salts are effective for the prevention or treatment of hypophosphatemia. Some products are approved by the US Food and Drug Administration (FDA) for this use. Details: Taking sodium or potassium phosphate orally is effective for preventing and treating hypophosphatemia (15). Treating hypophosphatemia with oral phosphates requires monitoring of serum electrolyte levels to determine appropriate dosing (15). The FDA-approved intravenous (IV) product is also used for the correction of hypophosphatemia (8302,8303,88135). FDA-approved intravenous (IV) sodium phosphate or potassium phosphate 15-30 mmol is typically given over 2-12 hours. Higher doses have been used if needed to increase efficacy (8302,8303,88135).

LIKELY EFFECTIVE

• Constipation. Oral or rectal sodium phosphate is approved by the US Food and Drug Administration (FDA) as an ingredient in over-the-counter (OTC) products to treat constipation. Details: Sodium phosphate is an FDA-permitted ingredient of oral and rectal OTC products intended for the treatment of constipation (88107).
• Dyspepsia. Oral aluminum phosphate and calcium phosphate are approved by the US Food and Drug Administration (FDA) as ingredients in over-the-counter (OTC) antacids. Details: Aluminum phosphate and calcium phosphate are FDA-permitted ingredients of oral OTC products intended for use as antacids (88107).
• Hypercalcemia. Although other treatments are preferred, oral non-calcium phosphate salts are beneficial for treatment of mild to moderate hypercalcemia. Details: Taking phosphate salts (except calcium phosphate) orally is effective for treating mild to moderate hypercalcemia (88144,88145). Treating hypercalcemia with oral phosphates requires monitoring of serum electrolyte levels to determine appropriate dosing (15); other agents are now preferred (6479). Intravenous phosphates should be avoided due to the risk of calcium precipitation in vital organs (metastatic calcification) (15,88144,88145).

POSSIBLY EFFECTIVE

• Kidney stones (nephrolithiasis). Oral potassium phosphate seems to be beneficial for prevention of kidney stones in individuals with hypercalciuria. Details: Taking potassium phosphate orally may help prevent calcium oxalate kidney stones in patients with hypercalciuria (6470). Clinical research in adults with absorptive hypercalciuria and at high risk for stone formation shows that taking a specific slow-release potassium phosphate product (Uro-Phos-K, Mission Pharmacal), providing phosphate 620 mg orally twice daily for 4 days, reduces urinary calcium excretion by 35% to 40% (2208,2209). Potassium and sodium phosphate salts providing 1200-1500 mg of elemental phosphate daily have been used (2209,6470).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Athletic performance. The evidence is mixed as to whether oral sodium phosphate improves cycling or running performance. Most research suggests that oral calcium phosphate and potassium phosphate are not beneficial. Details: Clinical research shows that taking calcium phosphate or potassium phosphate orally does not improve running or cycling performance (2499,9300,8301). Evidence for the use of sodium phosphate to improve cycling performance is mixed. One very small clinical study shows that taking sodium phosphate as tribasic sodium phosphate dodecahydrate for 6 days before a 10-mile cycling trial increases mean power output by about 10% and decreases the time needed to complete the trial by 3% in trained male cyclists (88150). Other small clinical trials in trained cyclists show that taking the same form of sodium phosphate as 50 mg/kg of fat-free mass in four divided doses daily for 6 days modestly improves work, power output, and peak oxygen uptake and reduces heart rate during high-intensity cycling exercise when compared to baseline (93857,93858,93859,107007). However, conflicting research shows that taking a similar dosage of this form of sodium phosphate does not improve time trial performance, work accomplished relative to energy expenditure, power output, or oxygen uptake in trained cyclists (93855,93856,107007). Sodium phosphate has also been evaluated for improving running performance, with mixed findings. Two small clinical trials in female athletes show that tribasic sodium phosphate dodecahydrate 50 mg/kg of fat-free mass taken in four divided doses daily for 6 days moderately improves repeated sprint times when compared with placebo (93843,93844). However, taking the same dosage does not significantly improve sprint times in male athletes (93849). Also, sodium phosphate does not seem to improve endurance or aerobic capacity in treadmill tests (8301,93854). Reasons for the discrepancies regarding the effects of sodium phosphate on athletic performance are not entirely clear, but likely relate to the very small number of participants in the included trials.
• Diabetic ketoacidosis. Potassium phosphate infusion is not recommended as first-line therapy for adults with diabetic ketoacidosis. Details: Clinical research shows that intravenous infusion of potassium phosphate 8.5 mmol/hour (approximately 6 grams of phosphate over 24 hours) along with potassium chloride 12.5 mEq/hour provides no benefit over potassium chloride alone in adults with diabetic ketoacidosis (88149). Guidelines for the treatment of diabetic ketoacidosis in the both the US and UK do not recommend phosphate replacement for most patients. However, it may be considered in specific cases, such as cardiac dysfunction, anemia, respiratory depression, and serum phosphate concentrations below 1 mg/dL (107349,107350A).
• Osteoporosis. Calcium phosphate seems to be beneficial for bone density improvement; however, it does not seem to be more beneficial than calcium carbonate. Details: In postmenopausal adults with osteoporosis and low phosphate intakes, taking calcium 1800 mg daily as tricalcium phosphate for 12 months improves lumbar spine and hip densities. However, it is no more effective than taking the same amount of calcium as calcium carbonate (93847). The calcium products were used in combination subcutaneous teriparatide and oral vitamin D (cholecalciferol) 1000 IU daily.
• Refeeding syndrome. It is unclear if intravenous potassium phosphate or sodium phosphate is beneficial for prevention of refeeding syndrome. Details: Preliminary clinical research shows that giving intravenous sodium and potassium phosphates, 50 mmol (1.56 grams) phosphate over 24 hours, prevents the refeeding syndrome seen when restarting adequate nutrition after severe malnutrition or starvation when compared with historical controls (88148). More evidence is needed to rate phosphate salts for these uses.

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

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

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

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

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

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

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LIKELY SAFE ...when used orally and appropriately. L-carnitine has been safely used in clinical trials lasting up to 12 months (1947,3620,3621,3623,3624,3625,3626,3627,3628,3629) (3630,3639,4949,8047,9790,12352,16104,16105,16106,16107) (16109,16110,23437,26496,26499,58150,58156,58161,58169,58182) (58189,58204,58207,58209,58213,58294,58523,58554,58556,58647) (58679,58715,58778,58793,58830,58831,58882,59023,59029,59043) (90624,90633,104177,111872,111876,111883,111884,111891,111898). ...when used parenterally as an FDA-approved prescription medicine. Avoid using D-carnitine and DL-carnitine. These forms of carnitine can act as competitive inhibitors of L-carnitine and may cause symptoms of L-carnitine deficiency (1946).

CHILDREN: POSSIBLY SAFE
when used orally or intravenously and appropriately. L-carnitine has been safely used orally in children for up to 6 months (1433,3622,58166,58502,58981,59188,111887,111900). It has also been safely used orally and intravenously in preterm infants (3633,3634,3635,3636,3637,58163,58190,58800,58902,59097)(59161).

PREGNANCY:
Insufficient reliable information available; avoid using.

LACTATION: POSSIBLY SAFE
when used orally. Supplemental doses of L-carnitine have been given to infants in breast milk and formula with no reported adverse effects. The effects of large doses used while nursing are unknown, but L-carnitine is secreted in the breast milk (3616).

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LIKELY SAFE ...when used orally and appropriately short-term (15). ...when sodium phosphate is used rectally and appropriately, no more than once every 24 hours, short-term (104471). Long-term use or high doses used orally or rectally require monitoring of serum electrolytes (2494,2495,2496,2497,2498,3092,112922). ...when used intravenously. Potassium phosphate is an FDA-approved prescription drug (15).

POSSIBLY UNSAFE ...when phosphate (expressed as phosphorus) intake exceeds the tolerable upper intake level (UL) of 4 grams daily for adults under 70 years and 3 grams daily for adults older than 70. Hyperphosphatemia, resulting in electrolyte disturbances, alterations in calcium homeostasis, and calcification of nonskeletal tissues, may occur (7555). ...when used rectally more frequently than once every 24 hours, in excessive doses, with longer retention enema time, or in older patients with comorbidity or renal impairment (112922). The US Food and Drug Administration (FDA) warns that this may increase the risk of hyperphosphatemia, dehydration, and electrolyte imbalances leading to kidney and heart damage (104471).

CHILDREN: LIKELY SAFE
when used orally and appropriately at recommended dietary allowances (RDAs). The daily RDAs are: children 1-3 years, 460 mg; children 4-8 years, 500 mg; males and females 9-18 years, 1250 mg (7555). ...when sodium phosphate is used rectally and appropriately, no more than once every 24 hours, short-term in children 2 years and older (104471). ...when used intravenously. Intravenous potassium phosphate is an FDA-approved prescription drug (15).

CHILDREN: POSSIBLY UNSAFE
when phosphate (expressed as phosphorus) intake exceeds the tolerable upper intake level (UL) of 3 grams daily for children 1-8 years of age and 4 grams daily for children 9 years and older. Hyperphosphatemia, resulting in electrolyte disturbances, alterations in calcium homeostasis, and calcification of nonskeletal tissues, may occur (7555). ...when sodium phosphate is used rectally more frequently than once every 24 hours, or in children under 2 years of age or with Hirchsprung disease (112922). The US Food and Drug Administration (FDA) warns that these uses may increase the risk of hyperphosphatemia, dehydration, and electrolyte imbalances leading to kidney and heart damage (104471).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately at the recommended dietary allowance (RDA) of 1250 mg daily for individuals 14-18 years of age and 700 mg daily for those over 18 years of age (7555). ...when sodium phosphate is used rectally and appropriately short-term (15). ...when used intravenously. Intravenous potassium phosphate is an FDA-approved prescription drug (15).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when phosphate (expressed as phosphorus) intake exceeds the tolerable upper intake level (UL). Hyperphosphatemia, resulting in electrolyte disturbances, alterations in calcium homeostasis, and calcification of nonskeletal tissues, may occur. The UL during pregnancy is 3.5 grams daily. During lactation, the UL is 4 grams daily (7555).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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ACENOCOUMAROL (Sintrom) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, L-carnitine might increase the anticoagulant effects of acenocoumarol.  Details L-carnitine might enhance the anticoagulant effects of acenocoumarol, an oral anticoagulant similar to warfarin, but shorter-acting (9878,12165). There are at least two case reports of INR elevation with concomitant use. In one case, a 33-year-old male with a previously stable INR had an elevated INR of 4.65 after L-carnitine was started and continued for 10 weeks. INR normalized after discontinuation of the L-carnitine-containing product (12165).

THYROID HORMONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, L-carnitine might decrease the effectiveness of thyroid hormone replacement.  Details L-carnitine appears to act as a peripheral thyroid hormone antagonist by inhibiting entry of thyroid hormone into the nucleus of cells (12761). Taking L-carnitine also seems to diminish some of the symptoms of hyperthyroidism (8047).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, L-carnitine might increase the anticoagulant effects of warfarin.  Details L-carnitine might increase the anticoagulant effects of acenocoumarol, a shorter-acting oral anticoagulant similar to warfarin (9878,12165). There is not enough information to know whether this interaction occurs with L-carnitine and warfarin.

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BISPHOSPHONATES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking phosphate salts with bisphosphonates might increase the risk of hypocalcemia.  Details Combining bisphosphonates and phosphate can cause hypocalcemia. In one report, hypocalcemic tetany developed in a patient taking alendronate (Fosamax) who received a large dose of phosphate salts as a pre-operative laxative (14589).

ERDAFITINIB (Balversa) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = A Taking erdafitinib with phosphate salts increases the risk of hyperphosphatemia.  Details Erdafitinib increases phosphate levels. It is recommended that patients taking erdafitinib restrict phosphate intake to no more than 600-800 mg daily (104470).

FUTIBATINIB (Lytgobi) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = A Taking futibatinib with phosphate salts increases the risk of hyperphosphatemia.  Details Futibatinib can cause hyperphosphatemia, as reported in 88% of patients in clinical studies. In addition, 77% of patients in clinical studies required use of a phosphate binder to manage hyperphosphatemia. Phosphate salts should generally be avoided by people taking this medication (112912).

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

Cardiovascular ...There has been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these results, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Many of these trials also only included postmenopausal females. Other analyses report conflicting results, and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Reasons for these discrepancies are not entirely clear. It may relate to whether calcium is taken as monotherapy or in combination with vitamin D. When taken with vitamin D, which is commonly recommended, calcium supplementation does not appear to be associated with an increased risk of CVD, CHD, or MI (93533,107231). Also, the association between calcium supplementation and CVD, CHD, or MI risk may be influenced by the amount of calcium consumed as part of the diet. Supplementation with calcium may be associated with an increased risk of MI in people with dietary calcium intake above 805 mg daily, but not in those with dietary calcium intake below 805 mg daily (17482). To minimize the possible risk of CVD, CHD, or MI, advise patients not to consume more than the recommended daily intake of 1000-1200 mg and to consider total calcium intake from both dietary and supplemental sources (17484). While dietary intake of calcium is preferred over supplemental intake, advise patients who require calcium supplements to take calcium along with vitamin D, as this combination does not appear to be associated with an increased risk of MI (93533).
Rarely, calcium intake can increase the risk of calciphylaxis, which usually occurs in patients with kidney failure. Calciphylaxis is the deposition of calcium phosphate in arterioles, which causes skin ulcers and skin necrosis. In a case report, a 64-year-old female with a history of neck fracture, sepsis, and ischemic colitis presented with painful leg ulcers due to calciphylaxis. She discontinued calcium and vitamin D supplementation and was treated with sodium thiosulfate and supportive care (95816).

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

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

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

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General ...Orally and intravenously, L-carnitine is generally well tolerated.
Most Common Adverse Effects:
All routes of administration: Abdominal cramps, abdominal pain, diarrhea, gastritis, heartburn, nausea, reduced appetite, and vomiting. A fish-like body odor has also been reported.
Serious Adverse Effects (Rare):
All routes of administration: Seizures.

Cardiovascular ...According to population research, plasma L-carnitine levels are associated with increased risk of cardiovascular disease and major cardiac events (90635). However, oral supplementation with L-carnitine does not appear to be associated with an increased risk of cardiovascular disease. In fact, a meta-analysis of clinical research shows that L-carnitine supplementation is associated with a reduction in all-cause mortality, as well as ventricular arrhythmias and the development of angina and does not increase the development of heart failure or myocardial reinfarction (59037). Also, another meta-analysis suggests that L-carnitine does not affect mortality or cardiovascular outcomes in patients with a previous myocardial infarction (90630).

Dermatologic ...Orally, L-carnitine has been reported to cause skin rash in a small number of cases (16105,91724). Two patients in a hair growth study using topical carnitine reported mild itching and increased dandruff, while a third reported strong itching with reddish bumps and a burning sensation (58390). When a specific formulation containing L-carnitine, licochalcone, and 1,2-decanediol was applied to the face, mild skin dryness and tightness was reported by 12% of volunteers, compared with 4% to 8% of those in the vehicle-only control group (26493).

Gastrointestinal ...Orally and intravenously, L-carnitine has been associated with nausea, epigastric discomfort, vomiting, abdominal cramps, heartburn, gastritis, anorexia, and diarrhea (3616,3624,59030,95069,95070,101562,107410,111870,111887,111891). Orally, diarrhea or colitis symptoms (1433,3630,16105,16107,16111,23437,58523,58554,59020,90623), nausea and abdominal pain (16105,16106,26499,58169,58392,58554,90623,90634), indigestion (26703), and constipation (58523) have been reported in various clinical trials.

Hematologic ...In one case report, L-carnitine 990 mg twice daily was started in a female presenting to hospital with valproic acid toxicity. Blood phosphorous levels subsequently fell from 2.3 mg/dL to 1.3 mg/dL over 4 days. After discontinuation of L-carnitine, blood phosphorus levels increased to 1.8 mg/dL. The authors suggested that the role of L-carnitine in improved protein metabolism may play a role in the declining levels of phosphorous in the blood and increased risk of hypophosphatemia (90628).

Neurologic/CNS ...Orally or intravenously, L-carnitine has been associated with seizures (3616). Orally, use of L-carnitine in clinical trials has resulted in headache, although this event is rare (58554,95070,111891). L-carnitine may also cause agitation (95070).

Other ...Orally or intravenously, L-carnitine has been associated with a fish-like body odor (1433,3616,58166,59854,90623). One of its metabolites, trimethylamine N-oxide, can cause the urine, breath, and sweat to have a fishy odor (12756,58664).

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General ...Orally, intravenously, and rectally, phosphate salts are generally well tolerated when used appropriately and/or as prescribed.
Most Common Adverse Effects:
Orally: Abdominal pain, anal irritation, bloating, diarrhea, headache, gastrointestinal irritation, hyperphosphatemia, hypocalcemia, malaise, nausea, sleep disturbance, and vomiting.
Rectally: Hyperphosphatemia and hypocalcemia.
Serious Adverse Effects (Rare):
Orally: Extraskeletal calcification.

Cardiovascular ...Orally, a case of allergic acute coronary syndrome e., Kounis syndrome) is reported in a 43-year-old female after ingesting a specific sodium phosphate laxative product (Travad oral). She presented with maculopapular rash that progressed to anaphylaxis and a non-ST elevation acute coronary syndrome. The patient recovered after hospitalization for 3 days with medical management (112894).

Gastrointestinal ...Orally, phosphate salts can cause gastrointestinal irritation, nausea, abdominal pain, bloating, anal irritation, and vomiting (15,2494,2495,2496,2497,93846,93848,93850,93851,93853,107008). Sodium and potassium phosphates can cause diarrhea (15). Aluminum phosphate can cause constipation (15). A large comparative study shows that, when taken orally as a bowel preparation for colonoscopy, sodium phosphate is associated with gastric mucosal lesions in about 4% of patients (93868).

Neurologic/CNS ...Orally, phosphate salts can commonly cause malaise (93846). Headaches and sleep disturbance may also occur (93848,93851).

Renal ...Orally, use of sodium phosphate for bowel cleansing has been associated with an increased risk of acute kidney injury in some patients (93863). However, a pooled analysis of clinical research suggests that results are not consistent for all patients (93864). Some evidence suggests that female gender, probably due to lower body weight, iron-deficiency anemia, dehydration, and chronic kidney disease are all associated with an increased risk of sodium phosphate-induced kidney dysfunction (93865).

Other ...Orally, phosphate salts can cause fluid and electrolyte disturbances including hyperphosphatemia and hypocalcemia, and extraskeletal calcification. Potassium phosphates can cause hyperkalemia. Sodium phosphates can cause hypernatremia and hypokalemia (15,2494,2495,2496,2497,107008).
Rectally, phosphate salts can cause fluid and electrolyte disturbances including hyperphosphatemia and hypocalcemia (15,112922).
Deaths related to intake of oral or rectal phosphate salts are rare and most have occurred in infants and are related to overdose (93866). However, death has also been reported in elderly patients using sodium phosphate enemas, mainly at standard doses of 250 mL (93867).

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