Cinnamon, Chromium & Biotin by Natrol

LIKELY EFFECTIVE

• Biotin deficiency. Oral and injectable biotin prevents and treats biotin deficiency. Details: Biotin up to 10 mg daily has been used to treat and prevent biotin deficiency. Injections of biotin 150 mcg daily for 3-5 days have been used in adults. Biotin deficiency might occur due to different etiologies such as inherited biotinidase deficiency, malnutrition, chronic use of anticonvulsants, pregnancy, and excessive and chronic raw egg consumption (6243,19347). A very small study in newborns aged 1-6 months shows that adding biotin to infant formula safely improves biotin status in formula-fed infants (111365). The validity of these findings is limited by a lack of blinding, no randomization, and the small sample size.

POSSIBLY INEFFECTIVE

• Multiple sclerosis (MS). In spite of contrary reports, high-dose biotin (300 mg daily) does not reduce disability in patients with progressive MS. It also does not seem to be linked to an increased risk for relapse. Details: Although most earlier research suggested benefit, the highest quality evidence shows that high-dose biotin does not improve outcomes in progressive MS (95662,102963,102966,104011). A large multi-centered randomized clinical trial (SPI2) in patients with progressive MS and high disability shows that taking biotin 100 mg three times daily for 15 months does not improve disability, as measured on the expanded disability status scale (EDSS), or 25-foot walking time, when compared with placebo. The SPI2 clinical trial also did not find that biotin increases the rate of relapse (104011), a concern raised in one observational study of high-dose biotin (104000). Also, a large observational study of adults with progressive MS failed to identity an increase in annualized relapse rates in patients that reported taking biotin when compared with controls (105716). Other observational research has also found no effect on the relapse risk (102963,102964). There is some speculation that any increased rate of relapse identified in some high-dose biotin cohorts might be due to detection bias or reduced compliance with disease-modifying therapies.
• Seborrheic dermatitis. Oral biotin doesn't seem to improve seborrheic dermatitis of infancy. Details: A clinical trial in infants with seborrheic dermatitis shows that biotin given by mouth does not improve symptoms when compared with placebo (8469).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alopecia areata. It is unclear if oral biotin is beneficial for alopecia areata. Details: A small clinical study in healthy adults with alopecia areata shows that weekly injections of intramuscular biotin 5 mg/1 mL and dexpanthenol 250 mg/2 mL for 6 weeks reduces hair fall count and transiently increases hair density compared with baseline (111366). The validity of these findings is limited by a lack of a placebo control group, small sample size, and short duration of treatment. It is unclear if the effects are due to biotin, dexpanthenol, or the combination. Another small clinical study in 9-year-old children with alopecia areata shows that taking biotin 20 mg with zinc aspartate 100 mg orally along with topical application of clobetasol propionate 0.025% daily for one year promotes hair regrowth in 33% of children, compared with 0% in the group receiving the steroid deflazacort (6932). It is unclear if these effects are due to biotin, zinc, topical clobetasol, or the combination.
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). Although there is interest in using oral biotin for ALS, there is insufficient reliable information about the clinical effects of biotin for this condition.
• Biotin-thiamine-responsive basal ganglia disease. Adding oral biotin to oral thiamine does not seem to improve most symptoms associated with this condition, although it may slightly speed recovery from acute crisis in children. Details: A small case series in children ages 1-12 years with biotin-thiamine-responsive basal ganglia disease has found that adding biotin 5 mg/kg daily to thiamine 40 mg/kg daily for 30 months is not associated with additional symptomatic improvement in encephalopathy, seizures, dystonia, or other neurologic sequelae when compared with taking only thiamine. However, taking biotin with thiamine is associated with a 1-day reduction in recovery from acute crisis when compared with thiamine alone (95661).
• Brittle nails. Low quality clinical studies suggest that oral biotin might improve nail thickness and prevent the splitting of brittle nails. Details: Some small, low quality clinical studies in people with brittle nails shows that taking biotin 2.5 mg orally daily for 1.5 to 15 months increases nail thickness and decreases the splitting of fingernails and toenails in some people when compared with baseline (171,35593). The validity of these findings is limited by the small study sizes and the lack of a comparator group.
• Depression. Although there is interest in using oral biotin for mild depression, there is insufficient reliable information about the clinical effects of biotin for this condition.
• Diabetes. It is unclear if oral biotin is beneficial for type 2 diabetes. Details: A meta-analysis of randomized controlled trials shows that taking biotin 1.5-15 mg orally daily for 1-3 months does not improve fasting blood glucose or serum insulin levels when compared with placebo. However, the validity of these results is limited by inclusion of subjects with and without diabetes (110044). A very small study in adults with type 2 diabetes also shows that taking biotin 5 mg three times daily for 28 days does not affect glucose or insulin levels when compared to baseline (11579). Biotin has also been studied in combination with other ingredients. Preliminary clinical research shows that a taking a specific supplement containing a combination of biotin 2 mg and chromium picolinate 600 mcg (Diachrome, Nutrition 21) can lower blood glucose and glycated hemoglobin levels in patients with type 2 diabetes who are poorly controlled on oral hypoglycemic drugs (12385,12390,15169). It is unclear if these effects are due to biotin, chromium, or the combination.
• Diabetic neuropathy. Although there is interest in using oral and intramuscular biotin for diabetic neuropathy, there is insufficient reliable information about the clinical effects of biotin for this condition.
• Muscle cramps. It is unclear if biotin is beneficial for improving muscle cramps in patients undergoing hemodialysis. Details: Patients undergoing hemodialysis are prone to muscle cramps. A small clinical study in patients with hemodialysis-related muscle cramps shows that taking biotin 1 mg in the morning daily for at least one week prevents and reduces severity of muscle cramps when compared to baseline. Cessation of biotin led to recurrence of cramps, and restarting oral biotin led to resolution of cramps during hemodialysis (89475). The validity of these findings is limited by the lack of comparator group. More evidence is needed to rate biotin for these uses.

(Read more about BIOTIN)

POSSIBLY INEFFECTIVE

• Diabetes. Most research shows that oral Ceylon cinnamon does not benefit patients with type 2 diabetes. Details: Clinical research in adults with well-controlled type 2 diabetes shows that taking Ceylon cinnamon 1-9 grams orally daily for 2-3 months does not improve fasting blood glucose when compared with placebo or a control group (99436,99437,99439). However, one small clinical study in adults with poorly controlled type 2 diabetes despite treatment with metformin showed a trend toward improvement in fasting blood glucose. Taking Ceylon cinnamon 3 grams daily for 8 weeks reduced fasting blood glucose by 12 mg/dL, compared with an increase of 9 mg/dL in those taking placebo. Although this difference was not statistically significant, the study might not have been adequately powered to show a difference. Also, the 8-week duration of this study was too short to reliably assess the effect of Ceylon cinnamon on glycated hemoglobin (HbA1c) (99438). Conversely, a large study clinical study in patients with type 2 diabetes conducted in India shows that taking Ceylon cinnamon 1.5 grams daily for 4 months improves fasting blood glucose by 40 mg/dL and HbA1c by 1% when compared with placebo but does not significantly improve either outcome when compared to baseline (112422). However, it is unclear whether modifications to diabetes medications were allowed during the study.
• Obesity. Preliminary clinical research suggests that oral Ceylon cinnamon does not help with weight loss. Details: Preliminary clinical research shows that drinking black tea steeped with 3 grams of Ceylon cinnamon dried powder three times daily for 8 weeks does not affect weight, waist circumference, or blood pressure when compared with baseline or black tea alone in overweight patients with diabetes (95597). Other preliminary research shows that taking Ceylon cinnamon, titrated up from 85 mg to 500 mg, daily for 3 months has no effect on weight or body mass index, but may reduce hip circumference by 1.8 cm, when compared with baseline in healthy, mostly normal weight adults (97250).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). A nasal spray containing a Ceylon cinnamon extract might improve symptoms of allergic rhinitis. It is unclear if oral Ceylon cinnamon is beneficial. Details: Using a nasal spray containing a polyphenol-rich standardized extract of Ceylon cinnamon 1 mg/mL, twice daily in each nostril for 7 days, reduces the severity of nasal, eye, and nocturnal symptoms, and improves quality of life and work productivity when compared with placebo in people with seasonal allergic rhinitis who are not using any other medications for the condition (103169). One small clinical study in patients with seasonal allergic rhinitis shows that taking a specific combination product (ClearGuard, Access Business Group LLC) containing Ceylon cinnamon extract, acerola fruit concentrate, and powdered Spanish needles (Bidens pilosa) orally, 450 mg three times daily for 3 days, improves nasal symptoms 8 hours after, but not immediately following, a nasal allergen challenge when compared with placebo (23709).
• Chronic obstructive pulmonary disease (COPD). Ceylon cinnamon has only been studied in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in adults with COPD shows that taking a combination product containing extracts of Ceylon cinnamon, ginger, alpinia, cardamom, and saffron in honey 3 times daily for 8 weeks improves confidence in leaving home and the ratio of forced exploratory volume per second to forced vital capacity of the lungs (FEV1/FVC) when compared with placebo. However, the combination product does not improve most measures of respiratory function or symptoms such as cough, phlegm, chest tightness, dyspnea, reduced energy levels, sleeping disorders, or activity limitations when compared with placebo (111542). It is unclear if these effects are due to Ceylon cinnamon, other ingredients, or the combination.
• Common cold. Although there has been interest in using oral Ceylon cinnamon for the common cold, there is insufficient reliable information about the clinical effects of Ceylon cinnamon for this purpose.
• Denture stomatitis. It is unclear if topical Ceylon cinnamon is beneficial in patients with denture stomatitis. Details: A small clinical trial in patients with denture stomatitis shows that using 10 mL of a mouthwash, as well as a denture spray, containing Ceylon cinnamon essential oil three times daily for 15 days modestly reduces Candida measurements and improves the severity of stomatitis in the oral mucosa and dentures when compared with baseline (108262). The validity of these findings is limited by the lack of a comparator group.
• Diarrhea. Although there has been interest in using oral Ceylon cinnamon for diarrhea, there is insufficient reliable information about the clinical effects of Ceylon cinnamon for this purpose.
• Dysmenorrhea. It is unclear if oral Ceylon cinnamon is beneficial in patients with dysmenorrhea. Details: One preliminary clinical trial in adults with primary dysmenorrhea shows that taking Ceylon cinnamon orally 1 gram three times daily during the first 72 hours of menstruation over the course of two cycles decreases pain by 1.6 points on a 10-point visual analog scale when compared with placebo (99875). The use of a per-protocol analysis limits the validity of these results.
• Dyspepsia. It is unclear if oral Ceylon cinnamon is beneficial in patients with dyspepsia. Details: A small clinical trial in patients with functional dyspepsia shows that taking one capsule of Ceylon cinnamon oil, providing an unspecified dose, three times daily for 6 weeks does not improve symptoms of dyspepsia when compared with sesame oil as placebo (108263).
• Hypertension. It is unclear if oral Ceylon cinnamon is beneficial in patients with prehypertension. Details: A small clinical trial in patients with prehypertension shows that taking Ceylon cinnamon 500 mg three times daily for 90 days does not affect final blood pressure measurements when compared with placebo. However, there was a modest reduction in mean daytime systolic blood pressure when compared with placebo (108261).
• Impaired glucose tolerance (prediabetes). Although there has been interest in using oral Ceylon cinnamon for impaired glucose tolerance, there is insufficient reliable information about the clinical effects of Ceylon cinnamon for this purpose.
• Influenza. Although there has been interest in using oral Ceylon cinnamon for influenza, there is insufficient reliable information about the clinical effects of Ceylon cinnamon for this purpose.
• Intestinal parasite infection. Although there has been interest in using oral Ceylon cinnamon for intestinal parasite infection, there is insufficient reliable information about the clinical effects of Ceylon cinnamon for this purpose.
• Irritable bowel syndrome (IBS). Oral Ceylon cinnamon has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination of powdered Ceylon cinnamon 1.5 grams, dried bilberry fruit 10 grams, slippery elm bark 4.5 grams, and agrimony 3 grams orally twice daily for 3 weeks increases the number of bowel movements and reduces symptoms such as abdominal pain, bloating, flatulence, and straining in patients with diarrhea-predominant IBS (35462).
• Migraine headache. It is unclear if oral Ceylon cinnamon is beneficial in patients with migraine headache. Details: Preliminary clinical research shows that taking Ceylon cinnamon powder orally 600 mg three times daily for 2 months, in addition to regular medications for migraine, decreases the frequency, severity, and duration of migraine attacks when compared with placebo (104520).
• Polycystic ovary syndrome (PCOS). It is unclear if oral Ceylon cinnamon is beneficial in patients with PCOS. Details: Taking Ceylon cinnamon orally 1.5 grams daily for 3 months in adults with PCOS does not appear to improve fasting insulin levels, fasting glucose levels, glycated hemoglobin, testosterone, lipid parameters, body weight, or body mass index when compared with placebo (97248). However, a meta-analysis of 5 low-quality studies shows that taking Ceylon cinnamon 0.5-1.5 grams daily for 8 weeks to 1 year reduces insulin resistance and fasting serum insulin levels (104518). Ceylon cinnamon has also been evaluated in combination with other ingredients. Some preliminary clinical research in overweight adults with PCOS shows that taking three tablets of a combination product containing extracts of Ceylon cinnamon, licorice root, peony root, and St. John's wort, providing the equivalent of 750 mg of dried herb for each ingredient, daily for 3 months, plus tribulus extract for 10 days during the follicular phase, in conjunction with lifestyle modification reduces the time between periods by around 43 days when compared with lifestyle modification alone. The rate of conception was four times higher with this combination when compared with control (97216). Another small clinical study shows that taking a mixture of Ceylon cinnamon, spearmint, ginger, and sweet orange daily for 3 months, in addition to clomiphene citrate for 5 days of each menstrual cycle, improves serum antioxidant levels, fasting blood glucose, and serum insulin levels when compared with clomiphene citrate alone. It is unclear whether these changes are associated with an increase in ovulation and pregnancy rates (103168). In both studies, it is unclear if the effects are related to Ceylon cinnamon, other ingredients, or to the combinations used.
• Premature ejaculation. Topical Ceylon cinnamon has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In patients with premature ejaculation, applying a multi-ingredient cream (SS Cream) containing Panax ginseng root, Angelica root, Cistanches deserticola, Zanthoxyl species, Torlidis seed, clove flower, Asiasari root, Ceylon cinnamon, and toad venom to the glans penis one hour prior to intercourse and washing off immediately before intercourse improves ejaculatory latency when compared with placebo (2537). The effects of Ceylon cinnamon alone are unclear. More evidence is needed to rate Ceylon cinnamon for these uses.

(Read more about CEYLON CINNAMON)

LIKELY EFFECTIVE

• Chromium deficiency. Oral or parenteral chromium is effective for the treatment and prevention of chromium deficiency. Details: Chromium is effective for preventing and treating symptoms of chromium deficiency, including hyperglycemia, glycosuria, sudden weight loss, peripheral neuropathy, and confusion (7135).

POSSIBLY EFFECTIVE

• Diabetes. Oral chromium seems to be modestly beneficial for improving glycemic control in diabetes, especially when used in doses greater than 200 mcg daily and in patients with poorly controlled diabetes. It is unclear if chromium helps to prevent the development of diabetes. Details: Epidemiological research has found that lower toenail chromium levels are associated with an increased risk of diabetes and cardiovascular disease (11908). In 2005, the US Food and Drug Administration (FDA) allowed a qualified health claim stating that chromium picolinate may reduce the risk of type 2 diabetes. However, the FDA has determined that any relationship between chromium picolinate and type 2 diabetes is highly uncertain and is based on limited scientific evidence (102362). Research on the use of chromium for the treatment of type 2 diabetes is conflicting but seems to show modest benefit in some patients. Several clinical studies, most including fewer than 80 patients with type 2 diabetes, show that taking chromium decreases fasting blood glucose, postprandial glucose, insulin, and glycated hemoglobin (HbA1c) levels and increases insulin sensitivity (6867,7137,12390,14440,15169,42628,42638,95097,103745). However, other small clinical studies show that chromium is no better than placebo for improving most glycemic indices in patients with diabetes (7060,14325,42679,42707,90059,103746,103749). Some of these studies may not have been adequately powered and some had a high risk of bias. Furthermore, these studies had high heterogeneity related to study population and size, chromium supplementation duration, formulation, and dose, and accepted standards of diabetes care. Multiple meta-analyses pooling results of these small clinical trials also show mixed results (90055,90063,95098,105026,110610,111420). The most recent of the aforementioned meta-analyses show that chromium picolinate lowers HbA1c by about 0.6%, with conflicting findings related to fasting blood glucose and measures of insulin resistance (110610,111420). It is unclear if chromium yeast, chromium dinicocysteinate, or chromium with biotin or other natural ingredients are beneficial. Chromium seems to be most beneficial in doses of greater than 200 mcg taken for 12 weeks or longer, and in patients with poorly controlled diabetes with a baseline HbA1c of 8% or greater (90063,105026). There is also speculation that chromium might primarily benefit patients with low chromium levels; however, there has not been an analysis specifically evaluating this population (6867,7058,13725,14325,95098). Some research suggests that chromium might also modestly improve lipid levels in patients with type 2 diabetes (1934,6867,95098). A meta-analysis of clinical trials in patients with type 2 diabetes shows that taking chromium 42-1000 mcg daily for 5-26 weeks decreases triglyceride levels by 7 mg/dL and increases high-density lipoprotein cholesterol levels by 2 mg/dL when compared with control. Taking chromium did not affect low-density lipoprotein cholesterol levels. However, the validity of these results is limited by high heterogeneity (110605). Another meta-analysis failed to demonstrate any effects of chromium on lipid levels (110610). Research on chromium's effect on blood pressure in patients with type 2 diabetes is mixed. A meta-analysis of clinical trials in patients with type 2 diabetes shows that taking chromium 200-1000 mcg daily for 8-25 weeks lowers diastolic blood pressure by 2 mmHg, but does not improve systolic blood pressure or body mass index, when compared with placebo (110607). Preliminary clinical research shows that chromium picolinate might improve metabolic parameters in patients with other forms of diabetes as well. This includes those with type 1 diabetes (1935), diabetes secondary to corticosteroid use (5039,42829), and gestational diabetes (42817).

POSSIBLY INEFFECTIVE

• Hypertension. Meta-analyses of small clinical trials suggest that oral chromium does not lower blood pressure by a clinically meaningful amount. Details: A meta-analysis of randomized clinical trials in adults with different metabolic disorders shows that taking chromium 42-1000 mcg daily for 12-24 weeks does not lower systolic or diastolic blood pressure when compared with placebo (110609). A meta-analysis of randomized clinical trials in adults with different chronic disorders shows that taking chromium 42-1000 mcg daily for 4-25 weeks lowers systolic and diastolic blood pressure by 3 mmHg and 1 mmHg, respectively, when compared with placebo. However, the validity of this meta-analysis is limited by high heterogeneity (110604). Another meta-analysis of randomized clinical trials including patients with type 2 diabetes shows that taking chromium 200-1000 mcg daily for 8-25 weeks lowers diastolic blood pressure by 2 mmHg, but not systolic blood pressure, when compared with placebo (110607). In addition, the validity of these results is limited by inclusion of patients with and without hypertension at baseline (110604,110607,110609).
• Impaired glucose tolerance (Prediabetes). Oral chromium does not seem to improve glycemic indices in patients with prediabetes. Details: Some clinical research shows that adults with impaired glucose tolerance do not have improved glycemic parameters or insulin sensitivity after taking chromium picolinate 500-1000 mcg daily for up to 6 months when compared with placebo (13053,42670). Likewise, a small clinical study in elderly patients with impaired glucose tolerance shows that chromium supplements do not improve glucose tolerance or triglyceride or cholesterol levels when compared with placebo (13722). Finally, a preliminary clinical study in overweight or obese adults with prediabetes shows that taking two capsules of a combination product containing chromium, cinnamon, and carnosine (Glycabiane, PiLeJe) daily for 4 months decreases fasting plasma glucose by approximately 4 mg/dL when compared with placebo, but does not improve fasting plasma insulin, measures of insulin sensitivity or resistance, or glycated hemoglobin (HbA1C) (94234). The small effect on fasting plasma glucose is clinically insignificant and may be due to the other ingredients in this product.
• Schizophrenia. Oral chromium does not seem to improve psychological measures in patients with schizophrenia. Details: Clinical research in patients with schizophrenia shows that taking chromium polynicotinate 400 mcg daily for 3 months does not affect weight or mental status when compared with placebo (42613).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Antiretroviral-induced insulin resistance. It is unclear if oral chromium is beneficial for preventing antiretroviral-induced insulin resistance. Details: Preliminary clinical research in patients with HIV treated with highly active antiretroviral therapy (HAART) shows that taking chromium nicotinate 200 mcg or chromium picolinate 1000 mcg daily for 8-16 weeks may help decrease insulin resistance and increase glucose disposal when compared to baseline (42630,42662). The validity of this finding is limited by the lack of a control group.
• Athletic performance. It is unclear if chromium enhances athletic performance, although some research suggests that it may improve body composition when used in conjunction with exercise. Details: One large clinical study shows taking chromium 400 mcg daily, in conjunction with resistance training, can increase weight loss, body fat loss, and lean body mass when compared with placebo in conjunction with resistance training (6868). However, other, very small clinical studies show that adding chromium picolinate or chromium chloride 177-400 mcg daily to a weight-training program does not improve body composition when compared with weight-training alone (6860,6861,6862,42747). These studies may not have been adequately powered to detect a difference in outcomes.
• Atypical depression. It is unclear if oral chromium is beneficial in patients with atypical depression. Details: Preliminary clinical research in patients with atypical depression shows that taking chromium picolinate 400 mcg daily for 2 weeks followed by 600 mcg daily for an additional 6 weeks improves response and remission rates when compared with placebo (10309). However, other clinical research shows that taking elemental chromium 400 mcg in the form of chromium picolinate daily for 2 weeks followed by 600 mcg daily for an additional 6 weeks does not improve most symptoms of atypical depression, although appetite and sexual drive may improve, when compared with placebo (42600).
• Beta blocker-induced dyslipidemia. It is unclear if oral chromium is beneficial in patients with dyslipidemia due to beta-blocker use. Details: One small clinical study in patients who take beta-blockers shows that taking glucose tolerance factor (GTF)-chromium 600 mcg daily for 2 months increases high-density lipoprotein (HDL) cholesterol levels by 16%, but does not affect other lipid parameters, when compared with placebo (5040).
• Binge eating disorder. It is unclear if oral chromium is beneficial in patients with binge eating disorder. Details: One small clinical study in adults with overweight and binge eating disorder shows that taking chromium picolinate 600 or 1000 mcg daily for 6 months does not affect binge eating frequency, body weight, or depressive symptoms when compared with placebo (90057).
• Bipolar disorder. It is unclear if oral chromium is beneficial in patients with treatment-resistant bipolar disorder. Details: Preliminary clinical research in patients with treatment-resistant, rapid-cycling bipolar disorder shows that taking chromium chloride (Hypo-A Chrom, Hypo-A GmbH) 600-800 mcg daily for up to 2 years can decrease the frequency of affective episodes by approximately three episodes annually when compared to baseline (42618). The validity of this finding is limited by the lack of a control group.
• Cognitive impairment. It is unclear if oral chromium prevents or treats cognitive impairment. Details: Some clinical research shows that taking chromium picolinate standardized to contain elemental chromium 1000 mcg daily for 12 weeks does not improve memory or depression in elderly patients with mild cognitive impairment when compared with placebo. However, results from neuroimaging scans suggest that chromium increases the activity of certain regions of the brain during memory tasks when compared with placebo (42666).
• Hyperlipidemia. Small clinical studies suggest that oral chromium may modestly reduce lipid levels in patients with hyperlipidemia. Details: One small clinical study in patients with atherosclerotic disease shows that taking chromium 250 mcg as chromium chloride daily for 7-16 months decreases triglycerides and increases high-density lipoprotein (HDL) cholesterol, but not other lipid parameters, when compared with placebo (7060). Other small clinical studies in adults with hyperlipidemia show that taking chromium picolinate 200 mcg daily for 6 weeks, chromium polynicotinate 200 mcg twice daily, or brewer's yeast containing 48 mcg elemental chromium daily for 6-8 weeks decrease total and low-density lipoprotein (LDL) cholesterol when compared to baseline (37178,42585,42710). The validity of this finding is limited by the lack of comparison with a control group. A meta-analysis of small heterogeneous clinical studies in patients mostly without hyperlipidemia shows that taking chromium does not affect lipid levels when compared with placebo (105029). A meta-analysis of randomized clinical trials including patients with type 2 diabetes shows that taking chromium 42-1000 mcg daily for 5-26 weeks modestly improves triglyceride and HDL cholesterol levels, but not LDL cholesterol levels, when compared with control. However, the validity of these results is limited by high heterogeneity and inclusion of patients with and without hyperlipidemia (110605). In addition, some meta-analyses have failed to demonstrate any effects of chromium on lipid levels in adults with diabetes (110610). Limited research has tested high-dose chromium in children. One small clinical study in children with hypercholesterolemia shows that taking chromium polynicotinate 400-600 mcg with glucomannan 1000-1500 mg twice daily for 8 weeks reduces total and LDL cholesterol when compared to baseline (90061). It is unclear if this effect is due to chromium, glucomannan, or the combination.
• Hypoglycemia. It is unclear if oral chromium helps to reverse or prevent hypoglycemia. Details: One very small clinical study in patients with reactive hypoglycemia shows that taking chromium chloride 200 mcg daily for 3 months increases blood glucose levels and improves insulin binding and hypoglycemic symptoms following an oral glucose load (6859). Another small clinical study in patients with symptomatic hypoglycemia shows that taking chromium yeast (Biochrome, Pharma-Nord) 125 mcg daily for 3 months improves symptoms, including chilliness, trembling, and disorientation, when compared with baseline (42711). The validity of this finding is limited by the lack of a control group.
• Metabolic syndrome. It is unclear if oral chromium is beneficial in patients with metabolic syndrome. Details: One small clinical study in patients with metabolic syndrome shows that taking a particular chromium picolinate product (Chromax, Nutrition 21) 500 mcg twice daily for 16 weeks does not affect weight, waist circumference, insulin sensitivity, glycated hemoglobin (HbA1C), or lipid levels when compared with placebo (42654).
• Myocardial infarction (MI). It is unclear if oral chromium helps to prevent MI. Details: Epidemiological research has found that low toenail chromium concentrations are associated with an increased risk of MI (13728). However, toenail chromium concentrations might not be a reliable predictor of body stores of chromium. There is also no reliable research showing that chromium supplements can prevent MI.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral chromium slows NAFLD progression. Details: One small clinical study in patients with NAFLD shows that taking chromium picolinate 200 mcg two times daily after meals for 12 weeks does not affect liver enzyme levels or body weight when compared with placebo (105027).
• Obesity. Although some research suggests that oral chromium may increase weight loss, this increase in weight loss is not likely to be considered clinically relevant. Details: Meta-analyses of clinical studies in adults with overweight or obesity show that taking chromium picolinate 200-1000 mcg daily for 12-16 weeks might result in a cumulative weight loss of about 0.5-1 kg when compared with placebo (90062,90065). However, this small reduction in weight is unlikely to be considered clinically significant. Additionally, small clinical studies in healthy adults and children with overweight or obesity show that taking oral chromium 200-1000 mcg daily for 6-24 weeks does not reduce weight when compared with control (6860,13727,17224,42680). Some of these studies may not have been adequately powered to detect a smaller effect. A meta-analysis of randomized clinical trials among adults with type 2 diabetes shows that taking chromium 200-1000 mcg daily for 8-25 weeks does not lower body mass index when compared with placebo. However, the validity of these results is limited by inclusion of patients with and without obesity at baseline (110607).
• Polycystic ovary syndrome (PCOS). It is unclear if oral chromium improves symptoms of PCOS. Details: One small clinical study in patients with PCOS shows that taking chromium picolinate 1000 mcg daily for 6 months along with diet and exercise counseling decreases body mass index and improves rates of ovulation and regular menstruation when compared with placebo (95094). Also, some clinical research shows that taking chromium picolinate (21st Century HealthCare, Inc. or Nature Made) 200 mcg daily for 8 weeks increases insulin sensitivity when compared with placebo (95095,98687). However, other preliminary clinical research shows that taking chromium picolinate 200 mcg daily for 4 months does not affect insulin sensitivity or improve ovulation rates (42603). Although chromium picolinate at doses of less than 1000 mcg might have very small effects on fasting glucose, these doses do not seem to have clinically beneficial effects on fasting glucose, pregnancy rate, or testosterone levels (95094,95095,98687). A lower dose of chromium has also been studied in combination with carnitine. One small clinical study in adults with overweight and PCOS shows that taking chromium picolinate 200 mcg daily with carnitine 1000 mg daily for 12 weeks modestly reduces fasting blood glucose, insulin resistance, and body weight, and slightly increases insulin sensitivity, when compared with placebo (103747). However, it is unclear if this benefit is clinically significant. Additionally, it is unclear if these effects are due to chromium, carnitine, or the combination. Carnitine has demonstrated clinical benefit when used alone in PCOS.
• Turner syndrome. It is unclear if oral chromium is beneficial in patients with this condition. Details: A small clinical study shows that taking brewer's yeast 30 grams containing chromium 50 mcg daily for 8 weeks might improve abnormalities in glucose and lipid metabolism when compared with baseline in patients with Turner syndrome, a genetic disorder that has a high incidence of diabetes (13729). The validity of this finding is limited by the lack of a comparator group. More evidence is needed to rate chromium for these uses.

(Read more about CHROMIUM)

LIKELY SAFE ...when used orally and appropriately. Biotin has been safely used in doses up to 300 mg daily for up to 6 months. A tolerable upper intake level (UL) has not been established (1900,6243,95662,102965). ...when applied topically as cosmetic products at concentrations of 0.0001% to 0.6% biotin (19344).

POSSIBLY SAFE ...when used intramuscularly and appropriately (8468,111366).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Biotin has been safely used at adequate intake doses of 5-25 mcg daily for up to 6 months (173,6243,19347,19348,111365). A tolerable upper intake level (UL) has not been established.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Biotin has been safely used at the adequate intake (AI) dose of 30 mcg daily during pregnancy and 35 mcg daily during lactation. It has also been used in supplemental doses of up to 300 mcg daily (6243,7878). A tolerable upper intake level (UL) has not been established.

(Read more about BIOTIN)

LIKELY SAFE ...when consumed in amounts commonly found in foods. Ceylon cinnamon has Generally Recognized As Safe (GRAS) status in the US for use as a spice or flavoring agent (4912).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts. Ceylon cinnamon 0.5-3 grams daily has been safely used in studies lasting up to 6 months (4,12,97248,97250,99874). ...when used as a mouth rinse for up to 15 days (92071). There is insufficient reliable information available about the safety of Ceylon cinnamon when used orally in greater amounts or for longer periods. Ceylon cinnamon contains trace amounts of coumarin (108260). In very high doses, coumarin can cause hepatotoxicity (15302). However, since the amount of coumarin in Ceylon cinnamon is negligible, it is unlikely to cause toxic effects (89652,92072,92073).

PREGNANCY: LIKELY SAFE
when consumed in amounts commonly found in foods (4912).

PREGNANCY: LIKELY UNSAFE
when used orally in amounts greater than those found in foods. Fetal abnormalities have been reported in animals (4,12).

LACTATION: LIKELY SAFE
when consumed in amounts commonly found in foods (4912). There is insufficient reliable information available about the safety of Ceylon cinnamon in amounts greater than those found in foods.

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LIKELY SAFE ...when used orally and appropriately in medicinal amounts, short-term. Chromium has been safely used in doses up to 1000 mcg daily for up to 6 months (1934,5039,5040,6858,6859,6860,6861,6862,6867,6868)(7135,7137,10309,13053,14325,14440,17224,90057,90061)(90063,94234,95095,95096,95097,98687); however, most of these studies have used chromium doses in a range of 150-600 mcg. The Food and Drug Administration (FDA) and Institute of Medicine (IOM) evaluations of the safety of chromium suggest that it is safe when used in doses of 200 mcg daily for up to 6 months (13241,13242).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts, long-term. Chromium has been safely used in a small number of studies at doses of 200-1000 mcg daily for up to 2 years (7060,7135,42618,42628,42666,110605,110607,110609). However, the Food and Drug Administration (FDA) and Institute of Medicine (IOM) evaluations of the safety of chromium suggest that it is safe when used in doses of 200 mcg daily for up to 6 months (13241,13242).

CHILDREN: LIKELY SAFE
when used orally and appropriately in amounts not exceeding the daily adequate intake (AI) levels by age: 0-6 months, 0. 2 mcg; 7-12 months, 5.5 mcg; 1-3 years, 11 mcg; 4-8 years, 15 mcg; males 9-13 years, 25 mcg; males 14-18 years, 35 mcg; females 9-13 years, 21 mcg; females 14-18 years, 24 mcg (7135). POSSIBLY SAFE...when used orally and appropriately in amounts exceeding AI levels. Chromium 400 mcg daily has been used safely for up to 6 weeks (42680).

PREGNANCY: LIKELY SAFE
when used orally and appropriately in amounts not exceeding adequate intake (AI) levels. The AI for pregnancy is 28 mcg daily for those 14-18 years of age and 30 mcg daily for those 19-50 years of age (7135).

PREGNANCY: POSSIBLY SAFE
when used orally in amounts exceeding the adequate intake (AI) levels. There is some evidence that patients with gestational diabetes can safely use chromium in doses of 4-8 mcg/kg (1953); however, patients should not take chromium supplements during pregnancy without medical supervision.

LACTATION: LIKELY SAFE
when used orally and appropriately in amounts not exceeding adequate intake (AI) levels. The AI for lactation is 44 mcg daily for those 14-18 years of age and 45 mcg daily for those 19-50 years of age (7135). Chromium supplements do not seem to increase normal chromium concentration in human breast milk (1937). There is insufficient reliable information available about the safety of chromium when used in higher amounts while breast-feeding.

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, Ceylon cinnamon may have additive effects with antidiabetes drugs.  Details Ceylon cinnamon may lower blood glucose levels (11247,11248,11973). Dose adjustments might be necessary.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, Ceylon cinnamon might have additive effects with antihypertensive drugs and increase the risk of hypotension.  Details Animal research shows that Ceylon cinnamon extract has vasorelaxant properties and reduces blood pressure in rat models of hypertension, possibly via inhibition of calcium influx through L-type voltage-sensitive channels (92085,92086).

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = A Theoretically, chromium may have additive effects with antidiabetic agents and increase the risk of hypoglycemia.  Details Some research shows that taking chromium might lower blood glucose levels, especially in patients with poorly controlled type 2 diabetes (7137,14440,15169,94234,95097,95098,98687).

ASPIRIN Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = D Theoretically, aspirin might increase chromium absorption.  Details Animal research suggests that aspirin may increase chromium absorption and chromium levels in the blood (21055).

INSULIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of chromium and insulin might increase the risk of hypoglycemia.  Details In clinical research, chromium has been shown to increase insulin sensitivity (1952,14440,95095),

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Chromium might bind levothyroxine in the intestinal tract and decrease levothyroxine absorption.  Details Clinical research in healthy volunteers shows that taking chromium picolinate 1000 mcg with levothyroxine 1 mg decreases serum levels of levothyroxine by 17% when compared to taking levothyroxine alone (16012). Advise patients to take levothyroxine at least 30 minutes before or 3-4 hours after taking chromium.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D NSAIDs might increase chromium levels in the body.  Details Drugs that are prostaglandin inhibitors, such as NSAIDs, seem to increase chromium absorption and retention (7135).

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General ...Orally and topically, biotin is generally well tolerated.
Most Common Adverse Effects: None.

Gastrointestinal ...Orally, high-dose biotin has been rarely associated with mild diarrhea. Transient mild diarrhea was reported by 2 patients taking biotin 300 mg daily (95662).

Pulmonary/Respiratory ...In one case report in France, a 76-year-old female frequent traveler developed eosinophilic pleuropericarditis after taking biotin 10 mg and pantothenic acid 300 mg daily for 2 months. She had also been taking trimetazidine for 6 years (3914). Whether eosinophilia in this case was related to biotin, pantothenic acid, other substances, or patient-specific conditions is unknown. There have been no other similar reports.

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General ...Orally, Ceylon cinnamon is generally well tolerated, and adverse reactions are uncommon.
Most Common Adverse Effects:
Orally: Bloating, dyspepsia, nausea.
Topically: Allergic dermatitis, irritation of mucous membranes and skin.

Dermatologic ...Orally, a case of systemic contact dermatitis has been reported in a patient who consumed cinnamon (type not specified) after being previously sensitized to cinnamyl alcohol via cutaneous exposure (95599). In a small study of oral Ceylon cinnamon, two patients reported itching (104520). In another small study, two patients reported rashes (108263).
Topically, cinnamon oil can cause skin irritation and allergic dermatitis, probably due to cinnamaldehyde which makes up 60% to 80% of cinnamon oil (2537,12635,92071,95596,95599). In one case report, a 16-year-old female experienced worsening dermatitis after using a homemade facial scrub containing cinnamon powder (type not specified). Symptoms improved after discontinuation of the scrub (95596). Several cases of intraoral allergic contact dermatitis have been reported in patients consuming cinnamon (type not specified) or using products containing constituents of cinnamon (95598).

Gastrointestinal ...Orally, gastrointestinal side effects such as heartburn, nausea, bloating, and dyspepsia have been reported (97250).

Hematologic ...Orally, a case of postoperative hemorrhage is reported in a 49-year-old patient after taking Ceylon cinnamon 1 tablespoon daily for 10 months. One day post-colectomy, the patient had an INR of 1.59 and intraabdominal bleeding that required exploratory laparotomies, blood transfusion, and fresh frozen plasma. Ultimately, the patient was discharged (112421).

Hepatic ...While there is concern about the coumarin content in cassia cinnamon increasing the risk for hepatic adverse effects and bleeding, the amount of coumarin in Ceylon cinnamon is negligible and unlikely to cause toxic effects (89652,92072,92073). In one case report, a 73-year-old female taking rosuvastatin for several months developed elevated liver function tests (LFTs), abdominal pain, nausea, and vomiting after taking cinnamon (unknown dose and type) for 7 days. The acute hepatitis and elevated LFTs resolved after stopping both cinnamon and rosuvastatin. The patient was later able to resume rosuvastatin without recurrence (97249).

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General ...Orally, chromium is generally well tolerated.
Most Common Adverse Effects:
Orally: Gastrointestinal irritation, headaches, insomnia, irritability, mood changes.
Serious Adverse Effects (Rare):
Orally: Rare cases of kidney and liver damage, rhabdomyolysis, and thrombocytopenia have been reported.

Dermatologic ...Orally, chromium-containing supplements may cause acute generalized exanthematous pustulosis (42561), skin rashes (42679), and urticaria (17224). Also, chromium picolinate or chromium chloride may cause systemic contact dermatitis when taken orally, especially in patients with contact allergy to chromium (6624,90058). In one clinical study, a patient taking chromium nicotinate 50 mcg daily reported itchy palms that improved after the intervention was discontinued. It is unclear of this effect was due to the chromium or another factor (95096).
Topically, hexavalent chromium, which can be present in some cement, leather products, or contaminated soil, may cause allergic contact dermatitis (42645,42789,90060,90064,110606).
A case of lichen planus has been reported for a patient following long-term occupational exposure to chromium (42688).

Endocrine ...Orally, cases of hypoglycemia have been reported for patients taking chromium picolinate 200-1000 mcg daily alone or 200-300 mcg two or three times weekly in combination with insulin (42672,42783). Chromium picolinate has also been associated with weight gain in young females who do not exercise and in those following a weight-lifting program (1938).

Gastrointestinal ...Orally, chromium in the form of chromium picolinate, chromium polynicotinate, chromium-containing brewer's yeast, or chromium-containing milk powder may cause nausea, vomiting, diarrhea, decreased appetite, constipation, flatulence, or gastrointestinal upset (14325,42594,42607,42622,42643,42679).
Long-term exposure to heavy metals, including chromium, has been associated with increased risk of gallbladder disease and cancer (42682,42704).

Genitourinary ...Orally, chromium polynicotinate has been associated with disrupted menstrual cycles in patients taking the supplement to prevent weight gain during smoking cessation (42643).

Hematologic ...Anemia, hemolysis, and thrombocytopenia were reported in a 33 year-old female taking chromium picolinate 1200-2400 mcg daily for 4-5 months (554). The patient received supportive care, blood product transfusions, and hemodialysis and was stabilized and discharged a few days later. Lab values were normal at a one-year follow-up.

Hepatic ...Liver damage has been reported for a 33-year-old female taking chromium picolinate 1200 mcg daily for 4-5 months (554). Also, acute hepatitis has been reported in a patient taking chromium polynicotinate 200 mcg daily for 5 months (9141). Symptoms resolved when the product was discontinued. Two cases of hepatotoxicity have been reported in patients who took a specific combination product (Hydroxycut), which also contained chromium polynicotinate in addition to several herbs (13037).

Musculoskeletal ...Acute rhabdomyolysis has been reported for a previously healthy 24-year-old female who ingested chromium picolinate 1200 mcg over a 48-hour time period (42786). Also, chromium polynicotinate has been associated with leg pain and paresthesia in patients taking the supplement to prevent weight gain during smoking cessation (42643).

Neurologic/CNS ...Orally, chromium picolinate may cause headache, paresthesia, insomnia, dizziness, and vertigo (6860,10309,14325,42594). Vague cognitive symptoms, slowed thought processes, and difficulty driving occurred on three separate occasions in a healthy 35-year-old male after oral intake of chromium picolinate 200-400 mcg (42751). Transient increases in dreaming have been reported in three patients with dysthymia treated with chromium picolinate in combination with sertraline (2659). A specific combination product (Hydroxycut) containing chromium, caffeine, and ephedra has been associated with seizures (10307). But the most likely causative agent in this case is ephedra.

Psychiatric ...Orally, chromium picolinate has been associated with irritability and mood changes in patients taking the supplement to lose weight, while chromium polynicotinate has been associated with agitation and mood changes in patients taking the supplement to prevent weight gain during smoking cessation (6860,42643).

Renal ...Orally, chromium picolinate has been associated with at least one report of chronic interstitial nephritis and two reports of acute tubular necrosis (554,1951,14312). Laboratory evidence suggests that chromium does not cause kidney tissue damage even after long-term, high-dose exposure (7135); however, patient- or product-specific factors could potentially increase the risk of chromium-related kidney damage. More evidence is needed to determine what role, if any, chromium has in potentially causing kidney damage.
Intravenously, chromium is associated with decreased glomerular filtration rate (GFR) in children who receive long-term chromium-containing total parenteral nutrition - TPN (11787). Topically, burns caused by chromic acid, a hexavalent form of chromium, have been associated with acute chromium poisoning with acute renal failure (42699). Early excision of affected skin and dialysis are performed to prevent systemic toxicity.

Other ...Another form of chromium, called hexavalent chromium, is unsafe. This type of chromium is a by-product of some manufacturing processes. Chronic exposure can cause liver, kidney, or cardiac failure, pulmonary complications, anemia, and hemolysis (9141,11786,42572,42573,42699). Occupational inhalation of hexavalent chromium can cause ulceration of the nasal mucosa and perforation of the nasal septum, and has been associated with pneumoconiosis, allergic asthma, cough, shortness of breath, wheezing, and increased susceptibility to respiratory tract cancer and even stomach and germ cell cancers (42572,42573,42601,42610,42636,42667,42648,42601,42788,90056,90066). Although rare, cases of interstitial pneumonia associated with chromium inhalation have been reported. Symptoms resolved with corticosteroid treatment (42614).

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