Celsius (assorted flavors) by Celsius

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.

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EFFECTIVE

• Migraine headache. Oral caffeine in combination with acetaminophen, aspirin, and/or sumatriptan is approved by the US Food and Drug Administration (FDA) for treating migraine headache. Details: Taking caffeine 100-260 mg orally in combination with acetaminophen 500-2000 mg, aspirin 500 mg, and/or sumatriptan 50-100 mg is effective for treating migraine headache (2715,2716,2717,37614,37626,37816,91068). Some evidence shows that caffeine in combination with aspirin and acetaminophen may be more effective than sumatriptan in treating a migraine attack (37666). However, taking caffeine 200 mg plus ergotamine seems to be less effective than sumatriptan or calcium carbasalate plus metoclopramide (37685,38312). Caffeine is an FDA-approved product for use with analgesics for the treatment of migraine.
• Neonatal apnea. Oral or intravenous caffeine citrate is approved by the US Food and Drug Administration (FDA) for the short-term treatment of neonatal apnea in very preterm infants. Details: Using caffeine orally or intravenously improves apnea of prematurity in very preterm infants and reduces the risk of bronchopulmonary dysplasia, invasive mechanical ventilation, and neurodevelopmental impairment (6023,6371,37857,37906,38124,38344,98807,100364,114658). The dosage approved in the FDA labeling is a single loading dose of caffeine citrate 20 mg/kg (10 mg/kg caffeine base), followed by 5 mg/kg of caffeine citrate (2.5 mg/kg caffeine base) every 24 hours for maintenance. Clinical research shows that caffeine citrate dose-dependently reduces the number of apnea episodes by at least 50% over 7-10 days of treatment (6371). Most research suggests that doses above 10 mg/kg daily reduce the risk of apnea, bronchopulmonary dysplasia, and problematic extubation when compared with doses below 10 mg/kg/day (98807,100364,114658). Additional clinical research shows that reinitiating caffeine treatment after termination of the original caffeine regimen, and continuing until 40 weeks postmenstrual age, reduces the incidence of intermittent hypoxia in premature infants by 46% when compared to standard care (91073). At 18-21 months of age, a history of neonatal caffeine treatment reduces the risk of long-term complications of apnea of prematurity, such as cerebral palsy or cognitive delay (37722,38340). At 11 years of age, individuals born prematurely and treated with caffeine have improved visuomotor, visuoperceptual, and visuospatial abilities when compared to those who received placebo (97452). At 6-11 years of age, these individuals may also have a reduced risk of motor impairment (114658). Data on the prophylactic use of caffeine in very low birth-weight infants (less than 1500 grams and 32 weeks' gestation) are conflicting. In a meta-analysis of 11 studies, 5 show a reduced risk of apnea of prematurity, oxygen therapy, bronchopulmonary dysplasia, patent ductus arteriosus, and retinopathy of prematurity, and a reduced duration of mechanical ventilation (111491). However, other studies do not show any benefit (38125,111491). A study of infants born at 34-36 weeks' gestation shows that caffeine citrate, 10 or 20 mg/kg orally daily, reduces the number of intermittent hypoxemia episodes per hour by 61% and 67% respectively, when compared with placebo (111493). Caffeine and aminophylline have similar effectiveness for management of apnea, bradycardia, and hypoxemia, but caffeine has a wider range of safe plasma levels and lower rates of tachycardia and feeding intolerance (111492).
• Postoperative headache. Oral or intravenous caffeine is approved by the US Food and Drug Administration (FDA) for preventing headache in postoperative patients who regularly consume caffeinated products. Details: Clinical research shows that using caffeine is effective for preventing postoperative headache in patients who regularly consume caffeinated products. Intravenous caffeine does not seem to be effective in non-regular caffeine consumers. Studied doses have included 200 mg intravenously or oral doses calculated based on average daily consumption (2725,2726). Caffeine is an FDA-approved product for preventing headache in postoperative patients who regularly consume caffeinated products.
• Tension headache. Oral caffeine in combination with analgesics is approved by the US Food and Drug Administration (FDA) for treating tension headache. Details: Taking caffeine orally in combination with analgesics is effective for treating simple tension headache. Taking caffeine 100 mg alone is more effective at reducing tension headache pain when compared with placebo, but less effective than the combination of caffeine and analgesics. Caffeine 130 mg has been used with acetaminophen 1000 mg or with acetaminophen 500 mg and aspirin 500 mg. Caffeine 50 mg has been used with acetylsalicylic acid 250 mg and acetaminophen 200 mg (2718,11832,37668,37773).

LIKELY EFFECTIVE

• Athletic performance. Oral caffeine taken as a single dose of at least 2-3 mg/kg can modestly improve endurance, muscle strength, power output, and overall athletic performance when taken prior to certain forms of athletic activity or exercise. However, the magnitude and duration of effect is variable and may be dependent on the form and dose of caffeine, as well as various individual- and activity-specific factors. Caffeine intake in excess of 800 mg daily can result in blood levels greater than those allowed by the National Collegiate Athletic Association. Details: Clinical research and meta-analyses of clinical research show that taking caffeine 2-10 mg/kg modestly improves work produced, aerobic endurance, muscle strength and endurance, power output, and overall athletic performance (10203,11832,37648,37894,38054,38063,95955,100362,100365,100371)(103701,103703,108798,111250,114655,114657,114661,114673). According to the International Society of Sports Nutrition, the most consistent and measurable effects are seen in aerobic endurance; the minimal effective dose for any form of exercise is unclear, but benefits have been most consistent at doses of 3-6 mg/kg (114673). Meta-analyses of studies using caffeine 3-9 mg/kg as a single dose prior to endurance time trials report variability in results. Sports studied included running, rowing, cycling, swimming, and Nordic skiing, and included both recreational and trained athletes. Overall there was a small positive effect on time to exhaustion, endurance performance, and mean power output, and a decrease in the time needed to complete the trials when compared with placebo (98808,111497,114655). One meta-analysis of studies that evaluated cycling time trial performance found that doses of 4-6 mg/kg, but not doses of 1-3 mg/kg, improved performance (114655). A separate meta-analysis of 14 clinical studies shows that taking caffeine 2-11 mg/kg approximately 45-60 minutes before exercise improves muscle strength and endurance in the upper and lower body when compared with placebo. However, a sub-group analysis shows that muscle strength only improves with caffeine doses of at least 6 mg/kg (114657). Another meta-analysis of small clinical trials shows that the benefit of caffeine on athletic performance seems to increase with increased duration of activity. This suggests that caffeine can improve physical endurance during athletic activities (100371). In these trials, caffeine is typically provided as a single dose 30-150 minutes prior to testing (98808), although one study suggests that taking caffeine 60 minutes prior to peak activity has the most consistent ergogenic benefits (104577). Caffeine might improve performance in some athletic activities but not others. Some research shows that caffeine does not improve performance during athletic activities requiring a high amount of exertion over a short period of time. Such activities include sprinting and lifting (11832,37564,37758,37837,37841,37890,38319,95963,97459,112740). However, it is possible that the negative lifting studies were underpowered. Ballistic exercise, such as jumping or throwing, requires rapid increases in velocity, force, and muscle activation. A meta-analysis of 10 studies shows that caffeine in a range of doses (mean: 3 mg/kg) has a significant ergogenic effect on throwing performance and velocity (111488). A meta-analysis of small studies shows that caffeine modestly improves bench press repetitions and maximum strength, but not perceived exertion, when compared with placebo. Caffeine also tends to improve these parameters for leg presses, but the improvement does not reach significance when compared with placebo (103701). A meta-analysis of small clinical studies in female team-sport athletes shows that caffeine improves specific team-sport skills but has no effect on perceived exertion or agility tests performed after exertion (108799). Conversely, a small individual clinical study shows that taking caffeine 6.5 mg/kg 60 minutes before strength training decreases perceived exertion while increasing the number of repetitions of both upper and lower limb exercises by 17% to 33% over placebo (104581). Some clinical research also shows that taking caffeine can decrease subjective feelings of exertion and fatigue during exercise such as fencing and cycling (17618,37656,91026,91058,91062). Although some other clinical studies show that caffeine does not affect perceived exertion, caffeine does seem to improve performance and cause small increases in the amount of physical work done when compared with placebo in various athletes, including cyclists, runners, basketball players, and golfers (37702,37860,37872,38031,38119,38320,91037,91077,97457,97459)(104580,108800,108804). These effects do not seem to be dependent upon the dose of caffeine (97459), although some research shows that the timing of caffeine intake and exercise may alter overall benefit, with a greater effect seen in the morning compared to the evening (97457,104580). Most research has investigated the acute effects of a single dose of caffeine. The evidence is mixed as to whether chronic intake of caffeine could induce tolerance and reduce any acute ergogenic benefits (114673). One study shows that the consistent consumption of caffeine 3 mg/kg daily for 28 days eliminates the acute benefits of caffeine in work produced when compared with placebo, suggesting the development of tolerance (95955). However, chronic use of caffeine at a dose of 6 mg/kg for 4 days does not seem to induce tolerance to an acute dose of caffeine 6 mg/kg taken 60 minutes prior to a cycling time trial in males who are moderate to high users of caffeine (104576). Similarly, a small clinical study in trained individuals shows that acute supplementation with oral caffeine 6 mg/kg about 1 hour prior to performance improves strength and endurance when compared with placebo or control, regardless of habitual caffeine consumption (108804). Differences may be due to the type of exercise, the acute dose of caffeine, the length of the chronic intake period, and/or the normal caffeine intake of the athlete. Most studies suggest that there is significant inter-individual variability in response to caffeine for improvement of athletic performance (100365). These differences might be due, at least in part, to genotype (100370,114673), although research is conflicting. Caffeine is metabolized by the cytochrome P450 1A2 (CYP1A2) enzyme. One small clinical trial in resistance-trained males shows that taking caffeine 6 mg/kg improves resistance exercise performance in those homozygous for the CYP1A2 rs762551 polymorphism (AA) when compared with those without or heterozygous for that polymorphism (CC or A/C, respectively) (100370). However, another clinical study in trained male athletes shows that taking oral caffeine 4 mg/kg about 30 minutes prior to performance decreases handgrip strength by about 13% in individuals with the CC genotype when compared with placebo, but not in those with the AA or A/C genotypes. No groups experienced an improvement in vertical jump performance (108803). Another small clinical study suggests that CYP1A2 genotype does not affect exercise performance in athletes 60 minutes after taking caffeine 3 mg/kg. In addition, the ADORA2A genotype, which plays a role in caffeine sensitivity, does not seem to affect exercise performance benefits from caffeine (104578). However, these studies are small and used different performance protocols; further research is needed to clarify how these polymorphisms may impact the athletic performance benefits of caffeine (114673). Limited research has also evaluated the use of a caffeine mouth rinse, with mixed findings. Two very small clinical studies in healthy trained males shows that rinsing the mouth with 25 mL of water containing caffeine 85 or 300 mg for 5-10 seconds does not affect athletic performance or time to exhaustion while cycling when compared with placebo (103709,108801). However, another small study in healthy Taekwondo athletes fasting for Ramadan suggests that using a mouth rinse containing caffeine 6 mg/kg, ten seconds prior to exertion, modestly reduces perceived exertion and modestly improves kick performance when compared with using a placebo rinse (103710). Similarly, another small clinical study in healthy, resistance-trained males shows that rinsing the mouth with 25 mL of a solution containing caffeine 3%, but not 1% or 2%, reduces perceived exertion and increases muscular endurance, but not strength, when compared with placebo. The mouth rinse was used for 5 seconds immediately prior to a strength test or once per minute for 2 minutes during a muscular endurance test (108802). Preliminary clinical research has also investigated the use of caffeine in combination with other ingredients, such as sodium bicarbonate or creatine. However these studies have not demonstrated clear benefits in athletic performance over taking caffeine alone (112740,114673).
• Mental alertness. Oral caffeine increases mental alertness. However, it might not improve performance or accuracy to the same extent achieved through adequate sleep. Details: Consumption of caffeinated beverages or caffeine supplements seems to prevent a decline in alertness and cognitive capacity when consumed throughout the day (4221,4224,36439,37727,37757,37759,38070,38075,38158,91093)(91075). Caffeine appears to be especially effective in individuals that are not regular users (91074). Taking caffeine 100-600 mg can improve alertness and speed following prolonged sleep deprivation but usually does not affect mental performance or accuracy (10205,37716,37755,37806,37992,38007,38035,38139,91049,91072)(103706,112736). Drinking coffee containing caffeine 100 mg prior to a cognitive performance test improves reaction times in people with recent poor sleep quality, and in those with adequate sleep. However, the increase in vigilance occurring in the sleep-deprived people does not bring their performance up to the level seen with adequate sleep. Also, the number of errors made by sleep-deprived people seems to increase, suggesting that caffeine may have a detrimental effect on inhibitory control (98809). Caffeine also appears to reduce cognitive impairment caused by medications such as chlorpheniramine (91058). Combining caffeine with certain other supplements may improve mental performance. Taking caffeine 80 mg with taurine seems to provide a small improvement in mental performance (9899), although this effect is not observed in sleep deprived subjects (38154). Some clinical research shows that combining caffeine 40-75 mg with glucose 37.5 grams or L-theanine 97-100 mg improves mental performance better than placebo or either substance alone (13732,37762,37903,38116); however, other clinical research shows no additional benefit from combining L-theanine and caffeine (91045).

POSSIBLY EFFECTIVE

• Bronchopulmonary dysplasia. Intravenous caffeine may reduce the risk for bronchopulmonary dysplasia in preterm infants. Details: Population research has found that initiating caffeine treatment prior to the third day of life in premature infants is associated with a reduced risk of developing bronchopulmonary dysplasia compared to later initiation of treatment with caffeine. Additionally, a meta-analysis of available clinical research shows that high-dose caffeine (40-80 mg/kg loading dose, 20 mg/kg daily maintenance) lowers the risk of bronchopulmonary dysplasia when compared with standard dosing (20 mg/kg loading dose, followed by 5-10 mg/kg daily maintenance). However, small sample sizes and high heterogeneity limit the validity of these findings (97462,100364).
• Diabetes. Dietary caffeine seems to be beneficial for the prevention of type 2 diabetes; it is unclear if it is beneficial for the prevention of gestational diabetes. Also, it is unclear if oral caffeine is beneficial in patients with type 1 or type 2 diabetes. Details: Total caffeine consumption from beverages such as coffee or tea is associated with a lower risk of developing type 2 diabetes. This effect appears to be dose-dependent (11353,14313,37850,37871,91040,100368). For example, an increase of 200 mg daily caffeine intake seems to be associated with a 14% decrease in the incidence of type 2 diabetes (91055). Additionally, in North American males, consuming caffeine 417 mg daily from coffee or tea is associated with a 20% lower risk of developing type 2 diabetes when compared with those consuming less than 37 mg daily. North American females consuming at least 258 mg of caffeine daily from coffee or tea seem to have a 10% to 30% lower risk of developing type 2 diabetes when compared with those consuming less than 140 mg daily (11353). Japanese adults who consume at least 416 mg of caffeine daily from beverages including coffee or green tea seem to have a 33% lower risk of developing type 2 diabetes compared to those who consume no more than 57 mg daily. The risk reduction appears to be more pronounced in Japanese females when compared with males (14313). It is unclear if caffeine is beneficial in adults with diabetes. A few small studies show that caffeine consumption may further reduce insulin sensitivity in patients with type 2 diabetes, gestational diabetes, or those at risk for developing diabetes (13744,37653,37820). Caffeine consumption has also been evaluated during pregnancy. An observational study has found that self-reported consumption of beverages containing up to 100 mg of caffeine at 16-22 weeks' gestation is associated with a 47% lower risk of developing gestational diabetes when compared with no intake (108814). Research regarding the effects of caffeine in patients with type 1 diabetes shows conflicting results. One study shows that taking caffeine 250 mg twice daily for 2 weeks can reduce the incidence of elevated blood sugar at night in patients with type 1 diabetes (37660). However, another study in patients with type 1 diabetes shows that taking caffeine 200 mg daily for 3 months may increase the ability to perceive hypoglycemic symptoms when compared with placebo, although overall glycemic control does not seem to be affected (6024). A small clinical crossover study evaluated caffeine for the prevention of exercise-induced hypoglycemia in adults with type 1 diabetes using ultra-long-acting insulin. This study shows that consuming a beverage containing caffeine 250 mg, glucose 10 grams, and aspartame 30 minutes before a moderate intensity cycling exercise does not reduce the risk of exercise-related hypoglycemia, alter the time to hypoglycemia, or increase peak plasma glucose levels during exercise when compared with taking glucose and aspartame (114662).
• Memory. Oral caffeine seems to be beneficial for short-term memory recall in college students and extroverted personalities. It is unclear if oral caffeine is beneficial for introverted personalities or other populations. Details: Taking a single dose of caffeine 65-200 mg orally daily seems to improve memory function in some individuals such as college students and people with extroverted personalities. A small study shows that taking caffeine does not improve memory function in individuals with introverted personalities (37845,38071,91080).
• Obesity. Oral caffeine, when taken in combination with ephedrine or as a component of green tea, seems to be beneficial for weight loss, short-term. Details: Taking caffeine orally, in combination with ephedrine or as a component of green tea, seems to help reduce weight, short-term (695,696,1704,8647,16892,37617,37831). Caffeine 192 mg in combination with ephedra 20-90 mg per day for 6 months seems to cause a modest weight reduction (5.3 kg) in people with a body mass index (BMI) between 25-40 kg/m². This combination, along with limiting fat intake to 30% of calories and moderate exercise, also seems to reduce body fat, decrease low-density lipoprotein (LDL) cholesterol, and increase high-density lipoprotein (HDL) cholesterol. However, even in carefully screened and monitored otherwise healthy adults, caffeine/ephedra combinations can cause small changes in blood pressure and heart rate (8647). Preliminary clinical research also shows that taking 1000 mg of a proprietary combination product containing caffeine and multiple other ingredients (Prograde Metabolism) twice daily for 8 weeks in conjunction with dieting reduces body weight, fat mass, waist circumference, and hip circumference by 1.5%, 5%, 1.8%, and 1.3%, respectively, when compared with dieting alone (40802).
• Pain (acute). Oral caffeine, when taken in combination with acetaminophen, propyphenazone, ibuprofen, or other pain-relieving agents, seems to be beneficial for acute pain. Details: Clinical research shows that taking caffeine 50-130 mg in combination with acetaminophen, propyphenazone, ibuprofen, or other pain-relieving agents can reduce acute pain when compared with the effects of pain-relieving agents alone (37587,37904,38036,38303,91038). Adding ≥100 mg caffeine to treatment with acetaminophen or ibuprofen results in 5% to 10% more patients that achieve at least 50% of maximum pain relief for over 4 hours when compared to treatment with acetaminophen or ibuprofen alone (91038).
• Postdural puncture headache. Oral or intravenous caffeine seem to be beneficial for preventing postdural puncture headache. Details: Using caffeine 300 mg orally or 500 mg in 1,000 mL normal saline intravenously seems to help treat and prevent postdural puncture headache (2727,2728). Using a combination of ergotamine and caffeine seems to be less effective than gabapentin for treating this condition (38147). Lower doses of oral caffeine may not be beneficial. Clinical research shows that oral caffeine, 75-125 mg, does not decrease the risk of postdural headache (91022).

POSSIBLY INEFFECTIVE

• Atrial fibrillation. Oral caffeine does not seem to prevent atrial fibrillation after cardiopulmonary bypass. In addition, it might increase the risk of gastrointestinal side effects. Details: In adults undergoing surgery with cardiopulmonary bypass, taking caffeine 400 mg every 8 hours for 6 doses does not seem to reduce the risk of developing atrial fibrillation during the first three post-operative days. This clinical study was stopped prior to the completion of recruitment after an interim analysis showed increased incidence of postoperative nausea and vomiting, and no effect on the incidence of atrial fibrillation (97451).
• Attention deficit-hyperactivity disorder (ADHD). Oral caffeine does not seem to reduce symptoms of ADHD in children. Details: Most research suggests caffeine does not significantly reduce ADHD symptoms in children when used at tolerable doses (10755,10756,10757,10758,10759,10760). The use of caffeine in adolescents and adults with ADHD has not been studied.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral caffeine prevents cognitive decline with aging. Details: Population research from a small cohort of elderly females shows that caffeine intake of more than 371 mg daily is associated with an attenuation in cognitive decline when compared to less than 30 mg daily. This is equivalent to the difference seen over a 7 year span of age. Caffeinated coffee consumption, but not caffeinated chocolate, tea, or cola, was associated with this attenuation in cognitive decline (91088).
• Alzheimer disease. It is unclear if oral caffeine is beneficial for preventing dementia; the available research is conflicting. Details: Population research from the UK Biobank has found that caffeine intake up to 400 mg daily is associated with a 24% to 34% reduced risk of developing Alzheimer disease when compared with lower intake. Conversely, population research from the Rush Memory and Aging Project in the US has found that caffeine intake of more than 100 mg daily is associated with a 41% increased risk of developing Alzheimer disease when compared with lower intake. However, when those with mild cognitive impairment at baseline or cases diagnosed within 2 years of follow-up are excluded, these findings become insignificant (108810).
• Asthma. Oral caffeine seems to modestly improve airway function for up to 4 hours in patients with mild to moderate asthma. However, it is unclear if oral caffeine has a clinically significant effect on asthma symptoms or quality of life. Details: Taking caffeine 9 mg/kg orally appears to modestly improve airway function for up to 4 hours in people with mild to moderate asthma (37907,37915). However, more research is needed to determine the appropriate dose, whether any benefit is clinically significant, or whether tolerance occurs with chronic dosing.
• Cancer pain. It is unclear if intravenous caffeine is beneficial for cancer pain. Details: Clinical research shows that receiving caffeine 200 mg intravenously once daily for 2 days results in a significant reduction in pain intensity by 0.833 points on the NRS scale when compared with control in patients receiving opioids for pain from advanced cancer (91081).
• Cognitive function. It is unclear if oral caffeine improves cognitive performance in trained athletes. Details: A meta-analysis of small studies in trained adult athletes shows that consumption of a low to moderate amount of caffeine 15-60 minutes prior to exercise and during exercise improves attention performance, but not reaction time or inhibitory control, when compared with placebo (108797). The validity of these findings is limited by unclear reporting.
• Dementia. It is unclear if oral caffeine is beneficial for preventing dementia or improving behavior in patients with dementia. Details: Population research from the Women's Health Initiative has found that caffeine intake of more than 175 mg daily is associated with a 26% reduced risk of developing probable dementia or global cognitive impairment when compared to less than 175 mg daily in postmenopausal adults 65-80 years of age (97458). Population research from the UK Biobank has found that caffeine intake up to 400 mg daily is associated with a 17% to 26% reduced risk for developing all-cause dementia when compared with lower intake. Conversely, population research from the Rush Memory and Aging Project in the US has found that caffeine intake of more than 100 mg daily is associated with a 35% increased risk of developing all-cause dementia when compared with lower intake. However, when those with mild cognitive impairment at baseline or cases diagnosed within 2 years of follow-up are excluded, these findings become insignificant (108810). Caffeine consumption has also been evaluated in patients with dementia. A cross-sectional study in patients with dementia in a care home has found that intake of 'normal' to 'high' amounts of caffeine are associated with reduced agitation and other behavioral symptoms when compared to 'low' intakes of caffeine (104574).
• Depression. It is unclear if oral caffeine is beneficial for depression prevention. Details: Some population research found that caffeine intake is associated with an increased incidence of depressive symptoms in pediatric patients (37839,38162). However, other population research found that caffeinated beverage intake is associated with a decreased incidence of depression in adults (37969,38165,91067,100366).
• Electroconvulsive therapy (ECT) augmentation. Although there has been interest in using intravenous caffeine sodium benzoate to augment electroconvulsive therapy, there is insufficient reliable information about the clinical effects of caffeine for this condition.
• Exercise-induced hypoxemia. It is unclear if oral caffeine is beneficial for hypoxemia associated with exercise. Details: Preliminary clinical research in athletes experiencing exercise-induced hypoxemia shows that taking caffeine 8 mg/kg can improve exercise ventilation, but not ventilatory response or oxygen saturation, when compared with placebo (37750).
• Exercise-induced muscle soreness. It is unclear if oral caffeine is beneficial for reducing muscle soreness during exercise. Details: There is conflicting clinical evidence as to whether caffeine can reduce exercise-induced muscle pain. Some evidence shows that taking caffeine 100 mg or 10 mg/kg can reduce muscle pain during exercise when compared with placebo (37622,38146). However, the effect of lower doses is unclear. Some evidence shows that taking caffeine 5 mg/kg may reduce exercise-induced muscle pain when compared with placebo (37747,91050), while other evidence suggests that taking caffeine 2-5 mg/kg does not affect muscle pain during exercise (38141).
• Gallbladder disease. It is unclear if increased dietary caffeine intake reduces the risk of developing gallstones. Details: Consumption of caffeinated beverages that provide 400 mg or greater of caffeine per day is associated with a significantly reduced risk of developing symptomatic gallstone disease (3345,8032). The effect seems to be dose-dependent; consumption of 800 mg caffeine per day has the greatest reduction in risk (3345).
• Hepatitis C. It is unclear if increased dietary caffeine reduces the risk for hepatitis C-associated severe liver inflammation, although it may reduce the risk of developing advanced fibrosis. Details: A meta-analysis of population research has found that regular consumption of caffeine at doses of at least 123 mg daily is associated with a 48% reduced risk of advanced liver fibrosis when compared to lower caffeine intake in patients with hepatitis C virus (95947). An individual population study also found that higher intake of caffeine from coffee is associated with reduced severity of liver fibrosis in patients with chronic hepatitis C virus. For these patients, the risk of advanced fibrosis is reduced by 14% for each 67 mg of caffeine (37896). However, caffeine intake does not appear to be associated with a reduced risk of moderate to severe liver inflammation in patients with hepatitis C (95947).
• Hypnic headache. It is unclear if oral caffeine reduces the pain associated with this rare condition. Details: Anecdotal evidence suggests that drinking a cup of coffee containing caffeine before bed or upon waking up may help alleviate pain associated with hypnic headaches (38078).
• Hypotension. It is unclear if oral caffeine is beneficial in people with low blood pressure. Details: Preliminary clinical research shows that consuming caffeinated beverages increase blood pressure in elderly people with postprandial hypotension (11834,11835).
• Intermittent claudication. It is unclear if oral caffeine is beneficial for intermittent claudication. Details: Taking a single dose of caffeine 6 mg/kg orally seems to improve walking distance, muscular strength, and endurance in patients with intermittent claudication; however, balance seems to be reduced (38038).
• Liver disease. It is unclear if oral caffeine is beneficial for liver disease prevention. Details: Population research found that there is an inverse association between intake of coffee and the incidence of liver cirrhosis (37576,37608). However, it is unclear if this effect of coffee is attributable to caffeine, since other caffeinated beverages do not show this effect.
• Multiple sclerosis (MS). It is unclear if oral caffeine is beneficial for the symptoms of multiple sclerosis (MS). Details: A small crossover study in adults with MS shows that taking caffeine 200 mg daily for 12 weeks may modestly improve balance, functional mobility, and MS-related quality of life, but not walking function, when compared to a 2-week placebo run-in period. All patients were told to eliminate all other forms of caffeine from their diets; however, baseline caffeine intake was not recorded (114663). The validity of this study is limited by the small size and heterogeneous nature of the study population, which included patients with various forms of MS at varying levels of severity.
• Narcolepsy. It is unclear if oral caffeine is beneficial for narcolepsy. Details: A small clinical study in patients with narcolepsy shows that taking caffeine 200 mg daily in the morning for 1 week does not affect reaction time, but modestly reduces drowsiness, when compared with baseline (103698). The validity of this finding is limited by the lack of a statistical comparison between the treatment and placebo groups.
• Neonatal resuscitation. It is unclear if oral caffeine improves the likelihood for successful extubation in preterm infants. Details: Preliminary clinical research in extremely preterm infants requiring mechanical ventilation within the first 5 days of birth shows that early administration of caffeine, given as a loading dose of caffeine citrate 20 mg/kg followed by a maintenance dose of 5 mg/kg daily until extubation, does not reduce mortality or shorten time to first successful extubation when compared to giving a bolus dose of caffeine citrate 20 mg/kg just prior to extubation (97461).
• Nocturnal enuresis. Reducing caffeine intake might reduce the frequency of nocturnal enuresis episodes in children. Details: Preliminary clinical research in children aged 6-15 years with primary nocturnal enuresis shows that limiting caffeine intake to less than 30 mg daily reduces the mean number of bedwetting episodes from 3.5 to 2.4 per week, when compared with no change in the group with intakes of 80-100 mg daily. The probability of bedwetting in the caffeine restricted group was about 14% lower than that in the control group (111495).
• Nonmelanoma skin cancer. It is unclear if oral caffeine is beneficial for nonmelanoma skin cancer prevention. Details: A review of available population research shows that increased caffeine intake from any source is associated with a 14% reduction in the risk of developing nonmelanoma skin cancer. Consumption of caffeinated coffee, but not decaffeinated coffee, is associated with an 18% reduced risk (97465).
• Parkinson disease. Although consuming caffeinated beverages might reduce the risk of developing Parkinson disease, it is unclear if oral caffeine is beneficial for improving symptoms. Also, oral caffeine does not seem to prevent tardive dyskinesia. Details: It is unclear whether caffeine improves some symptoms of Parkinson disease, as results from clinical research are conflicting (91069,95951,95954,103705). One clinical study in Parkinson disease patients with extreme daytime somnolence shows that taking caffeine 100 mg twice daily for 3 weeks and then 200 mg twice daily for 3 weeks results in modest improvements in rigidity and bradykinesia, but inconsistent improvements in drowsiness, when compared with placebo (91069). Other clinical research shows that caffeine 200 mg twice daily does not lead to improvements in motor severity, cognition, or somnolence after 6, 12, or 18 months when compared with placebo (95954). Furthermore, a large retrospective study has found that caffeine consumption of more than 300 mg daily for 18 months in conjunction with dopaminergic therapy does not slow the rate of Parkinson disease progression. This research also shows that a reported consumption of caffeine greater than 300 mg, in conjunction with creatine 10 grams daily for 18 months, may accelerate the rate of Parkinson disease progression (95951). The retrospective nature of this study limits the validity of these findings. Caffeine does not appear to be helpful for reducing the risk of tardive dyskinesia. A retrospective analysis has found no definitive difference in onset of tardive dyskinesia in Parkinson patients consuming more than 204 mg caffeine daily when compared with those consuming less than 68 mg daily (91090). Despite these mainly negative findings, large-scale epidemiological studies have found that people who consume caffeinated beverages, such as coffee, tea, and cola, have a decreased risk of Parkinson disease (37931,91060,91071,103705). Males consuming 3-4 cups (28 oz) of caffeinated coffee per day, or 421-2716 mg total caffeine, seem to have the lowest risk of developing this condition. However, a lower risk is also associated with consumption of as little as 124-208 mg of caffeine (6022). In females, more moderate caffeinated coffee consumption, such as 1-3 cups per day, seems to be best (1238). Caffeine does not appear to provide additional protection from Parkinson disease in cigarette smokers (9236,91060).
• Postoperative ileus. It is unclear if oral caffeine is beneficial for improving bowel recovery following colorectal surgery. Research is conflicting and may vary depending on the type of procedure performed. Details: A meta-analysis of two small clinical trials in adults undergoing elective laparoscopic colorectal resection shows that taking caffeine 100-200 mg three times daily, starting on postoperative day 1, does not reduce the time to the first stool, time to first flatus, or length of hospital stay (LOS) when compared with placebo (112732). Another meta-analysis of 8 trials, including the 2 trials discussed previously, pooled 610 patients undergoing open and laparoscopic colorectal procedures. The analysis shows that caffeine taken three times daily, starting either on the day of surgery or on postoperative day 1, reduces LOS and the time to first bowel movement when compared with placebo, tea, or decaffeinated coffee. However, a sub-analysis of only laparoscopic procedures shows no difference in LOS between groups. These findings are limited by high heterogeneity, which appears to be due primarily to differences between open and laparoscopic procedures (114660).
• Postoperative pain. It is unclear if intravenous caffeine is beneficial for reducing opioid consumption in adults undergoing surgery. Details: A small clinical study in adults undergoing laparoscopic colorectal and gastrointestinal surgery shows that intravenous caffeine citrate 200 mg at the initiation of surgical closure has no effect on cumulative opioid consumption through postoperative day 3 when compared with placebo. In fact, post-hoc analysis with adjustment for age, sex, comorbidities, history of anxiety or depression, and open surgical conversion suggests an increase in opioid consumption with administration of caffeine when compared with placebo (108809).
• Pre-eclampsia. It is unclear if oral caffeine intake affects the risk of gestational hypertension or pre-eclampsia. Details: a meta-analysis of 10 observational studies including about 115,000 pregnant people did not find an association between the level of caffeine intake during pregnancy and the risk of developing gestational hypertension or pre-eclampsia (111485).
• Stroke. It is unclear if oral caffeine is beneficial for stroke prevention. Details: Population research has found that increased intake of either caffeinated or decaffeinated coffee is associated with a decreased risk of stroke in females (37804). However, it is not clear if the effect of coffee is attributable to the caffeine component.
• Tinnitus. It is unclear if oral caffeine is beneficial in patients with chronic tinnitus. Details: A small clinical study in adults with chronic tinnitus shows that taking a single dose of caffeine 300 mg improves mood and quality of life at 1 hour when compared with baseline. (108805). The lack of statistical comparison to the placebo group limits the validity of these findings. More evidence is needed to rate the effectiveness of caffeine for these uses.

(Read more about CAFFEINE)

EFFECTIVE

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

LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

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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.

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POSSIBLY EFFECTIVE

• Dysmenorrhea. In people with dysmenorrhea, taking oral ginger seems to reduce pain. Clinical research shows that ginger might be comparable to ibuprofen or mefenamic acid. In addition, taking ginger seems to be beneficial when used as an adjunct to mefenamic acid 250 mg twice daily. Details: Clinical research in individuals at least 15 years of age shows that ginger can reduce pain from dysmenorrhea. Clinical studies show that taking ginger powder 500-2000 mg daily usually for the first 3-4 days of a menstrual cycle modestly decreases pain severity by an average of 2.3-2.7 points on a 10-point scale when compared to control groups (89889,89899,91139,91892,96255,106077). However, a meta-analysis of clinical research shows that taking ginger does not reduce pain duration when compared with placebo (106077). Clinical research also shows that ginger might be as effective as some anti-inflammatory agents. Taking a specific ginger extract (Zintoma, Goldaru) 250 mg four times daily for 3 days at the beginning of the menstrual period or until pain relief improves symptoms similarly to ibuprofen or mefenamic acid (17931,96259,106077). Also, taking a ginger extract 200 mg four times daily for 3-4 days at the beginning of pain is equally effective to taking Novafen, a combination of acetaminophen, caffeine, and ibuprofen (99444). Ginger also seems to improve pain when given as an adjunct to anti-inflammatory agents. A small clinical study in young females with dysmenorrhea shows that adding ginger (Vomigone, Dineh Co.) 500 mg daily to mefenamic acid 250 mg twice daily for 5 days further reduces pain when compared with taking mefenamic acid alone (102464).
• Osteoarthritis. Most clinical research shows that taking ginger extract by mouth improves pain in some patients with osteoarthritis. Topical ginger, on the other hand, has not shown benefit for knee osteoarthritis in low quality research. Details: Meta-analyses of clinical research show that taking ginger extract 500-1000 mg daily for 3-12 weeks can modestly improve pain when compared with placebo in some patients with osteoarthritis of the knee or hip (96253,103357). However, a meta-analysis of two clinical studies shows that taking ginger extract about 500 mg daily for 6 weeks does not have an effect on function (103357). One small clinical trial in patients with mild osteoarthritis of the knee also shows that taking steamed golden ginger extract 480 mg daily for 12 weeks moderately improves pain and functional scores when compared with placebo (114784). Some clinical research has also compared ginger to conventional drug treatment. In one clinical trial, there was no significant difference between ginger extract 30 mg daily and ibuprofen 400 mg three times daily for one month in patients with osteoarthritis of the hip or knee (17930). However, taking a specific ginger extract (Eurovita Extract 33; EV ext-33) orally 170 mg three times daily for 3 weeks was significantly less effective than ibuprofen 400 mg three times daily for reducing pain (7048). Since ginger is thought to take several weeks for significant benefit, this trial might not have lasted long enough. Ginger has also been compared with diclofenac. When used orally as 1500 mg daily in two divided doses, ginger is less effective than oral diclofenac 100 mg daily in two divided doses, or the combination of ginger and diclofenac, for 12 weeks (89898). Various studies have evaluated formulations containing ginger with other ingredients. These combinations have all been shown to improve osteoarthritis pain, and in some cases, functionality. Studied formulations include ginger (Eurovita Extract 35; EV ext-35) 340 mg with glucosamine (Zinaxin glucosamine, Ferrosan AS) 1000 mg daily for 4 weeks, a ginger extract with an alpinia (Alpinia galanga) extract (Eurovita Extract 77; EV ext-77) 255 mg twice daily for 6 weeks, a ginger extract with curcuminoids, and extracts of devil's claw, Boswellia serrata, and celery (Tregocel) for 36 weeks, or Ayurvedic shunthi-guduchi formulations containing ginger, Indian gooseberry, and Tinospora cordifolia, either with or without Boswellia serrata (7084,18210,89557,106078). However, it's too early to know if the effects of these combination agents are associated with ginger or other ingredients in the formulations. Topical ginger, alone or in combination with other ingredients, has also been studied for knee osteoarthritis. Although a meta-analysis of two randomized clinical trials shows no evidence of benefit of topical ginger for pain and disability when compared with placebo or standard therapy (103357), some benefits have been shown in individual preliminary studies (20340,20341,89897,96668,97537,97542). These trials have used a specific gel containing ginger and plai 4% by weight (Plygersic gel, Thailand Institute of Scientific and Technological Research) 4 grams/day in four divided doses for 6 weeks (89897), an ointment composed of ginger, cinnamon, mastic (Saghez), and sesame oil twice daily for 6 weeks (20340), or one gram of ginger extract 5% (standardized to 11.18% of 6-gingerol) in a nanostructure lipid carrier three times daily for up to 12 weeks to the affected knee (96668,97537). Some studies have used ginger essential oil in a massage oil, alone or with sweet orange essential oil or standard therapy, twice weekly for 3 or 6 weeks (20341,97542).
• Pregnancy-induced nausea and vomiting. Oral ginger seems to reduce the severity of nausea and vomiting in some people during pregnancy. Ginger seems to be more effective than placebo, comparable to vitamin B6 or dimenhydrinate, and less effective than metoclopramide. Details: Although most clinical studies are small and have methodological limitations, the available research shows that ginger is more effective than placebo, and comparable to vitamin B6 or dimenhydrinate (721,1922,5343,11346,13071,16306,20312,20315,90103,91201,102462). Although ginger is comparable to dimenhydrinate for reducing symptoms of morning sickness, it seems to take about 3 days to reduce vomiting episodes compared to 1 day with dimenhydrinate (16305). In addition, clinical research shows that ginger is less effective than metoclopramide at relieving nausea and vomiting associated with pregnancy (20315). Ginger doses of 500 to 2500 mg daily, divided into two to four daily doses for 3 days to 3 weeks, have been used in clinical research (721,5343,16305,16306,20312,20315,90103,91201). The American College of Obstetrics and Gynecology (ACOG) considers ginger capsules 250 mg 4 times daily a first-line nonpharmacological treatment option for pregnancy-induced nausea based on limited evidence. However, there is no evidence that ginger reduces vomiting (111601).

POSSIBLY INEFFECTIVE

• Chemotherapy-induced nausea and vomiting (CINV). Most clinical research shows that oral ginger does not reduce acute or delayed CINV. The effect of ginger might depend on the dose, the other antiemetics used, or the specific chemotherapy regimen. Details: Most clinical research shows that taking ginger as adjunct to adequate antiemetic therapy does not reduce DELAYED CINV when compared with antiemetic therapy alone (20316,96260,89891,96675,97538,97541,101760,102461,113616). Clinical research from meta-analyses and most individual clinical studies also show that taking ginger 0.5-3.5 grams as an adjunct to standard antiemetic therapy does not reduce the incidence or severity of ACUTE CINV when compared with antiemetic therapy alone (89891,96675,101760,102461,102466,113616). However, conflicting results exist from some individual clinical studies (20316,102466). These individual studies evaluated powdered ginger root or liquid extract of ginger root 0.5-2 grams taken in two to four divided doses daily, starting on either the day of or 3 days before chemotherapy and continuing for 3-5 days after chemotherapy initiation (20316,102466). Also, one small study shows that ginger in doses of 1 gram or less for more than 3 days reduces the likelihood of acute vomiting by 60% (101760). More research is needed to confirm the efficacy of this lower dose. Reasons for the conflicting results are unclear, but several theories have been postulated. One theory is that ginger might help reduce CINV associated with some, but not all, chemotherapy regimens. One preliminary clinical study shows that ginger 500 mg twice daily for 3 days reduces vomiting in patients receiving cyclophosphamide and doxorubicin, but not in patients also receiving 5-fluorouracil or docetaxel (96251). However, since there is limited evidence supporting this theory, additional research is needed to confirm. Another theory is that ginger helps when used with certain antiemetic drugs, but not others. For example, ginger seems to help in cases when optimal antiemetic therapy, such as 5-HT3 receptor antagonists, is not available. Small clinical studies show that ginger reduces the severity of acute nausea when compared with prochlorperazine or metoclopramide, both of which are suboptimal antiemetic therapy for CINV (89891). Another small study shows that ginger is comparable to metoclopramide for improving delayed chemotherapy-induced nausea (13244). On the other hand, several studies show that taking ginger 0.5-2 grams daily along with antiemetic therapy that includes aprepitant does NOT improve acute or delayed CINV (20318,89891,96251,96675). In fact, one study found an association between concomitant use of ginger 2 grams daily with aprepitant and worsened severity of delayed nausea. Ginger is hypothesized to decrease the absorption of aprepitant and reduce its effectiveness for delayed nausea (20318,96675). However, this effect has not been replicated, and aprepitant serum levels were not measured to confirm this hypothesis. Finally, many of the studies showing a benefit of ginger for CINV when used as an adjunct to standard antiemetic therapy are considered to be methodologically flawed (20317,96252,96677). For instance, one study using powdered ginger root 1-2 grams daily during the first three days of chemotherapy in children and adults (20317) has been criticized for inaccurately representing data (89891). Other studies of ginger 500 mg twice daily for up to 10 days used questionable methods to measure outcomes and usually did not differentiate between acute and delayed CINV (96252,96677). Ginger essential oil aromatherapy has also been evaluated. One small study shows that using two drops of ginger essential oil on an aromatherapy necklace for 2 minutes daily for 5 days, starting on the first day of chemotherapy, reduces acute nausea, but not vomiting or delayed nausea, when compared with placebo in females with breast cancer taking standard antiemetics including granisetron, dexamethasone, and metoclopramide (96256).
• Exercise-induced muscle soreness. Most research shows that oral ginger in single or multiple doses does not prevent or treat exercise-induced muscle soreness. Details: Two small studies in healthy adults show that single doses of ginger supplements do not seem to reduce muscle soreness from exercise. Taking capsules of ground ginger 2 grams, 30 minutes before a 30-minute cycling bout, or 24-48 hours after eccentric exercise, does not reduce muscle pain during exercise or within one hour of ingestion when compared with placebo (17932,17934). Taking multiple doses also does not seem to help. One small study in healthy adults shows that taking capsules with ginger powder 4 grams daily for 5 days before high-intensity eccentric exercise does not reduce muscle soreness over 4 days when compared with placebo (96258). Another small study in healthy adults shows that taking capsules of heated or raw ground ginger 2 grams daily for 8 days prior to eccentric exercise, and continuing supplementation for 3 more days, might modestly reduce muscle soreness 24 hours post-exercise, but not at later time points, when compared with placebo (17933,96258). Ginger has also been tested in combination with other ingredients. One small study in healthy adults shows that taking a specific combination product (ReWin(d), Natural Origins) containing a 4:3 ratio of ginger and annatto powder, 2 grams in divided doses daily for 4 weeks before eccentric exercise and continuing for 3 days after exercise, may modestly reduce muscle pain 48 hours after exercise but not at other time points (105057). This study was funded by the supplement manufacturer.
• Motion sickness. Most research shows that oral ginger does not prevent or treat motion sickness. Details: Most clinical research shows that taking ginger 500-1000 mg up to 4 hours prior to travel does not prevent motion sickness (7624,7625,20330,20331). Some patients report subjective feelings of improvement, but in many studies objective measures did not significantly improve (7400). However, one clinical trial suggests that ginger is more effective than dimenhydrinate at reducing gastrointestinal distress associated with motion sickness (20332). Another clinical study seems to show that taking ginger 1-2 grams as a single dose reduces nausea severity and increases the latency before the onset of nausea caused by simulated motion sickness when compared to baseline (20333). The validity of this finding is limited by the lack of a comparator group.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acute respiratory distress syndrome (ARDS). Some small clinical studies show that giving ginger with tube feeds to hospitalized patients might reduce the duration of serious sequelae from ARDS. Details: A small clinical trial in adults with ARDS shows that administering ginger extract 120 mg in three divided doses daily via nasogastric tubing for 21 days increases the number of ventilator-free days and the amount of feeding tolerated and decreases the number of intensive care unit (ICU) days when compared with placebo. However, it does not seem to improve overall mortality (20343). Also, another small clinical study shows that adding ginger extract 120 mg to tube feeds in three divided doses daily for 8-21 days improves blood oxygen levels by 13% to 20%, as well as the ability of the lungs to expand by 17%, when compared with a coconut oil placebo. The duration of mechanical ventilation and stay in the ICU also improved. However, ginger does not affect other measurements of lung function or physical organ damage in these patients (89886).
• Allergic rhinitis (hay fever). It is unclear if oral ginger is beneficial in allergic rhinitis. Details: A small clinical trial shows that taking ginger extract 500 mg daily for 6 weeks is as effective as loratadine 10 mg daily for reducing nasal symptoms of allergic rhinitis (103359).
• Antiretroviral-induced nausea and vomiting. Oral ginger seems to improve nausea and vomiting in patients using antiretroviral agents. Details: A small clinical study in patients with HIV shows that taking ginger 0.5 grams twice daily, 30 minutes prior to each dose of antiretroviral for 14 days, reduces the relative likelihood of nausea and vomiting by about 63% and 79%, respectively, when compared with placebo (89887).
• Asthma. Although there has been interest in using oral ginger for asthma, there is insufficient reliable information about the clinical effects of ginger for this condition.
• Atopic dermatitis (eczema). Topical ginger has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical trial in adults and children with eczema shows that applying a combination topical product containing ginger and cannabidiol twice daily for 5 days moderately improves eczema scores, including erythema, dryness, itching, and scaling, when compared to baseline. It is unclear if this effect is due to ginger, other ingredients, or the combination. The validity of this study is limited by the lack of a comparator group (114783).
• Back pain. Although there has been interest in using oral ginger for back pain, there is insufficient reliable information about the clinical effects of ginger for this condition.
• Burns. Although there has been interest in using topical ginger for burns, there is insufficient reliable information about the clinical effects of ginger for this condition.
• Cancer-related anorexia. It is unclear if oral ginger improves appetite in people with cancer-related anorexia. Details: A small clinical study in patients with cancer-related anorexia and cachexia shows that taking a capsule containing ginger 1650 mg daily for 14 days improves nausea, appetite, reflux, dysmotility, and other gastrointestinal symptoms when compared to baseline (102460). The validity of these findings is limited by the lack of comparator group.
• Chronic obstructive pulmonary disease (COPD). Oral ginger has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking two capsules of a specific combination product (AKL1, AKL International Ltd.) containing ginkgo extract, ginger, and Picrorhiza kurroa twice daily for 8 weeks does not improve respiratory symptoms when compared with placebo in patients with COPD (89702). Another moderate-sized clinical study in adults with COPD shows that taking a combination product containing extracts of ginger, alpinia, cardamom, cinnamon, 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 ginger, other ingredients, or the combination.
• Colic. Although there has been interest in using oral ginger for colic, there is insufficient reliable information about the clinical effects of ginger for this condition.
• Constipation. Although there has been interest in using oral ginger for constipation, there is insufficient reliable information about the clinical effects of ginger for this condition.
• Coronavirus disease 2019 (COVID-19). It is unclear whether oral ginger is beneficial for patients with COVID-19. Details: Clinical research in adults hospitalized with asymptomatic COVID-19 infection shows that taking ginger 1.5 grams twice daily orally until hospital discharge reduces length of stay from around 8.5 days to 6 days, when compared with placebo. The strongest effect is seen in males over 60 years of age (110005). The relevance of these results is reduced by a lack of blinding, and the fact that the subjects were initially asymptomatic. Another small study in adults with COVID-19 treated in the community shows that taking ginger 1000 mg three times a day for 7 days does not improve viral clearance, oxygen saturation, or respiratory rate when compared with placebo. Taking ginger also did not reduce the risk of hospitalization (114779). The efficacy of ginger for treating COVID-19 has also been evaluated in combination with other ingredients. In adults with uncomplicated, moderate COVID-19, taking a combination of ginger, turmeric, ashwagandha, and boswellia (BV-4051, Artovid-20), 1776 mg twice daily orally for 14 days in addition to standard care and starting 48-96 hours after symptom onset, reduces the mean duration of symptoms from about 8 days to 7 days, when compared with placebo (109899). A small open-label study in adults with confirmed mild to moderate COVID-19 shows that taking ginger 1000 mg and ashwagandha 500 mg twice daily for 15 days, along with conventional therapy, leads to a 13.8-fold and 2.6-fold increase in the relative rate of clinical cure at 7 days and 15 days, respectively, when compared with conventional therapy alone. Taking this combination also appears to reduce time to recovery by around 6 days but does not improve the rate of negative COVID-19 tests, chest imaging findings, viral clearance, serum antibodies, or other measures of disease progression when compared with conventional therapy alone (112094). The validity of these findings is limited by a lack of blinding, and the study may have been inadequately powered to detect a difference between groups. Additionally, it is unclear if these effects are due to ginger, ashwagandha, or the combination.
• Diabetes. Some preliminary clinical studies suggest that oral ginger might have a small beneficial effect on glycemic control in patients with type 2 diabetes or gestational diabetes. Details: Meta-analyses of several small clinical trials in adults with type 2 diabetes show that taking ginger 1200-3000 mg daily for 8-13 weeks reduces glycated hemoglobin (HbA1c) by around 0.6% to 1% and fasting blood glucose by 19-21 mg/dL when compared with placebo (96680,107898). However, a recent meta-analysis of randomized clinical trials in adults with type 2 diabetes shows that taking ginger 1200-2000 mg daily for 4-12 weeks does not improve HbA1c or fasting blood glucose when compared with placebo (114780). The reasons for these discordant results are not entirely clear, but they are likely related to heterogeneity of the included populations, treatment dose, and duration of follow up. Additionally, a small clinical study in adults with diabetes on hemodialysis for end stage renal disease shows that taking ginger powder 2000 mg daily for 8 weeks reduces fasting blood glucose and measures of insulin resistance, but not serum insulin levels, when compared with placebo (111543). In patients with gestational diabetes at weeks 24-28 of pregnancy, clinical research shows that taking ginger 1500 mg daily in three divided doses for 6 weeks reduces fasting blood glucose, insulin levels, and measures of insulin resistance by a small amount when compared with placebo, with no effect on postprandial glucose levels (103358).
• Diabetic neuropathy. Topical ginger has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in adults treated with gabapentin for diabetic neuropathy of the foot shows that applying a combination balm containing ginger, menthol, camphor, and other ingredients three times a day for 4 weeks moderately improves pain scores when compared with a placebo balm without ginger but containing menthol, camphor, and other ingredients.(114781). It is unclear if this effect is due to ginger, other ingredients, or the combination.
• Diarrhea. Although there has been interest in using oral ginger for various types of diarrhea, including cholera and acute bacterial dysentery, there is insufficient reliable information about the clinical effects of ginger for these conditions.
• Dry mouth. It is unclear if rinsing the mouth with ginger extract is beneficial for dry mouth. Details: In patients with dry mouth related to type 2 diabetes, clinical research shows that use of a ginger extract 25% mouthwash 20 mL three times daily for 14 days modestly reduces symptoms of dry mouth when compared with rinsing with a saline control mouthwash (106068). Although this study was indicated as being triple-blind, it is unclear how the taste of ginger was masked.
• Dyspepsia. It is unclear if oral ginger is beneficial for dyspepsia. Details: In patients with dyspepsia, a small clinical trial shows that a single dose of ginger root powder 1.2 grams, taken 1 hour prior to eating, does not reduce abdominal discomfort when compared with placebo. However, it increases the rate of gastric emptying (20325).
• Erectile dysfunction (ED). It is unclear if oral ginger is beneficial for erectile dysfunction. Details: Preliminary clinical research in middle-aged males with ED shows that taking two capsules of a specific combination product (Revactin, MD Concepts LLC) containing ginger root 250 mg, muira puama 250 mg, guarana 250 mg, and L-citrulline 800 mg twice daily for 3 months improves scores related to erectile function and intercourse satisfaction, but does not improve sexual desire or orgasmic function scores, when compared to baseline (103224). This study is limited by the lack of a placebo control, the use of per-protocol analysis, and a high dropout rate. In fact, 44% of patients withdrew in order to resume use of phosphodiesterase type 5 (PDE5) inhibitors. Further, it is unclear if these effects are due to ginger, other ingredients, or the combination.
• Gastroenteritis-associated nausea and vomiting. It is unclear if oral ginger is beneficial for children with gastroenteritis-associated vomiting. Details: In children aged 1-10 years with acute gastroenteritis-associated vomiting, clinical research shows that taking a single dose of ginger reduces the risk of vomiting at least once in the subsequent 8 hours by 20% when compared with placebo. The incidence of vomiting over the next 24 and 48 hours was also modestly reduced. The children were given 20 drops of ginger equivalent to 10 mg immediately, followed by every 8 hours until cessation of vomiting. All children were offered hypotonic oral rehydration solution (ORS) 30 minutes after the first dose (106076). The number of children accepting ORS, and the quantity of ORS consumed, was less in the group receiving placebo. It is unclear if this affected the outcomes of this study. Also, the incidence or severity of nausea was not investigated.
• Hangover. It is unclear if oral ginger is beneficial for managing symptoms of hangover. Details: Preliminary clinical research shows that use of a decoction containing a combination of ginger 6 grams, pith of Citrus tangerine 3 grams, and brown sugar decreases symptoms of alcohol hangovers, including nausea, vomiting, and diarrhea, when compared with placebo. The decoction was taken once 5 hours prior to drinking alcohol or four times after drinking alcohol (20320).
• Hyperlipidemia. Oral ginger may be modestly beneficial for some patients with hyperlipidemia. Details: A meta-analysis of preliminary clinical research in adults with and without hyperlipidemia shows that taking ginger 200-3000 mg orally daily for 2-24 weeks reduces triglyceride and low-density lipoprotein cholesterol levels by 12 mg/dL and 5 mg/dL, respectively, and increases high-density lipoprotein cholesterol levels by 1 mg/dL when compared with placebo (109521). However, the validity of this study is limited by high heterogeneity. A clinical study in adults with hyperlipidemia shows that taking ginger powder 1 gram three times daily for 45 days reduces triglyceride and cholesterol levels by an additional 36% and 90%, respectively, when compared with placebo (20327).
• Hypertension. It is unclear if oral ginger is beneficial for lowering blood pressure. Details: A preliminary clinical study in patients with diabetes and elevated systolic blood pressure shows that drinking black tea containing ginger 3 grams three times daily for 8 weeks does not reduce blood pressure by a clinically significant amount when compared with plain black tea (96669).
• Hypothyroidism. It is unclear if oral ginger is beneficial in patients with hypothyroidism. Details: A small clinical study in patients with primary hypothyroidism who are stabilized on thyroid hormone therapy shows that taking ginger powder 500 mg twice daily for 30 days improves symptoms associated with hypothyroidism, including cold intolerance, constipation, dizziness, dry skin, weight gain, and concentration and memory issues, when compared with placebo. However, ginger supplementation does not seem to improve hair loss, hearing, nail fragility, speech, or feelings of depression in these patients (107903).
• Insect bite. It is unclear if topical ginger is beneficial for reducing the size of insect bites. Details: Preliminary clinical research shows that a topical application of Trikatu, which contains ginger, long pepper, and black pepper extracts with 0.074% piperine and 0.046% gingerol, does not reduce the papule size associated with mosquito bites when compared with a control compound containing the same base ingredients of camphor 2%, menthol 2%, and eucalyptus oil 4% (89893).
• Intraoperative nausea and vomiting (IONV). It is unclear if oral ginger is beneficial for preventing IONV. Details: Clinical research in individuals undergoing elective C-section and receiving cimetidine and metoclopramide, shows that taking ginger 1 gram orally 30 minutes prior to anesthesia reduces the number of episodes of intraoperative nausea, but not vomiting, when compared with placebo (89890). In other clinical research in adults undergoing elective surgical procedures, adding ginger to a high calorie drink consumed pre-operatively reduces the incidence of nausea from 40% to 10%, and the incidence of vomiting from 25% to 10% when compared with the high calorie drink alone (110007). The validity of these results is unclear as only patients were blinded to the treatment group.
• Irritable bowel syndrome (IBS). Oral ginger might reduce symptoms of IBS when used in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial shows that taking ginger 1-2 grams daily for 28 days does not improve symptoms or the number of responders when compared with placebo (90102). However, some research shows that ginger might be beneficial in some patients when used along with other herbal ingredients. Taking a capsule containing ginger, boswellia, and yarrow three times daily for 30 days reduces the frequency and severity of abdominal pain, as well as the severity of bloating, when compared with placebo in females, but not males, with mild to moderate IBS (96673). Another clinical study shows that taking an herbal mixture containing ginger, English horsemint, and purple nut sedge tuber three times daily for 8 weeks improves IBS symptoms including abdominal pain, stool frequency, stool consistency, incomplete evacuation, and urgency, when compared to baseline; these improvements are similar to those achieved by taking mebeverine 135 mg three times daily (89900). However, it is unclear if these effects are due to ginger, other ingredients, or the combination.
• Joint pain. Oral ginger has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a specific combination product (Instaflex Joint Support, Direct Digital) containing glucosamine sulfate 1500 mg, methylsufonlylmethane 500 mg, white willow bark extract 250 mg, ginger root concentrate 50 mg, Boswellia extract 125 mg, turmeric root extract 50 mg, cayenne 40 m H.U. 50 mg, and hyaluronic acid 4 mg in three divided doses daily for 8 weeks reduces joint pain severity by 37% compared to only 16% with placebo. However, it does not improve joint stiffness or function when compared with placebo (89560). It is unclear if these effects are due to ginger, other ingredients, or the combination.
• Menorrhagia. It is unclear if oral ginger is beneficial for menorrhagia. Details: Preliminary clinical research in healthy adults experiencing heavy menstrual bleeding shows that taking ginger 250 mg three times daily for 4 days, starting the day prior to menstruation, and repeating for three menstrual cycles, reduces the amount of menstrual bleeding when compared with placebo (96672).
• Menopausal symptoms. Although there has been interest in using oral ginger for menopausal symptoms such as insomnia, there is insufficient reliable information about the clinical effects of ginger for this purpose.
• Migraine headache. Small clinical studies suggest that oral ginger may modestly reduce migraine pain severity and duration. However, taking ginger doesn't seem to PREVENT migraines. Details: Ginger does not seem to be effective for the prevention of migraines. Clinical research in patients with episodic migraine shows that taking ginger extract 200 mg three times daily for 3 months does not reduce the number of migraine attacks, the use of analgesics, or the number of days with pain, any more than taking placebo (101761). However, ginger may be beneficial for the treatment of migraine. Clinical research shows that taking ginger extract 400 mg orally in the emergency room along with intravenous ketoprofen 100 mg reduces pain over the next 2 hours when compared with ketoprofen and placebo. This combination also resulted in an overall better response with a higher likelihood of having no or mild pain with treatment (101762). Taking ginger 250 mg at the onset of a common migraine headache seems to be as effective as taking sumatriptan 50 mg for reducing headache severity within two hours of treatment (89894). Furthermore, a combination of ginger and feverfew (GelStat Migraine, GelStat Corporation; LipiGesic M, PuraMed BioScience), administered sublingually at the onset of a migraine attack, decreases the duration and intensity of migraine pain when compared with placebo (19357,22602). It is unclear if these effects are due to ginger, feverfew, or the combination. Feverfew alone has demonstrated some benefit in treating migraines.
• Multiple sclerosis (MS). It is unclear if oral ginger is beneficial for MS. Details: A small clinical study in adults with MS shows that taking ginger 500 mg three times daily for 12 weeks reduces disability scores and improves physical and psychological quality of life scores when compared with placebo (111541). Another small clinical study in adults with relapsing-remitting MS shows that taking ginger 500 mg three times daily for 12 weeks reduces the frequency and severity of nausea and constipation and the severity but not frequency of bloating when compared with placebo. However, no improvement was noted in other gastrointestinal symptoms of MS including abdominal pain, anorexia, diarrhea, dysphagia, gas, or heartburn (113614).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral ginger is beneficial for NAFLD. Details: A small clinical study in patients with NAFLD shows that taking ginger 1000 mg twice daily for 12 weeks improves liver steatosis scores but not liver fibrosis scores when compared with placebo. Ginger also modestly improves levels of alanine aminotransferase and gamma-glutamyl transferase but not aspartate aminotransferase (113615). However, it is unclear whether any improvements are clinically significant. Another small clinical study in patients with NAFLD shows that taking ginger root 1500 mg daily for 12 weeks reduces low-density lipoprotein (LDL) cholesterol and fasting blood glucose levels, but does not affect triglycerides, high-density lipoprotein (HDL) cholesterol, insulin resistance, blood pressure, or fatty liver index, when compared with placebo (102465).
• Obesity. Oral ginger has primarily been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Although some individual research disagrees (40802), a meta-analysis and most individual clinical trials show that taking ginger alone or with other ingredients does not reduce weight by a clinically significant amount when compared with placebo in overweight or obese individuals (20346,20347,96676,109521). Ginger has been taken alone or in combination with green tea and capsaicin; rhubarb, astragalus, red sage, turmeric, and gallic acid (Number Ten); or raspberry ketone (Razberi K, Integrity Nutraceuticals), caffeine, capsicum extract (Capsimax, OmniActive Health Technologies), bitter orange fruit (Advantra Z, Nutratech Inc), L-theanine, and black pepper fruit extract (Biperine, Sabinsa Corporation) (Prograde Metabolism) (20346,20347,40802,96676). Due to the various other ingredients contained in available formulations, any effect from ginger is unclear.
• Parturition. It is unclear if bathing in a ginger bath is beneficial for shortening the duration of labor. Details: Preliminary clinical research shows that bathing in 228 liters of water containing 4 drops of ginger essential oil does not shorten the duration of labor when compared with a regular bath (20345).
• Polycystic ovary syndrome (PCOS). It is unclear if oral ginger is beneficial for females with PCOS. Details: Preliminary clinical research in females with PCOS shows that taking ginger 500 mg three times daily orally for 8 weeks decreases body weight, body mass index, and levels of follicle stimulating hormone and luteinizing hormone, when compared with placebo. It does not affect testosterone levels (110006).
• Postoperative nausea and vomiting (PONV). Evidence for the use of oral ginger for preventing PONV is inconclusive and conflicting. Reasons for the conflicting findings may relate to the ginger formulation used and the outcomes measured. It is unclear if ginger aromatherapy is beneficial for PONV. Details: Some individual clinical studies, as well as a large, recent meta-analysis of the available clinical research, show that taking ginger by mouth 1 hour prior to surgery does not reduce the incidence of 24-hour PONV (3452,3453,17369,99445). Also, the meta-analysis found that, although ginger reduces the severity of PONV when measured on a visual analogue scale (VAS), it does not reduce the severity of PONV when measured on a verbal descriptive scale (VDS). Furthermore, ginger does not reduce the use of rescue antiemetic medications (99445). However, some small, individual clinical studies and a meta-analysis of older clinical research show that taking ginger by mouth prior to surgery reduces the incidence of 24-hour PONV by up to 16% to 38% (722,723,1919,13237,20336,20338,20339). In addition, large clinical trials show that the frequency and severity of PONV 2-6 hours after surgery are similar when ginger 1 gram is given orally or when medications such as metoclopramide or dexmedetomidine are given intravenously prior to undergoing anesthesia (103356,103360). However, taking ginger prior to general anesthesia, in combination with other antiemetics like dexamethasone or cimetidine and metoclopramide, does not seem to reduce nausea and vomiting when compared with the other medications alone (20337,89890). In contrast, other research shows that powdered ginger 1-2 grams 30-60 minutes before induction of anesthesia has been used in most studies showing benefit, occasionally followed by 1 gram of ginger administered two hours after surgery (722,723,13237,20336,20338,103356,103360). Ginger aromatherapy has also been evaluated for the prevention of PONV. Application of 5% ginger essential oil to the wrists of patients prior to the induction of general anesthesia seems to prevent PONV in approximately 80% of treated patients (20334). Also, use of ginger essential oil aromatherapy on a gauze pad results in nausea relief in approximately 67% of patients compared with 40% in the placebo group; however, a blend of essential oils including ginger, spearmint, peppermint, and cardamom, results in nausea relief in 82% of patients (89888).These conflicting findings may be due to differences in outcome measures and the chemical compositions of ginger preparations used in the various clinical studies. Some evidence suggests that the efficacy of ginger for preventing PONV differs based on the formulation used. A network meta-analysis of 18 studies evaluating various ginger preparations, including ginger oil, ginger powder, ginger extract, and a combination of ginger powder and antiemetics, for the prevention of PONV suggests that ginger powder and ginger oil are the most effective formulations for preventing nausea and vomiting, respectively. The analysis also shows that while no ginger formulation is superior to another for the prevention of nausea, ginger powder and ginger oil have a lower risk of postoperative vomiting when compared with ginger extract. A subgroup analysis suggests that ginger seems to be most effective in adults over 30 years of age, when administered preoperatively, and when used for gastrointestinal, hepatobiliary, obstetric, or ophthalmic surgeries (112108).
• Postoperative recovery. It is unclear if oral ginger is beneficial for postoperative recovery. Details: One preliminary clinical study in adults who had a tonsillectomy shows that taking a specific ginger supplement (Solgar, Leonia) 500 mg twice daily for 7 days along with acetaminophen and antibiotics modestly improves pain and wound healing when compared with acetaminophen and antibiotics alone (96674).
• Postpartum complications. It is unclear if oral ginger is beneficial in patients with postpartum pain. Details: A small clinical study in patients recovering from vaginal delivery shows that taking ginger powder 500 mg 8-hours post-delivery, followed by 250 mg every 8 hours thereafter for 24 hours, reduces postpartum pain by nearly 1 point on a 10-point rating scale when compared with placebo (107904). It is unclear if this improvement would be considered clinically relevant.
• Radiation-induced nausea and vomiting. It is unclear if oral ginger is beneficial in patients with radiation-induced nausea and vomiting. Details: A very small study in adults with cervical cancer undergoing treatment with cisplatin and radiotherapy shows that taking ginger 250-500 mg twice daily for 6 weeks in addition to standard antiemetic therapy does not reduce acute or delayed nausea and vomiting when compared with antiemetic therapy alone (113616).
• Rheumatoid arthritis (RA). One small clinical study suggests that oral ginger may improve some symptoms of RA. Details: Preliminary clinical research in adults with RA shows that taking ginger powder 1500 mg daily for 12 weeks improves disease activity on the Disease Activity Score-28 when compared with placebo (100697). Another small study in adults with RA shows that taking a combination product containing ginger, ashwagandha, black pepper, and colchicum luteum twice daily for 4 weeks does not improve RA disease scores when compared with celecoxib 100 mg orally twice daily (114785). However, the interpretation of these results is limited by. poor methodology, and the study may have been inadequately powered to detect a difference between groups.
• Smoking cessation. Oral ginger has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in adults in India with a history of smoking 5 or more cigarettes daily for at least 3 years shows that taking a specific combination product containing ginger 50 mg, ashwagandha, cowhage, turmeric and other herbal extracts (Smotect, Smotect India) twice daily for 3 months reduces the number of cigarettes smoked by approximately 3 per day when compared with placebo. This product also reduces levels of alveolar carbon monoxide and carboxyhemoglobin but does not improve lung capacity (112115). However, only data from patients who completed treatment were analyzed, which limits the validity of this study. It is also unclear if these effects are due to ginger, other ingredients, or the combination.
• Swallowing dysfunction. The effects of oral ginger for treating swallowing dysfunction are inconclusive. Reasons for the conflicting findings may relate to the route of administration or the number of treatments provided. Details: Clinical research shows that applying a spray containing ginger and clematix root (Tongyan) to the oropharynx for 28 days is more effective than placebo at treating grade 2 or 3 dysphagia in stroke victims. However, there does not seem to be a beneficial effect in patients with grade 1 dysphagia (20342). Other clinical research in elderly patients with dysphagia shows that taking a single dose of ginger 2 mg orally does not improve swallowing but increases saliva (96671). It is possible that a single dose of ginger is not enough to improve swallowing function.
• Toxin-induced liver damage. Oral ginger might help to prevent liver damage in patients using antimycobacterial drugs. Details: Preliminary clinical research shows that a specific ginger supplement (Zintoma, Goldaru) 500 mg taken 30 minutes prior to antimycobacterial drugs daily for 4 weeks reduces the percentage of patients experiencing an increase in liver function enzymes to greater than five times the upper limit of normal by 54% when compared with placebo. Antimycobacterial drugs used for tuberculosis in the study included isoniazid 5 mg/kg, rifampin 10 mg/kg, ethambutol 15 mg/kg, and pyrazinamide 25 mg/kg daily (96670).
• Traumatic brain injury (TBI). Oral ginger has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary research in young adults with subjective memory dysfunction associated with mild TBI, shows that taking a combination of ginger 36 mg and boswellia 360 mg (Memoral) every 8 hours orally for one month improves scores for some, but not all, parameters on an auditory-visual learning test performed at one and three months, when compared with placebo. Total learning scores increased by about 7.5 points with the ginger combination product, compared with 4 points for placebo (110132). It is unclear if these effects are due to ginger, boswellia, or the combination.
• Ulcerative colitis. It is unclear if oral ginger is beneficial for improving symptoms of ulcerative colitis. Details: Preliminary clinical research in adults with ulcerative colitis shows that taking ginger powder 1000 mg twice daily for 12 weeks improves disease activity as measured by the Simple Clinical Colitis Activity Index Questionnaire when compared with taking placebo. However, taking ginger did not improve quality of life, stool frequency, bowel distress, or flatulence when compared with placebo (100694). It is possible that this study was not adequately powered to detect a difference in these secondary outcomes.
• Upper respiratory tract infection (URTI). Although there has been interest in using oral ginger for various upper respiratory tract infections, there is insufficient reliable information about the clinical effects of ginger for this condition.
• Vertigo. It is unclear if oral ginger is beneficial for improving symptoms of vertigo. Details: A small clinical study shows that taking 1 gram of ginger orally as a single dose prior to stimulated vertigo seems to reduce symptoms of vertigo, including nausea, when compared with placebo. However, it does not seem to reduce nystagmus (7623). More evidence is needed to rate ginger for these uses.

(Read more about GINGER)

There is insufficient reliable information available about the effectiveness of glucuronolactone.

(Read more about GLUCURONOLACTONE)

LIKELY EFFECTIVE

• Human papillomavirus (HPV). A specific green tea extract ointment (Polyphenon E ointment 15%) is approved by the US Food and Drug Administration (FDA) for treating external genital warts caused by HPV. Details: A specific green tea extract ointment (Veregen, Bradley Pharmaceuticals; Polyphenon E ointment 15%, MediGene AG) providing 150 mg of sinecatechins per gram of ointment, applied three times daily to external warts, completely clears external genital and perianal warts in 24% to 60% of patients after 10-16 weeks of treatment (15067,36438,36442,53777,53907,54018). This green tea extract is an FDA-approved prescription product (15067).

POSSIBLY EFFECTIVE

• Cardiovascular disease (CVD). Drinking green tea seems to reduce the risk of CVD and CVD-related mortality. Details: Large-scale population research in Japan suggests that consuming at least 3-5 cups of green tea daily is associated with a reduced risk of cardiovascular mortality when compared with drinking less than 1 cup daily. This association appears to be primarily related to a decrease in risk for cerebral infarction and heart disease. This association appears to be stronger in females than in males (14498,53789,100202). Population research also suggests that drinking green tea is associated with a reduced risk of CVD. One meta-analysis suggests that drinking green tea is associated with a 28% reduced risk of CAD (54017). Another meta-analysis suggests that consuming small to moderate amounts of green tea, 1-5 cups or 300 to 1500 mL daily, is associated with an 8% to 16% reduced risk of coronary heart disease over 5 to 13 years when compared with consuming no green tea (111017). One meta-analysis suggests that a 1 cup increase in green tea consumption is associated with a 5% reduced risk of CVD mortality and a 3% reduced risk of CVD events (102728). When compared with drinking less than 1 cup of green tea daily, epidemiological research in a population at high risk of coronary artery disease (CAD) suggests that drinking more than 3 cups of green tea daily is associated with a 46% reduced odds of having CAD, especially severe CAD, as determined by a coronary angiography (104588). A sub-group analysis suggests that these odds only occurred in individuals consuming fruits more than 4 times weekly and not in individuals consuming fruits less often (104588). However, some population research suggests that any association seems to be greater for males than females (53691). Other population studies suggest that general tea consumption might protect against ischemic heart disease or death from CVD; however, many of the tea drinkers in some of these studies consumed black tea rather than green tea (8119,8120,8121,102728).
• Endometrial cancer. Drinking green tea seems to be beneficial for endometrial cancer prevention. Details: Meta-analyses of epidemiological research have found that people who drink green tea often, usually more than once daily, have a 21% to 23% reduced risk of developing endometrial cancer when compared with those who never or rarely drink green tea (53919,92409,102716). One of these meta-analyses also found that increasing green tea intake by one cup per day is associated with an 11% reduced risk of developing endometrial cancer (92409).
• Hyperlipidemia. Oral green tea seems to reduce levels of low-density lipoprotein (LDL) cholesterol by a small amount. Details: Clinical research and a meta-analysis of clinical research in people with or without hyperlipidemia shows that consuming green tea or green tea extract containing 150-2500 mg catechins daily for up to 24 weeks reduces total cholesterol by about 5-24 mg/dL and LDL cholesterol by about 2-25 mg/dL when compared with control (11308,54038,54048,90146,90161,97135,104605). There is also preliminary evidence that taking a green tea extract containing catechins 676 mg daily for 12 weeks reduces oxidation of LDL cholesterol when compared with placebo, which might lead to reduced damage to the vascular endothelium and reduced arteriosclerosis (98458). Epidemiological research has found that higher consumption of green tea, especially 10 cups daily or more, is associated with improved serum lipids in males, but not females (6403,97134).
• Ovarian cancer. Drinking green tea seems to be beneficial for ovarian cancer prevention. Details: Consuming tea, including green tea or black tea, appears to significantly lower the risk of developing ovarian cancer when compared with never or seldom consuming tea (9228,13208,90144,102716). One meta-analysis of population research suggests that the highest intake of green tea is associated with a 36% reduced risk of ovarian cancer when compared with the lowest intake (102716). Also, one prospective population study found that those who consume 2 or more cups of tea daily have a 46% lower risk of ovarian cancer when compared with those who don't regularly consume tea (13208). There also appears to be a trend that suggests higher consumption of tea or longer duration of use further reduces the risk of ovarian cancer (9228,13208). However, green tea does not appear to prevent ovarian cancer recurrence. Preliminary clinical research shows that drinking 500 mL of double-brewed green tea (DBGT), prepared with 35 grams/L of tea leaves standardized to contain approximately 640 mg/L of EGCG, daily for up to 18 months does not prevent cancer recurrence in adults with a history of advanced stage serous or endometrioid ovarian cancer (90175).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Topical green tea might reduce acne lesions by a small amount. It is unclear if oral green tea is beneficial for acne. Details: A meta-analysis of preliminary clinical research shows that topical application of green tea extract reduces the number of inflammatory and non-inflammatory lesions by a small amount (104609). In one small study, applying a solution containing the green tea constituent epigallocathechin-3-gallate (EGCG) 1% or 5% twice daily for 8 weeks was used (54074). However, oral green tea extract had limited or no effect in one study included in a meta-analysis (104609). Higher quality studies are needed to confirm this finding.
• Age-related cognitive decline. It is unclear if oral green tea is beneficial for cognitive decline associated with age. Details: In elderly individuals living in the community, clinical research shows that taking matcha green tea powder (Yabukita, Kyoeiseicha Co., Ltd.) 3 grams daily for 12 weeks does not improve overall measures of cognitive function when compared with placebo. However, a sub-group analysis in females found a small improvement in language, but not other measures, including memory, impulsivity, and attention (104602). Other clinical research in middle aged and older adults shows that taking green tea extract (Thea-Flan 90S, ITO EN Ltd.) providing catechins 336.4 mg daily for 12 weeks does not improve most measures of cognitive function, although there was a small effect on one measure of working memory. In addition, a single dose has a small effect on errors during an attention task (104603).
• Amyloidosis. It is unclear if oral green tea is beneficial for amyloidosis. Details: Preliminary clinical research in patients with cardiac transthyretin amyloidosis shows that drinking green tea (Green Darjeeling, FTGFOP1, Teekampagne Projektwerkstatt GmbH) 1.5-2 liters standardized to contain epigallocatechin-3-gallate (EGCG) 340 mg/L and/or taking specific capsules (Praevent-loges, Dr. Loges + Co. GmbH) containing 300 mg green tea extract standardized to contain EGCG 75 mg/capsule for 12 months protects against an increase in left ventricular wall thickness and left ventricular myocardial mass (54064).
• Anxiety. Although there has been interest in using oral green tea for anxiety, there is insufficient reliable information about the clinical effects of green tea for this condition.
• Athletic performance. The evidence on the effects of green tea constituents for athletic performance is conflicting. Details: Some preliminary clinical research shows that taking green tea extract containing up to 572.8 mg of catechins as a beverage does not improve respiration efficiency, maximal oxygen uptake, or time trial performance in individuals undergoing endurance training when compared with beverages without catechins (53987,53991). However, other preliminary research shows that taking specific pills (Teavigo, Healthy Origins) containing epigallocatechin-3-gallate (EGCG) 135 mg/pill, taken three times daily with meals for a total dose of seven pills, improves maximal oxygen uptake but not maximum work rate or respiration efficiency, in healthy adults when compared with placebo (53944). Also, a small study in untrained adults shows that taking a single dose of green tea polyphenols 640 mg, 90 minutes before exercise, increases maximal oxygen uptake. However, the effect on athletic performance was not determined (104606).
• Beta-thalassemia. It is unclear if oral green tea is beneficial for reducing iron accumulation in beta-thalassemia. Details: A small clinical trial shows that taking green tea 3 cups daily after meals for 12 months, in addition to usual treatment with blood transfusions and deferasirox, an iron chelator, reduces levels of liver iron and serum ferritin by moderate amounts when compared with usual treatment alone. Hemoglobin values did not differ between groups. Each green tea bag contained 2 grams green tea (Lipton, Unilever Gulf) (104601).
• Bladder cancer. It is unclear if drinking green tea is beneficial for bladder cancer prevention. Details: Some epidemiological evidence suggests that drinking green tea is associated with a reduced risk of bladder cancer (1458,1459,90179). However, conflicting evidence exists. A meta-analysis of some epidemiological evidence suggests that drinking green tea is not associated with a reduced risk of bladder cancer (54077,90166,102716).
• Breast cancer. Evidence evaluating the association between green tea intake and breast cancer risk is inconsistent; any association may be dependent on genotype and menopausal status. Details: Meta-analyses of cohort and case-control studies have found that green tea intake is not associated with a reduced risk of breast cancer (98460,102716). However, some individual population studies suggests that green tea intake is associated with a reduced odds of developing breast cancer in Asian-American (14427,53866), but not Asian (13189,14426,90181), populations. Any protective effect of green tea on breast cancer risk might depend on patient genotype or menopausal status. Green tea consumption does not seem to lower breast cancer risk in Asian females with low-activity angiotensin-converting enzyme (ACE) genotype, although it does seem to decrease breast cancer risk in Asian females with high-activity ACE genotype (14430). Similarly, Asian-American females who drink green tea seem to have a lower breast cancer risk if they have low-activity catechol-O-methyltransferase (COMT) genotype. However, they do not seem to benefit if they do not have the low-activity COMT genotype (14431). Additionally, some observational research suggests that there is a link between green tea and modestly reduced breast cancer risk in pre-menopausal, but not postmenopausal, females (99788). Some research has evaluated the effect of green tea on breast cancer recurrence. Population research suggests that Asian females who have had stage I or II breast cancer who drink at least 3 cups of green tea daily seem to have reduced risk of breast cancer recurrence (3926,13189,54112). However, drinking green tea does not seem to significantly reduce the risk of recurrence of later-stage breast cancer. In April 2012, the US Food and Drug Administration (FDA) determined that it would allow a qualified health claim stating that consuming green tea may reduce the risk of breast cancer, although the FDA has concluded that there is very little scientific evidence to support this claim (102106).
• Cervical cancer. It is unclear if oral green tea is beneficial for cervical cancer. Details: Clinical research in adults with persistent high-risk HPV (HR HPV) infection and concomitant low-grade cervical intraepithelial neoplasia shows that taking a specific green tea extract (Polyphenon E), four capsules standardized to contain epigallocatechin-3-gallate (EGCG) 200 mg/capsule, once daily for 4 months does not affect HR HPV-positive status or histological outcomes when compared with placebo (90145).
• Cervical dysplasia. It is unclear if topical green tea is beneficial for cervical dysplasia. Details: Preliminary clinical research shows that applying a specific ointment (Polyphenon E ointment 15%, MediGene AG) containing epigallocatechin-3-gallate (EGCG) to human papilloma virus (HPV)-infected cervical lesions twice weekly and/or taking a specific green tea extract (Polyphenon E) 200 mg daily containing EGCG by mouth for 8-12 weeks can improve lesion appearance when compared with control (11310).
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral green tea for CFS, there is insufficient reliable information about the clinical effects of green tea for this condition.
• Chronic obstructive pulmonary disease (COPD). It is unclear if drinking green tea reduces the risk of COPD. Details: One prospective, observational study in older adults has found that consumption of at least 3 cups daily of tea, including green tea, oolong tea, and black tea, is associated with a 23% reduction in COPD prevalence and a 65% reduced risk of developing COPD in models adjusted for potential confounders when compared with the lowest tea consumption (107201). However, green tea was only consumed by about 19% of the population included in this study and consumption of green tea itself was not associated with a reduced risk of COPD.
• Cognitive function. It is unclear if oral green tea improves cognitive function in healthy adults. Details: A small clinical study in adults ages 50-69 years shows that taking matcha powder (Hojin no shiro, Ito En, Ltd.) 9 capsules daily for 12 weeks, providing 170 mg total catechins daily, modestly improves some measures of attention and work performance when compared with taking placebo or caffeine. However, there was no effect on other measures of these outcomes, or on verbal memory tasks, visual information processing, working memory, motor function, or facial expression recognition (107168). Another small clinical study shows that taking a single dose of the green tea constituent, epigallocathechin-3-gallate (EGCG), 135 or 270 mg does not seem to improve mood or cognitive performance in healthy adults (54059). Green tea has also been evaluated in combination with other ingredients. A small clinical study in healthy adults shows that consuming a multi-ingredient beverage containing green tea powder 50 mg, elderberry extract, carob extract, and guarana seed extract improves some measures of cognitive function such as rapid visual information processing and multitasking, but not others, 120 minutes later when compared with placebo (113940). It is unclear if this effect is due to green tea, other ingredients, or the combination.
• Cognitive impairment. It is unclear if oral green tea is beneficial for the prevention or treatment of mild cognitive impairment in elderly adults. Details: Some population research in elderly individuals has found that drinking green tea at least once per week is associated with a 53% reduced incidence of dementia or mild cognitive impairment when compared to not consuming green tea (104598). In addition, drinking at least two cups of green tea daily was associated with a 54% lower prevalence of cognitive impairment (104611). Some clinical research shows that taking two capsules of a specific combination product containing green tea extract 360 mg/capsule and L-theanine 60 mg/capsule (LGNC-07, LG Household & Health Care, Ltd) twice daily after meals for 16 weeks improves memory and attention in patients with mild cognitive impairment when compared with placebo (54019).
• Colorectal adenoma. It is unclear if oral green tea extract is beneficial for reducing colorectal adenoma recurrence. Details: A large clinical trial in patients with previously removed colorectal adenomas shows that taking green tea extract (Dr. Loges + Co. GmbH) standardized to epigallocatechin gallate (EGCG) 150 mg twice daily for 3 years does not affect the risk of developing new metachronous adenomas when compared with taking placebo (111020). However, a sub-group analysis shows that taking green tea extract results in a 10% absolute reduction in risk of adenoma formation in males, but not females (111020). Also, preliminary clinical research in patients with previously removed colorectal adenomas shows that taking green tea extract 1.5 grams daily for 12 months reduces the incidence of metachronous adenomas when compared with placebo (53816).
• Colorectal cancer. It is unclear if oral green tea is beneficial for colorectal cancer prevention. Details: Although evidence from individual population studies is mixed (9222,9223,14498,90176,90178,90181,102718), meta-analyses of population research suggest that a high intake of green tea is associated with a reduced risk of colorectal cancer (36416,102716). The highest intake of green tea is associated with a 16% reduced risk when compared with the lowest; however, the benefit appears to be specific to colon cancer, not rectal cancer (102716). When subdivided according to gender, evidence from case-control research suggests that green tea is associated with a reduced risk of colon and rectal cancer for females (54096).
• Common cold. It is unclear if oral green tea is beneficial for the common cold. Details: Preliminary clinical research shows that taking two capsules of a specific formulation (ImmuneGuard, Nutraceutical Holdings LLC) containing L-theanine (Suntheanine, Taiyo International) plus epigallocatechin gallate (Sunphenon, Taiyo International) twice daily for 3 months reduces cold or flu symptoms and duration of symptoms when compared with placebo in healthy adults (53754).
• Crohn disease. Although there has been interest in using oral green tea for Crohn disease, there is insufficient reliable information about the clinical effects of green tea for this condition.
• Dementia. It is unclear if drinking green tea is beneficial for dementia prevention. Details: A meta-analysis of observational studies in over 20,000 adults suggests that the risk of any cognitive deficit (including mild cognitive impairment and dementia) is associated with a 6% reduction per cup of green tea consumed daily (107829). Some population research in elderly individuals suggests that drinking green tea at least once per week is associated with a 53% reduced incidence of dementia or mild cognitive impairment when compared to not consuming green tea (104598). Other population research in adults ages 40-74 years suggests that drinking at least 600 mL of green tea daily is not associated with a reduced risk of developing dementia when compared with drinking less than 60 mL daily. However, there is a modest reduction in dementia risk specifically in individuals ages 60-69 years (107164). A prospective, observational study suggests that consumption of tea, including both green and black tea, of at least 4 cups, in conjunction with 0.5-1 cups of coffee, daily is associated with a 30% reduced risk of dementia when compared with not drinking tea or coffee. Also, drinking 2-3 cups daily of both tea and coffee is associated with a 28% reduced risk of dementia when compared with not drinking tea and coffee (107204). Any association between drinking green tea specifically and developing dementia cannot be determined from this study.
• Dental plaque. It is unclear if oral or topical green tea is beneficial for reducing dental plaque. Details: A meta-analysis of clinical research shows that use of oral or topical products containing green tea modestly reduces dental plaque when compared with control products, including triclosan toothpaste, placebo, and chlorhexidine rinse. However, a sub-group analysis shows that a green tea rinse is no more effective than a chlorhexidine rinse. Green tea products in these studies included mouth rinse, paste, tea, capsules, and strips (107156). Many of these studies are limited by a lack of clear blinding. A more recent clinical study in children ages 10-14 years with plaque and gingivitis shows that using a mouthwash containing green tea extract 5% twice daily, alone or at half strength with ginger extract, for 30 days reduces plaque and gingivitis severity. The mouthwash containing the combination of green tea and ginger extract was most effective, and the green tea extract alone was at least as effective as chlorhexidine (107163).
• Depression. It is unclear if drinking green tea is beneficial for depression prevention. Details: Epidemiological research suggests that consuming green tea is associated with a reduced prevalence of depression and depressive symptoms. In Japanese adults, drinking four or more cups of green tea daily is associated with a 44% to 51% lower prevalence of mild to severe depression when compared to consuming one cup or less daily (90160,90163). A meta-analysis suggests that the highest green tea consumption is associated with a 34% reduced risk of depressive symptoms when compared with the lowest (111024). Other research in a general population of Chinese adults suggests that consuming at least 1 cup of green tea daily is associated with a 22% decreased risk of depressive symptoms over 2 years when compared with almost never consuming green tea. However, there is no association between depressive symptoms and less frequent green tea consumption in this population (111023).
• Diabetes. It is unclear if drinking green tea or taking green tea extract is beneficial for the prevention of diabetes or the improvement of glycemic control. Details: Epidemiological research has found that Japanese adults who consume 6 or more cups of green tea daily have a 33% lower risk of developing type 2 diabetes when compared to those who consume one cup or less daily. The risk reduction appears to be more pronounced in females when compared with males (14313). Also, epidemiological research has found that Chinese adults who consume at least one cup of green tea per week have a 59% to 77% lower risk of impaired fasting glucose when compared to those who consume less than one cup per week (90149). Other epidemiological research has found that consumption of any amount of green tea daily by Chinese adults is associated with an 8% reduced risk of developing type 2 diabetes when compared with never drinking green tea (107165). In contrast, some epidemiological research in Chinese adults has found that green tea consumption is associated with a 20% increased risk of developing type 2 diabetes when compared with non-green tea drinkers. A dose-response relationship was found for both the amount and duration of tea consumed (107170). Also, clinical research in patients with prediabetes shows that drinking one cup of green tea three times daily for 14 weeks does not improve fasting blood glucose or glycated hemoglobin (HbA1c) when compared to control (90174). There is inconsistent evidence regarding the effects of green tea in patients with type 2 diabetes. Epidemiological research suggests that drinking at least 4 cups of green tea daily is associated with a 40% reduction in mortality risk when compared to not drinking green tea (104589). Other epidemiological research in patients with type 2 diabetes has found that consumption of any amount of green tea daily is associated with a 10% reduction in mortality risk when compared to never drinking green tea. However, there was no association between green tea intake and the incidence of developing macrovascular or microvascular complications (107165). Meta-analyses of clinical research show that green tea extract and green tea catechins reduce fasting blood glucose when compared to control when patients with type 2 diabetes, borderline diabetes, or normal blood glucose status are evaluated together (90154,90187). However, a meta-analysis of up to 15 mainly small clinical trials involving patients with type 2 diabetes shows that taking green tea does not affect fasting blood glucose or insulin or improve insulin resistance or glucose control when compared with placebo. Most included studies used green tea or its extract in doses of 400-10,000 mg daily for 8-16 weeks (104604). Also, clinical research shows that taking green tea extract daily for up to 16 weeks does not improve blood glucose, HbA1c, or insulin when compared with placebo in patients with type 2 diabetes or borderline diabetes (37678,37781,54035). Some research has evaluated the effect of green tea on other outcomes in patients with type 2 diabetes. One meta-analysis shows that taking green tea extract modestly reduces fasting triglyceride levels when compared with control. This benefit was seen with doses of at least 800 mg daily taken for longer than 8 weeks. This dose and duration reduces levels of total cholesterol, but not low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol levels (102715). Another meta-analysis shows that taking green tea modestly reduces body weight, body mass index (BM), and body fat. A sub-analysis shows that these benefits occur in studies lasting more than 8 weeks, using doses of up to 800 mg daily, and in patients who were overweight. There was no effect on waist circumference. Most patients included in the analysis were overweight or had obesity (104610).
• Diabetic neuropathy. It is unclear if oral green tea is beneficial for improving diabetic neuropathy symptoms. Details: Clinical research in patients with mild-to-moderate diabetic peripheral neuropathy shows that taking decaffeinated green tea extract 500 mg three times daily for 16 weeks modestly reduces neural pain and dysfunction, as well as overall symptom severity, when compared with placebo (107159).
• Down syndrome. It is unclear if oral green tea is able to alter facial morphology in children with Down syndrome.
• Down syndrome. There was no effect in children aged 4-18 years (107167). This study is limited by its observational design. The dosage, time of onset, and duration of treatment differed between individuals.
• Dry eye. It is unclear if oral green tea is beneficial for improving dry eye symptoms. Details: In patients with mild to moderate dry eye and meibomian gland dysfunction, preliminary clinical research shows that applying green tea extract into the eyes three times daily for one month, in addition to artificial tears three times daily, improves symptoms of dry eye. Symptoms of itching, burning, foreign body sensation, and redness were improved by a moderate amount over artificial tears alone (104612).
• Dysmenorrhea. It is unclear if drinking green tea is beneficial for preventing dysmenorrhea symptoms. Details: Population research has found that drinking green tea is associated with a 37% reduced odds of experiencing dysmenorrhea and a 58% reduced odds of having moderate-to-severe dysmenorrhea when compared with not drinking green tea (102729).
• Esophageal cancer. It is unclear if drinking green tea is beneficial for preventing esophageal cancer; the available research is conflicting. Details: Although some epidemiological evidence and observational studies have found that drinking green tea is associated with a reduced risk of esophageal cancer, most meta-analyses do not support this finding in a mixed group of adults (1457,36542,90169,90185,90186,102004,102716,107154). Meta-analyses of epidemiological studies suggest that drinking green tea is associated with a 54% reduction in the risk of esophageal cancer, or a 21% reduced odds per cup of green tea consumed daily, only in females (90169,90185,102004,107154). Also, some epidemiological research found that drinking green tea that is very hot is associated with an increased risk of esophageal cancer (53828). In addition, drinking decaffeinated green tea 5 mg daily for 12 months does not seem to be an effective treatment for patients diagnosed with esophageal precancerous lesions (53702).
• Fractures. It is unclear if drinking green tea reduces fracture risk. Details: Population research has found that consumption of green tea is associated with a 12% lower risk of any fracture and 20% lower risk of hip fracture when compared with no tea consumption (99800).
• Gastric cancer. Evidence evaluating an association between green tea consumption and gastric cancer risk is conflicting. Details: Most meta-analyses of epidemiological studies suggest that green tea consumption is not associated with gastric cancer risk (53767,53813,90181,102716). Although the most recent meta-analysis of epidemiological research suggests that drinking green tea regularly is associated with up to a 9% reduced risk of gastric cancer when compared with non-regular consumption, sub-analyses suggest that there is no association between gastric cancer and intake of specific amounts of green tea up to at least 3 cups daily (111025). Also, other population research suggests that drinking 10 or more cups of green tea daily is associated with a reduced risk of gastric cancer (8903,9222,9225,9226,9227), while consuming less than 10 cups daily is not consistently associated with a reduced risk (7033,9223,54090). The association between drinking green tea and gastric cancer-related mortality has also been investigated, A large-scale population study in Japan suggests that drinking 5 or more cups of green tea daily is not associated with a reduced risk of gastric cancer-related mortality when compared to drinking less than one cup daily (14498). Discrepancies might be related to the temperature of the green tea. The most recent meta-analysis suggests that intake of cold or warm green tea, and not hot green tea, is associated with a modest reduction in gastric cancer risk (111025).
• Gingivitis. It is unclear if oral or topical green tea is beneficial for gingivitis. Details: A meta-analysis of clinical research shows that use of oral or topical products containing green tea modestly reduces gingivitis and gingival bleeding when compared with control products, including triclosan toothpaste, placebo, and chlorhexidine rinse. However, a sub-group analysis shows that a green tea rinse is no more effective than a chlorhexidine rinse. Green tea products used in these studies were heterogeneous and included mouth rinse, gel, paste, tea, strips, and capsules (107156). Many of these studies are limited by a lack of clear blinding. A more recent clinical study in children ages 10-14 years with plaque and gingivitis shows that using a mouthwash containing green tea extract 5% twice daily, alone or at half-strength with ginger extract, for 30 days reduces plaque and gingivitis severity. The mouthwash containing the combination of green tea and ginger extract was most effective, and the green tea extract alone was at least as effective as chlorhexidine (107163).
• Headache. Although there has been interest in using oral green tea for headache, there is insufficient reliable information about the clinical effects of green tea for this condition.
• Hypertension. The evidence is mixed as to whether drinking green tea reduces the risk of hypertension and whether oral green tea lowers blood pressure in patients with hypertension. Details: Some epidemiological research from China shows that drinking 120-599 mL of green tea or oolong tea daily is associated with a 46% lower risk of developing hypertension when compared with non-habitual tea drinkers; drinking more than 600 mL daily is associated with a 65% reduced risk (12518). In contrast, drinking green tea daily is associated with a 38% increased odds of having hypertension when compared with never drinking green tea in elderly Chinese males, but not females (107166). Green tea may help lower blood pressure in patients with or without hypertension; however, the evidence is mixed, and any reductions appear to be small. A meta-analysis of two clinical trials in patients with hypertension shows that drinking green tea for 4-16 weeks reduces systolic, but not diastolic, blood pressure by about 6 mmHg (104583). Meta-analyses in patients with or without hypertension, including overweight or obese adults, suggest that green tea reduces systolic and diastolic blood pressure by 1-3 mmHg (90146,90155,90161,98423,102726,111018). Some studies used green tea, made by boiling a 3 gram tea bag with 150 mL water and then waiting for 5 minutes and consuming three times daily approximately 2 hours after each meal for 4 weeks (90159), or green tea extract up to 1500 mg daily for up to 12 weeks (111018), including a specific product (Olimp Labs) 379 mg, taken daily with the morning meal for 3 months (54068).
• Hypotension. It is unclear if oral green tea is beneficial for postprandial hypotension in elderly adults. Details: Some research shows that consuming caffeinated beverages increases blood pressure in elderly people with postprandial hypotension (11834,11835). Also, preliminary clinical research shows that drinking 400 mL of green tea before lunch increases postprandial systolic and diastolic blood pressure by 15 mmHg and 6 mmHg, respectively, in older elderly people with postprandial hypotension (89482).
• Infertility. Oral green tea has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in females with a history of problems conceiving shows that taking three capsules daily of a proprietary blend of Vitex agnus-castus extract (standardized to 0.5% agnusides), green tea extract (standardized to 50% phenols), L-arginine, vitamins E, B6, and B12, folate, iron, magnesium, zinc, and selenium (FertilityBlend, The Daily Wellness Company) for three menstrual cycles increases the rate of pregnancy at three months by 61% when compared with placebo (41479).
• Influenza. It is unclear if oral green tea is beneficial for preventing the flu. Details: A meta-analysis of five clinical trials in individuals with or without prior influenza vaccination shows that use of green tea catechins, either in capsule form or as a gargled liquid, reduces the rate of influenza infections by 33% when compared with control. Also, a meta-analysis of observational research has found that gargling with or consuming green tea containing catechins is associated with a 48% reduced risk of influenza when compared with not taking green tea catechins. More information is needed to compare the efficacy of the different forms of green tea catechins (107152). Some epidemiological research not included in this meta-analysis has found that drinking at least 5 cups of green tea weekly is associated with a 32% reduced odds of developing confirmed influenza when compared with drinking less than one cup weekly. A sub-group analysis suggests that this association is only evident in individuals who had not received the influenza vaccination (104608). Conversely, other preliminary research shows that gargling with green tea at least three times daily for 90 days does not prevent influenza in high school students when compared with water (90150). Green tea has also been evaluated in combination with theanine. One small study shows that taking a combination of green tea catechins (THEA-FLAN 90S, Ito-en Co) 378 mg standardized to 270 mg of epigallocatechin gallate (EGCG) with theanine 210 mg daily for 5 months reduces the risk of developing clinically defined influenza, but not laboratory-confirmed influenza infection, when compared with placebo (54021). Other preliminary clinical research in healthy adults shows that taking two capsules of a specific formulation (ImmuneGuard, Nutraceutical Holdings LLC) containing L-theanine (Suntheanine, Taiyo International) plus EGCG (Sunphenon, Taiyo International) twice daily for 3 months reduces the number of subjects with cold or flu symptoms and the number of days with symptoms when compared with placebo (53754).
• Japanese cedar pollinosis. It is unclear if oral green tea is beneficial for preventing Japanese cedar pollinosis symptoms. Details: In patients with Japanese cedar pollinosis, clinical research shows that drinking Benifuuki green tea drink 350 mL containing O-methylated catechin 34-40 mg daily beginning 6-10 weeks before pollen exposure until the end of pollen season can reduce nasal and ocular symptoms. Clinical research compared the "benifuuki" drink enriched in O-methylated EGCG with that of another green tea "yabukita," containing no O-methylated EGCG (53884,90156).
• Kidney stones (nephrolithiasis). It is unclear if drinking green tea prevents kidney stones. Details: Population research suggests that drinking green tea is associated with a reduced risk of having kidney stones. This risk was 22% lower in males and 16% lower in females when compared with never or former green tea drinkers (104613).
• Leukemia. It is unclear if drinking green tea is beneficial for leukemia prevention. Details: Although some large epidemiological studies suggest that drinking green tea reduces the risk of leukemia by 51% to 80% (53799,90183,102723), a meta-analysis of generally low-quality population research shows a variable association between green tea intake and risk of leukemia (102716).
• Liver cancer. It is unclear if drinking green tea is beneficial for liver cancer prevention. Details: Two meta-analyses of epidemiological research suggest that green tea consumption is associated with a reduced risk of liver cancer (97132,111016). The most recent meta-analysis in approximately 1.5 million adults in Asia, North America, and Europe suggests that the highest intake of green tea is associated with a 20% reduced risk of liver cancer when compared with the lowest. The most benefit was associated with consumption of at least 4 cups daily (111016). Another meta-analysis that included studies conducted in Japan, China, or Singapore suggests that higher green tea consumption is associated with a 12% reduced incidence of liver cancer when compared with the lowest consumption of green tea. However, the benefit appears to be limited to females; green tea consumption was not associated with a reduced risk of liver cancer in males (97132). A large epidemiological study in Chinese females also suggests that green tea consumption is associated with a reduced risk of liver cancer. Consuming a cumulative intake of 30 kg dried green tea leaves is associated with a 46% reduced risk of primary liver cancer over a median of 18 years when compared with never drinking green tea (111030). In contrast, some individual epidemiological studies suggest that green tea consumption is not associated with a reduced risk of liver cancer in Japanese individuals (90181,102716).
• Lung cancer. It is unclear if drinking green tea is beneficial for lung cancer prevention. Details: Individual observational studies and meta-analyses of population research have yielded conflicting evidence about the effects of green tea on lung cancer risk (13190,14498,53829,90177,102716). Although one meta-analysis of population research suggests that the highest intake of green tea does not reduce lung cancer risk when compared to the lowest intakes (102716), other analyses suggest that increasing green tea consumption by two cups daily is associated with an 18% decreased risk of lung cancer, and that drinking 7-10 cups of green tea daily is associated with an 18% to 33% reduced risk of lung cancer when compared with drinking less than one cup daily (53829,90177).
• Mental alertness. It is unclear if oral green tea is beneficial for mental alertness. Details: Green tea contains caffeine. Consumption of caffeinated beverages seems to prevent a decline in alertness and cognitive capacity when consumed throughout the day (4221,4224). Also, combining caffeine with glucose as an "energy drink" seems to improve mental performance better than placebo or either caffeine or glucose alone (13732). However, there is mixed evidence regarding the effects of green tea on mental alertness.
• Metabolic syndrome. It is unclear if oral green tea is beneficial for improving metabolic parameters in people with this condition. Details: Preliminary clinical research shows that taking green tea extract 1000 mg daily or drinking four cups of green tea daily for 8 weeks does not improve metabolic syndrome features, including waist circumference, blood pressure, cholesterol levels, or blood sugar in obese patients with metabolic syndrome when compared to control (53995).
• Multiple myeloma. It is unclear if drinking green tea is beneficial for multiple myeloma prevention. Details: Population research suggests that drinking at least 5 cups of green tea each day is not associated with a reduced risk of multiple myeloma when compared with never drinking green tea (102723).
• Myocardial infarction (MI). It is unclear if drinking green tea prevents MI or if drinking green tea prevents mortality in patients with a previous MI. Details: When compared with drinking less than one cup of green tea daily, epidemiological research in a population at high risk of coronary artery disease has found that drinking more than three cups of green tea daily is associated with a 49% reduced odds of having a past MI as determined by a coronary angiography. A sub-group analysis found that these odds only occurred in individuals consuming both fruits and vegetables more than four times weekly and not in individuals consuming fruits or vegetables less often (104588). In addition, observational research has found that drinking either 1-3 cups or at least 4 cups of green tea daily is associated with 19% and 32% lower odds of MI, respectively, when compared to drinking less than 1 cup daily (97134). In patients with a previous MI, drinking at least 7 cups of green tea daily is associated with a 53% reduced odds of all-cause mortality over a median of 18.5 years when compared with not drinking green tea (107160).
• Nasopharyngeal cancer. It is unclear if drinking green tea is beneficial for nasopharyngeal cancer prevention. Details: A meta-analysis of epidemiological research has found that the highest intake of green tea is associated with a 51% reduced risk of nasopharyngeal cancer when compared with the lowest intake (102716).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral green tea is beneficial for NAFLD. Details: Clinical research shows that drinking green tea 700 mL containing 1080 mg of catechins daily for 12 weeks does not affect body weight or body mass index (BMI), but does reduce body fat percentage from 34% to 32%, when compared with drinking either green tea 700 mL containing 200 mg of catechins or a control tea. Also, the liver-to-spleen attenuation ratio increased by 11% when compared with baseline (90168). Meta-analyses of four studies in patients with NAFLD show that taking green tea extract 500-1000 mg daily or green tea catechins 600 mg daily improves liver function tests when compared with placebo (98459,102720). One meta-analysis also shows that these doses improve BMI, total cholesterol, and low-density lipoprotein (LDL) cholesterol when compared with placebo (98459).
• Non-Hodgkin lymphoma. It is unclear if drinking green tea is beneficial for non-Hodgkin lymphoma prevention. Details: Population research has found that drinking at least 3.5 cups of green tea daily is not associated with a reduced risk of non-Hodgkin lymphoma when compared with never drinking or drinking less than 1 cup of green tea daily (102005,102723).
• Obesity. Evidence for the use of green tea products for weight loss is conflicting. The conflicting findings may be related to the caffeine and catechin content of the studied products, as well as the physical activity level of the individual. Details: Many clinical studies show that drinking green tea or taking green tea extract that contains caffeine (about 70-200 mg) and high levels of catechins (about 576-886 mg) daily for 12-24 weeks modestly improves weight loss when compared to control in overweight individuals or patients with obesity (8114,37725,53906,90184). A meta-analysis of 25 randomized clinical trials shows that taking green tea extract containing caffeine results in an additional weight loss of 1.8 kg when compared with a control group not taking green tea extract (102719). In addition, a meta-analysis of clinical trials shows that taking green tea reduces body weight by 0.4 kg in mainly overweight individuals with type 2 diabetes (104610). Some research also shows that drinking green tea or taking green tea extract containing high levels of catechins but no caffeine reduces weight and visceral fat in overweight individuals or patients with obesity when used for up to 12 weeks (53994,54039,90184). In these clinical trials, the following doses have been used: two capsules of green tea extract daily standardized to containing 870 mg of catechins (460 mg EGCG) or 4 cups of green tea daily standardized to contain 928 mg of catechins (440 mg EGCG) for 8 weeks (53994); a specific decaffeinated green tea extract (Sunphenon 90LB, Taiyo Kagaku Ltd.) 530 mg twice daily for 6 weeks (54039); catechin-enriched green tea beverages providing 234-886 mg of catechins once or twice daily for approximately 3 months (37705,53906,90184); a specific green tea extract (AR25, Exolise, Arkopharma), taken as four capsules standardized to contain 375 mg of catechins (epigallocatechin gallate 270 mg) in two divided doses daily for 12 weeks (8114). Some research has also shown weight loss benefits of multi-ingredient products or diets containing green tea. Multi-ingredient products have included an herbal mixture of garcinia extract 650 mg, green tea extract 100 mg, coffee extract 75 mg, and banaba extract 25 mg per tablet (IQP-GC-101, InQpharm Europe Ltd.) 30 minutes before meals twice daily for 12 weeks (90137) and a specific product (Sanavita Industry, Piracicaba) containing powdered green tea (40 mg of caffeine), orange pulp, vitamin C, zinc, and selenium, taken as 20 grams in two divided doses daily for 8 weeks (90134). Drinking green tea has also been used as part of a Mediterranean diet also including Wolffia globose (109888). However, many studies show conflicting results (37715,37753,54035,98419,98420,98422). Reasons for these inconsistent findings are not entirely clear, but may relate to the use of decaffeinated green tea products, the use of green tea products containing low catechin amounts, or the presence and type of concomitant exercise. Some research shows that green tea extract containing a lower catechin amount (491 mg daily) or decaffeinated green tea products do not improve weight loss when compared with placebo in patients with obesity (37753,54035,98419). One meta-analysis of 15 clinical studies including about 1240 patients with obesity shows that using green tea products that are decaffeinated does not improve body weight, body mass index, or waist circumference when compared with control, while green tea products containing catechins 576-714 mg daily and caffeine do improve these outcomes (16892). Taking green tea after weight loss does not seem to improve weight maintenance when compared with control (14428,54076). Other clinical research shows that green tea does not improve weight loss in individuals with obesity who are already participating in exercise, such as walking and interval sprinting (37715,98420). In contrast, another small clinical study shows that taking green tea 500 mg daily for 10 weeks while participating in HIIT improves weight, body fat percentage, triglycerides, and low-density lipoprotein (LDL) cholesterol levels when compared with either green tea or HIIT alone. However, it appears that the majority of these improvements are due to participation in HIIT (100201). There is also some limited research in children. One small clinical trial in obese children ages 6-16 years shows that taking green tea providing 576 mg catechins daily for 24 weeks modestly reduces waist circumference, as well as systolic blood pressure and low-density lipoprotein (LDL) cholesterol, when compared with taking green tea providing 75 mg catechins daily. However, there were no significant difference between groups for other anthropometric measures or cardiovascular risk factors (37743). Another clinical trial in obese females ages 6-10 years who were also given diet and exercise advice shows that taking decaffeinated green tea polyphenols 400 mg daily for 12 weeks modestly reduces fat mass, but does not affect other anthropometric measures, when compared with placebo. Also, taking green tea polyphenols modestly reduces ovary volume, but has no effect on other measures of early puberty, such as breast development, uterine volume, or levels of sex hormones (107162).
• Oral cancer. It is unclear if oral green tea is beneficial for oral cancer prevention. Details: Meta-analyses of epidemiological research suggest that the highest intake of green tea is associated with a 20% to 29% reduction in risk of oral cancer when compared with the lowest intake (90180,102716). Also, preliminary clinical research in patients with high-risk oral premalignant lesions shows that taking a green tea extract 500-1000 mg/m2 three times daily after meals for 12 weeks increases the rate of clinical and histological response when compared with placebo (53936).
• Oral leukoplakia. It is unclear if drinking green tea and concomitantly applying topical green tea to lesions is beneficial for oral leukoplakia. Details: Preliminary clinical research in patients with oral leukoplakia shows that drinking 3 grams of a mixed tea product containing green tea daily for 6 months, while also topically applying a 10% mixed tea product in the mouth three times daily, reduces oral lesion size by about 38%, compared with a 3% increase in those taking placebo. It is not clear if this effect is due to green tea, the other ingredients, or the combination (4213).
• Osteopenia. It is unclear if oral green tea is beneficial for preventing osteopenia. Details: Population research suggests that drinking green tea for 10 years is associated with increased bone mineral density (8116). Other population research suggests that drinking less than one cup of green tea daily is associated with an 81% to 85% increased odds of having osteopenia when compared with drinking green tea 1-3 times daily (111026). Preliminary clinical research in postmenopausal adults with osteopenia shows that taking capsules containing green tea polyphenols 500 mg (233 mg as epigallocatechin-3-gallate or EGCG) daily, possibly while practicing tai chi 60 minutes three times weekly, for 24 weeks improves serum markers of bone turnover and muscle strength when compared to baseline (54040). However, the results from this study are limited by a lack of control group and the fact that diagnostic measures of bone health, such as T-score or Z-score, were not assessed.
• Osteoporosis. It is unclear if oral green tea is beneficial for preventing osteoporosis. Details: Population research suggests that drinking green tea for 10 years is associated with increased bone mineral density (8116). Other population research suggests that drinking less than one cup of green tea daily is associated with up to a 91% increased odds of having osteoporosis when compared with drinking green tea 1-3 times daily (111026). More recent clinical research shows that taking decaffeinated green tea extract supplying approximately 1315 mg of catechins (843 mg as EGCG) daily does not improve bone mineral density, T-score, or Z-score in postmenopausal adults (98419).
• Overall mortality. Some population research suggests that drinking green tea may reduce the risk of overall mortality by a small amount. Details: A meta-analysis of population research in Japanese adults found that drinking at least 5 cups of green tea daily is associated with reduced risk of all-cause mortality when compared with drinking less than 1 cup daily (102002). Another meta-analysis of population research found that each one cup per day increase in green tea consumption is associated with a 3% reduced risk of all-cause mortality (102728). However, more recent population research has found that although drinking green tea is associated with reduced risk of all-cause mortality in patients with a previous MI and stroke, drinking as much as 7 cups of green tea daily is not associated with a reduced odds of all-cause mortality over a median of 18.5 years in individuals with no history of stroke or MI when compared with not drinking green tea (107160).
• Pancreatic cancer. It is unclear if drinking green tea is beneficial for pancreatic cancer prevention. Details: A meta-analysis of population research suggests that the highest intake of green tea is not associated with a reduced risk of pancreatic cancer when compared with the lowest intake (102716). However, one epidemiological study suggests that drinking green tea is associated with a reduced risk of pancreatic cancer (54096).
• Parkinson disease. Although consuming caffeinated beverages might reduce the risk of developing Parkinson disease, it is unclear if oral green tea prevents or improves symptoms in people with this condition. Details: There is some evidence from large-scale epidemiological studies that the incidence of Parkinson disease decreases with increased consumption of caffeinated beverages such as coffee, tea, and cola. For men, the effects seem to be dose related. Men consuming a total of 421-2716 mg of caffeine (approximately 5-33 cups of tea) from any source daily seem to have the greatest reduction in risk. However, there seems to be a significant reduction in risk even with consumption of as little as 124-208 mg caffeine daily (approximately one to three cups tea) (6022). In females, the effects do not seem to be dose related. Moderate consumption of approximately 1-4 cups daily seems to provide the most reduction in risk (1238). It is unclear if consuming green tea is more or less effective than other caffeinated beverages for reducing Parkinson disease risk.
• Periodontitis. It is unclear if oral or topical green tea is beneficial for improving oral health or improving periodontal disease. Details: Epidemiological research has found that intake of green tea is inversely associated with symptoms of periodontal disease, including probing depth, attachment loss, and bleeding on probing (53844). A small clinical trial shows that taking green tea extract 1.55% by weight in chewable candy for 28 days appears to reduce plaque accumulation and gingival inflammation (7594). A small clinical trial in patients with chronic periodontitis shows that applying a gel containing green tea extract 1 gram/100 mL into the periodontal pocket as an adjunct to scaling improves gingivitis, periodontal disease, and clinical attachment by 7%, 112%, and 116%, respectively, when compared with placebo gel (90135). A meta-analysis of low-quality clinical research also shows that use of oral or topical products containing green tea modestly improve clinical attachment when compared with control products, including triclosan toothpaste and placebo. Green tea products included gel, paste, and tea (107156).
• Pneumonia. It is unclear if drinking green tea is beneficial for pneumonia prevention. Details: Epidemiological research in Japanese females has found that consuming green tea is associated with a lower risk of death from pneumonia when compared to those who do not drink green tea (53897). However, other epidemiological research in hospitalized elderly Japanese adults has found that there is no association between green tea consumption during the past month and prevalence of pneumonia at time of hospitalization (107161).
• Polycystic ovary syndrome (PCOS). It is unclear if oral green tea is beneficial for PCOS. Details: A meta-analysis of 4 small clinical trials shows that taking green tea modestly reduces weight in patients with PCOS when compared with placebo. However, there was no effect on other endpoints including body mass index (BMI), percent body fat, or waist or hip circumference. Three studies in the meta-analysis used green tea 1000-2000 mg/daily in tablets or capsules; the other study used green tea powder providing epigallocatechin gallate 1620 mg daily (111019). However, the included studies were small and utilized heterogeneous dosing regimens. Subsequently, a moderate-sized clinical study in patients with PCOS shows that taking green tea leaf powder, 500 mg twice daily for 1 week followed by 1500 mg daily for 3 months, improves menstrual cycle regularity, but does not reduce BMI or waist or hip circumference, when compared with metformin or placebo (114894).
• Postoperative pain. It is unclear if rinsing the mouth with green tea is beneficial for postoperative pain associated with molar removal. Details: In patients undergoing third molar extraction, a small clinical trial shows that using 15 mL of a mouthwash containing green tea extract 5 grams/100 mL twice daily, beginning the day after surgical removal of impacted molars and continuing for 7 days thereafter, reduces pain by 60% and analgesic use during the first three days when compared with using a mouthwash that does not contain green tea (90141).
• Prostate cancer. It is unclear if drinking green tea or taking green tea catechins by mouth is beneficial for prostate cancer treatment or prevention. Details: Green tea catechins have been evaluated for reducing prostate cancer risk in high-risk patients (14127,98421,102716). A meta-analysis of results from three clinical trials shows that taking green tea catechins 400-600 mg daily for 12-30 months reduces the risk of prostate cancer by approximately 62% when compared with placebo in high-risk patients (98421). However, another meta-analysis including two of these studies plus one additional does not show that taking green tea catechins reduces the incidence of prostate cancer in high-risk patients (102716). Most population research has found that drinking higher amounts of green tea is not associated with a reduced risk for prostate cancer when compared with those who never or rarely drink green tea (14128,54036,53741,53753,90153,90181,98421). However, one meta-analysis of population research found that people who drink very high amounts of green tea (7-15 cups daily) have a 19% to 44% reduced risk of prostate cancer (98421). Another population study found that higher green tea intake is associated with a reduced risk of advanced, but not overall, prostate cancer risk (53753). In April 2012, the US Food and Drug Administration (FDA) determined that it would allow a qualified health claim stating that consuming green tea may reduce the risk of prostate cancer, although the FDA has concluded that there is very little scientific evidence to support this claim (102106). Additionally, most clinical research shows that drinking large amounts of green tea or taking green tea extract does not reduce disease progression in patients with prostate cancer (11366,53726). Green tea and green tea catechins have also been evaluated for reducing prostate specific antigen (PSA) levels. A meta-analysis of clinical research in patients with or at risk of prostate cancer shows that taking green tea or green tea extract for 3 weeks to 12 months does not modify PSA levels when compared with water or placebo. However, sub-analyses suggest that there is significant heterogeneity with respect to findings between geographical locations, with some evidence of benefit in studies conducted in the US (107155).
• Radiation dermatitis. It is unclear if topical green tea is beneficial for preventing radiation dermatitis. Details: Preliminary clinical research in patients undergoing radiotherapy after breast cancer surgery shows that spraying epigallocatechin gallate (EGCG) over the radiation field prevents the development of at least moderate severity radiation dermatitis by 30% when compared with saline as placebo. Also, occurrence of symptoms was delayed by about 2.7 days and symptom severity was reduced. EGCG 660 mcmol/L was sprayed 3 times daily from the first day of radiation until 2 weeks after completion at 0.05 mL per squared cm (111031). The interpretation of these results is limited by the unbalanced treatment groups.
• Radiation-induced diarrhea. It is unclear if oral green tea is beneficial for reducing diarrhea associated with radiotherapy. Details: A small clinical trial shows that taking a green tea tablet (Camgreen, Iran Giahessence Pharmacy Co.) 450 mg daily for 5 weeks during pelvic irradiation reduces the frequency of diarrhea in patients undergoing radiotherapy treatment. In the fifth week of treatment, 19% of patients taking green tea had diarrhea, compared with approximately 62% of those taking placebo (104614).
• Radiation-induced nausea and vomiting. It is unclear if oral green tea is beneficial for reducing vomiting associated with radiotherapy. Details: A small clinical trial shows that taking a green tea tablet (Camgreen, Iran Giahessence Pharmacy Co.) 450 mg daily for 5 weeks during pelvic irradiation does not reduce the frequency of vomiting when compared with placebo in patients undergoing radiotherapy treatment (104614).
• Renal cell carcinoma. It is unclear if oral green tea is beneficial for preventing kidney cancer. Details: Epidemiological research suggests that green tea intake is not associated with risk of kidney cancer over a mean of 19 years in Japanese adults. However, in females, consuming at least 5 cups of green tea daily, but not lesser amounts, is associated with a 55% reduced risk of kidney cancer when compared with rare intake (111022).
• Skin cancer. Although there has been interest in using oral or topical green tea for skin cancer, there is insufficient reliable information about the clinical effects of green tea for this condition.
• Stress. It is unclear if oral green tea is beneficial for stress reduction. Details: Preliminary clinical research shows that taking a specific brand of green tea extract (Teavigo, DSM) 300 mg orally for 7 days reduces stress and increases calmness when compared with placebo in healthy individuals (54055).
• Stretch marks (striae distensae). It is unclear if topical green tea is beneficial for stretch marks. Details: A small clinical study in young adult females shows that applying a green tea extract 3% cream to stretch marks on the leg twice daily for 8 weeks reduces stretch mark severity when compared to baseline (114893). The validity of this study is limited by the lack of a control group.
• Stroke. It is unclear if consumption of green tea is associated with a reduced risk of stroke or with reduced all-cause mortality in patients with a previous stroke. Details: Large-scale population research in Japanese individuals suggests that consuming at least 3-5 cups of green tea daily is associated with a reduced risk of cerebrovascular mortality when compared with drinking less than 1 cup daily. This association appears to be primarily related to a decrease in risk for cerebral infarction or hemorrhage (14498,54080,102002). Other population research suggests that drinking 1-3 cups of green tea daily is associated with a 36% reduced odds of stroke when compared with drinking less than 1 cup daily, while drinking 4 or more cups daily has no effect. Also, green tea consumption was not associated with reduced incidence of cerebral hemorrhage or infarction in this study (97134). Meta-analyses of population research suggest that an increase of 1 cup per day in green tea consumption is associated with a 6% reduced risk of stroke or cerebral hemorrhage (102728,111021). A prospective, observational study also suggests that higher intake of tea, including green and black tea, of at least 2 cups daily is associated with a 16% reduced risk of stroke when compared with not drinking tea. This study also found that drinking 2-3 cups daily of each tea and coffee is associated with a 38% reduced risk of stroke when compared with not drinking tea and coffee. The combination of 0.5-1 cups of coffee and 2-3 cups of tea daily, but not tea alone, was associated with a 50% reduced risk of post-stroke dementia when compared with not drinking tea and coffee (107204). In patients with a previous stroke, drinking at least 3 cups of green tea daily is associated with a 48% to 62% reduced odds of all-cause mortality over a median of 18.5 years when compared with not drinking green tea (107160).
• Sunburn. It is unclear if oral or topical green tea is beneficial for preventing ultraviolet radiation-induced erythema. Details: A meta-analysis of three small clinical trials shows that taking green tea catechins 540-1402 mg daily for 6 to 12 weeks has a small to moderate protective effect against ultraviolet radiation-induced erythema when compared with placebo, especially at lower doses of ultraviolet radiation. A single topical dose of green tea ingredients may also be beneficial, but data is limited (107153).
• Systemic lupus erythematosus (SLE). It is unclear if oral green tea is beneficial for SLE. Details: Preliminary clinical research shows that taking green tea extract 500 mg (containing 22% polyphenols) twice daily for 3 months modestly improves disease activity, general health, and vitality when compared with placebo (97136).
• Tinea pedis. It is unclear if a topical green tea footbath is beneficial for athlete's foot. Details: In bedridden, elderly patients with cognitive deficiency, use of a footbath containing a 0.1% green tea extract for 15 minutes once daily for 12 weeks does not improve symptoms of athlete's foot, but does improve skin condition, when compared with a footbath not containing green tea. The green tea extract Sunphenon BG-3 (Taiyo Kagaku Co. Ltd., Yokkaichi), prepared by dissolving 5 grams of the Sunphenon BG-3 product in 5 liters of water to create a 0.1% green tea solution, was used (90151).
• Tooth extraction. Topical green tea has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small, split-mouth clinical study in patients undergoing third molar extractions shows that applying a gel containing green tea extract 0.5% and hyaluronic acid into the surgical site immediately after extraction and three times daily for 7 days improves some post-operative outcomes, such as reducing exudate or facial edema when compared with placebo (114895). It is unclear if these effects are due to green tea, hyaluronic acid, or the combination.
• Ulcerative colitis. It is unclear if oral green tea is beneficial for ulcerative colitis. Details: Preliminary clinical research in patients with mild to moderate ulcerative colitis shows that taking a specific green tea product (Polyphenon E, Mitsui-Norin) 200 mg or 400 mg twice daily for 8 weeks may increase the number of people who respond to therapy and achieve remission when compared with placebo. After treatment, 10 of 15 patients in the green tea extract group responded to therapy and 8 of 15 patients achieved remission, compared with 0 in the placebo group (90140).
• Upper respiratory tract infection (URTI). It is unclear if gargling and swallowing green tea is beneficial for reducing URTI symptoms. Details: Preliminary clinical research shows that gargling and swallowing green tea (Morgentau, Ronnefeld KG) 100 mL daily over 4 days is less effective than proprietary labdanum lozenges (CYSTUS052, Dr Pandalis Urheimische Medizin GmbH & Co.) for upper respiratory tract symptoms in patients with URTIs (53867).
• Urinary tract infections (UTIs). It is unclear if oral green tea is beneficial for reducing UTI symptoms. Details: A small clinical study in females with acute uncomplicated cystitis shows that adding green tea 2000 mg daily for 3 days to treatment with trimethoprim-sulfamethoxazole reduces symptoms of cystitis when compared with placebo (99799). This study is limited by its small size and the lack of information on antibiotic resistance in each treatment group.
• Wrinkled skin. It is unclear if oral or topical green tea is beneficial for wrinkles. Details: Some preliminary clinical research shows that taking green tea catechins 175 mg twice daily for two years does not reduce signs of photo-aging of the skin in females with facial photo-aging when compared with placebo (53873). However, using a combination of topical green tea 10% cream and oral green tea extract 300 mg twice daily for 8 weeks seems to improve skin elasticity in females with moderate photo-aging based on microscopic analysis, although the clinical appearance of the skin does not seem to significantly improve (53731). Other preliminary clinical research shows that consuming one liter of a beverage with green tea polyphenols for 12 weeks improves skin elasticity, roughness, and hydration in middle-aged females when compared with placebo (54030). More evidence is needed to rate green tea for these uses.

(Read more about GREEN TEA)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Anxiety. Oral guarana has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking two tablets of a specific product (Euphytose) containing hawthorn, black horehound, passionflower, valerian, cola nut, and guarana three times daily for 28 days can reduce the severity of anxiety in a greater percentage of patients with adjustment disorder with anxious mood compared to placebo (6250). However, because guarana was included in the supplement as a mild stimulant, it is unclear if this component contributed to the antianxiety effect of the product.
• Athletic performance. Oral guarana has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a single dose of a specific product (Berocca Boost, Bayer) containing guarana 222.2 mg (standardized to 40 mg caffeine), B vitamins, vitamin C, and minerals slightly improves exercise tolerance in trained individuals by approximately 2% when compared with placebo (91491). A small crossover study in young adult recreational handball players shows that taking a specific multi-ingredient supplement product (Olimp, Poland) containing guarana, caffeine, and other ingredients (total caffeine content 300 mg) prior to exercise slightly improves the time to complete agility testing but does not increase jump height when compared with placebo. However, taking a supplement containing only guarana and caffeine (total caffeine content 300 mg) does not improve agility or jump height (111577). It is unclear if the effects in these studies are due to guarana, other ingredients, or the combination.
• Cancer-related anorexia. It is unclear if oral guarana is beneficial for anorexia in patients with cancer. Details: A preliminary clinical study shows that taking guarana extract might improve appetite and reduce weight loss in some patients with cancer-related anorexia. Taking guarana extract (Pharmanostra) 50 mg twice daily for 4 weeks stabilized or increased weight in 55% of patients and stabilized or improved appetite in 89% of patients. However, only two patients achieved a weight gain of at least 5%, which was the minimum weight gain considered to be a positive response (91487).
• Cancer-related fatigue. It is unclear if oral guarana is beneficial for fatigue in patients with cancer. Details: Meta-analyses of small clinical studies in patients with solid tumors or breast cancer who are receiving chemotherapy or radiation therapy show that taking guarana 75-100 mg daily for 2-12 weeks does not improve cancer-related fatigue when compared with placebo (108016,111576). Additionally, a systematic review of clinical studies in patients with a variety of solid tumor types found no difference in cancer-related fatigue following at least 5 weeks of guarana consumption (108016). Most studies included in the meta-analysis and systematic review were low-quality, and all studies were conducted in Brazil. Higher quality studies in other geographic locations are needed to confirm these findings.
• Chemotherapy-related fatigue. It is unclear if oral guarana is beneficial for fatigue in patients receiving chemotherapy. Details: In patients with breast cancer, clinical research shows taking guarana extract 50 mg twice daily for 21 days improves fatigue in 52% to 66% of patients, compared with only 10% to 13% in the placebo group (91482). Other preliminary clinical research shows that taking guarana extract 37.5 mg twice daily for 3 weeks improves or stabilizes fatigue in 90% of patients with chemotherapy-related fatigue when compared with baseline. However, when compared with placebo for an additional 3 weeks, guarana does not affect fatigue (91483). Other clinical research shows that taking a dried, purified extract of guarana (PC-18) in doses of 7.5, 12.5, or 37.5 mg twice daily for 21 days improves fatigue in patients with breast cancer when compared with baseline, but not when compared with placebo. It is possible that the magnesium silicate used as a filler in both active and placebo treatments in this study contributed a fatigue-reducing effect (99049).
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral guarana for CFS, there is insufficient reliable information about the clinical effects of guarana for this condition.
• Cognitive function. It is unclear if oral guarana is beneficial for improving cognitive function. Details: In healthy individuals, some clinical research shows that taking a single dose of guarana dry extract 37.5-75 mg, containing 11% to 12% caffeine, improves the speed of cognitive task performance and memory for up to 6 hours, but does not improve reaction time or speed and accuracy of memory, when compared with placebo. Higher doses of guarana 150-300 mg do not appear to be effective (54374,91484). However, a small clinical study in young adult cyclists shows that taking guarana powder 125 mg/kg 30 minutes prior to cognitive testing improves reaction time and alertness scores when compared with placebo, but not when compared with caffeine (111361). Other clinical research shows that taking guarana powder 500 mg, containing 2.1% to 2.5% caffeine, twice daily for 3-150 days does not improve cognitive function when compared with placebo in adults or elderly individuals (54402,54414). Some research has evaluated guarana in combination with other ingredients. Preliminary clinical studies show that taking a specific product containing guarana 222 mg, B vitamins, vitamin C, and minerals (Berocca Boost, Bayer) can improve the speed and accuracy of visual information processing, working memory, and attention, as well as decrease mental fatigue, when compared to placebo (91485,91489,91491). Another specific combination product containing guarana 300 mg and other ingredients (Isoxan Actiflash, Menarini, NHS) improves reaction time by almost 600 msec for up to 90 minutes when compared with placebo or caffeine alone (91488). Conversely, a small clinical study in experienced young-adult video gamers shows that taking guarana 500 mg in combination with microalgae extract 440-880 mg daily for 30 days does not improve most measures of accuracy, reaction time, or gaming performance when compared to baseline (111360). A meta-analysis of 8 small clinical studies in healthy adults, that includes many of these studies, shows that taking a single dose of guarana 37.5-500 mg (median dose 222 mg; caffeine content 4-100 mg), alone or with other ingredients (i.e., B vitamins, vitamin C), within 360 minutes before a cognitive task does not improve overall cognitive performance or accuracy, but modestly improves reaction time when compared with placebo. In addition, cognitive performance was not related to guarana dose (111359). The validity of this analysis is limited by the heterogeneity of the included studies which utilized widely varying doses and various cognitive tests.
• Dysmenorrhea. Although there has been interest in using oral guarana for dysmenorrhea, there is insufficient reliable information about the clinical effects of guarana for this condition.
• Dyspepsia. Although there has been interest in using oral guarana for dyspepsia, there is insufficient reliable information about the clinical effects of guarana for this purpose.
• Erectile dysfunction (ED). Oral guarana has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In middle-aged patients with ED, preliminary clinical research shows that taking two capsules of a specific combination product (Revactin, MD Concepts LLC) containing guarana 125 mg, muira puama 125 mg, ginger root 125 mg, and L-citrulline 400 mg twice daily for 3 months improves scores related to erectile function and intercourse satisfaction, but not sexual desire or orgasmic function, when compared to baseline (103224). The validity of this study is limited by the lack of a placebo control, the use of per-protocol analysis, and a high dropout rate. In fact, 44% of patients withdrew in order to resume use of phosphodiesterase type 5 (PDE5) inhibitors. Further, it is unclear if these effects are due to guarana, other ingredients, or the combination.
• Fatigue. Although there has been interest in using oral guarana for fatigue, there is insufficient reliable information about the clinical effects of guarana for this purpose.
• Headache. Although there has been interest in using oral guarana for headache, there is insufficient reliable information about the clinical effects of guarana for this purpose.
• Obesity. Oral guarana has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One very small exploratory clinical study in overweight females shows that taking guarana 855 mg, yerba mate 1008 mg, and damiana 325 mg in divided doses daily for up to 45 days delays gastric emptying, increases satiety, and modestly improves weight loss when compared to baseline (11866). The validity of these findings is limited by the small study size and lack of a comparator group.
• Psychological well-being. It is unclear if oral guarana is beneficial for improving feelings of well-being. Details: Preliminary clinical research shows that taking guarana 1080 mg daily after breakfast for 5 days does not improve feelings of well-being or mood in healthy individuals (91490).
• Radiation-induced fatigue. It is unclear if oral guarana is beneficial for improving fatigue related to radiation therapy. Details: A small clinical trial shows that taking guarana 75 mg daily does not improve symptoms of depression or fatigue when compared with placebo in patients with breast cancer undergoing radiation therapy treatments (91481).

(Read more about GUARANA)

LIKELY EFFECTIVE

• Pellagra. Oral niacinamide is approved for the treatment of pellagra and niacin deficiency. Details: Niacinamide is FDA-approved for the prevention and treatment of niacin deficiency and pellagra. Niacinamide is sometimes preferred over niacin for this indication because it lacks the vasodilating and flushing effects of niacin (15,6243).

POSSIBLY EFFECTIVE

• Acne. Topical niacinamide seems to improve acne symptoms in some patients. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical study shows that applying niacinamide 4% gel twice daily for 8 weeks is as effective as clindamycin 1% gel for reducing the number and severity of acne lesions. The niacinamide gel appears to be more effective in patients with oily skin than those with non-oily skin (93360). Other preliminary clinical research in adults with mild to moderate acne vulgaris shows that applying niacinamide 5% cream twice daily, 10 minutes after applying benzoyl peroxide 2.5% gel, for 12 weeks reduces the number of acne lesions, but not erythema or inflammation, when compared with benzoyl peroxide alone (107711). Niacinamide has also been studied in combination with other ingredients. In preliminary clinical research, oral niacinamide has been reported to improve acne when used in combination with zinc, copper, and folic acid (Nicomide) (25557), or in combination with azelaic acid, zinc, pyridoxine, copper, and folic acid (NicAzel, Elorac Inc.) (90800). In a small observational study, topical niacinamide 4% combined with gallic acid 1% and lauric acid 1% was associated with some improvement in acne (104931). It is unclear if the effects in these studies are due to niacinamide, other ingredients, or the combinations.
• Diabetes. Oral niacinamide does not seem to prevent the onset of type 1 diabetes, although it might slow its progression. Details: Although some older research has suggested that taking high-dose niacinamide can reduce the risk of type 1 diabetes in high-risk children (4874), results from higher quality, more rigorous clinical trials show that taking niacinamide up to 3 grams daily for 5 years does not prevent the onset of type 1 diabetes in first-degree relatives of patients with type 1 diabetes (4875,25553,25554). However, taking niacinamide 1.2 grams/m2 daily for 5 years may prevent the loss of beta-cell function in these patients (25555). Also, there is evidence showing that niacinamide can preserve residual beta-cell function in patients with newly diagnosed type 1 diabetes (4877,4878,4879,4880,25556). Clinical trials, including one placebo-controlled trial and one vitamin E-comparison study, show niacinamide can prolong the "honeymoon period" in those newly diagnosed with type 1 diabetes, when the pancreas is still capable of producing some insulin (4877,4878,4879,4880,25556). However, some scientists have raised concerns about potential induction of insulin resistance with short-term use of niacinamide 2 grams daily for 2 weeks (4881). Niacinamide has also been evaluated in adults with type 2 diabetes. A small clinical study in lean patients with type 2 diabetes who failed sulfonylurea therapy shows that taking niacinamide 500 mg three times daily for 6 months in addition to continuing insulin or a sulfonylurea increases C-peptide release and improves insulin secretion when compared with insulin alone (4882).
• Hyperphosphatemia. Adding oral niacinamide to standard treatment with phosphate binders further lowers blood levels of phosphorus in patients on hemodialysis. Details: A meta-analysis of nine small clinical trials in patients on hemodialysis with hyperphosphatemia who are using a phosphate binder shows that taking niacinamide 250-1500 mg daily for 2-6 months lowers serum phosphorus and parathyroid hormone levels when compared with placebo (98940) Another meta-analysis of two small clinical trials in the same patient population also shows that taking niacinamide, titrated from 500 mg to 1500 mg daily over 8 weeks, reduces serum phosphorus levels by about 0.9 mg/dL when compared with placebo (94188). Other clinical research in this population shows that taking modified-release niacinamide 250-1500 mg orally daily for 12-24 weeks also lowers serum phosphate and parathyroid levels when compared with placebo. However, these effects were not maintained at 40-52 weeks follow-up (107709,110499). In addition, this product was not compared with immediate-release niacinamide. Niacinamide has also been studied in place of phosphate binders. One small clinical study in patients on hemodialysis with hyperphosphatemia shows that taking niacinamide 500-1750 mg daily for 12 weeks, beginning 2 weeks after discontinuation of phosphate binders, decreases serum phosphorus levels by 1.5 mg/dL and intact parathyroid hormone levels by 50 pg/mL, without affecting calcium levels, when compared to baseline (25561).The validity of these findings is limited due to the lack of a control group.
• Osteoarthritis. Oral high-dose niacinamide might be beneficial for improving osteoarthritis symptoms. Details: Clinical research in patients with osteoarthritis shows that taking niacinamide 3 grams daily in six divided doses for 12 weeks improves joint flexibility, reduces inflammation, and modestly decreases use of nonsteroidal anti-inflammatory drugs (NSAIDs) when compared with placebo (4883).

POSSIBLY INEFFECTIVE

• Brain tumor. Adding high-dose oral niacinamide to chemotherapy does not seem to improve survival in patients with brain tumors. Details: Preliminary clinical research in patients with surgically resected brain tumors shows that treatment with radiotherapy, niacinamide, and carbogen does not improve survival when compared with radiotherapy alone or radiotherapy plus carbogen (11695,11696).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Actinic keratoses. It is unclear if oral or topical niacinamide is beneficial for reducing actinic keratoses. Research results are conflicting. Details: A large clinical trial in healthy Australian adults with actinic keratoses shows that taking a specific niacinamide product (Insolar, Blackmores) 500 mg twice daily for 12 months reduces the number of actinic keratoses by 13% when compared with placebo. The difference between the 2 groups was observed as early as 3 months after starting niacinamide (93362). Additionally, a small clinical study in healthy, older Australian adults with actinic keratoses shows that taking niacinamide (Nature's Own, Virginia) 500 mg once or twice daily for 4 months reduces the total number of actinic keratoses by 29% and 35%, respectively, when compared with placebo (93365). However, a large clinical trial in solid organ transplant recipients in Australia shows that taking a specific niacinamide product (Insolar, Blackmores) 500 mg twice daily for 6 months does not reduce the number of actinic keratoses when compared with placebo (113559). Also, a small clinical trial in kidney transplant recipients with actinic keratoses and a history of nonmelanoma skin cancer shows that taking niacinamide 500 mg twice daily for 12 months does not decrease the number of actinic keratoses when compared with placebo (113682). The study may have been inadequately powered to detect a difference between groups. Two small clinical studies conducted in Brazil in elderly adults with actinic keratoses shows that taking niacinamide 500 mg twice daily for 120 days or applying a cream containing niacinamide 5% twice daily for 56 days does not reduce the number of actinic keratoses when compared with placebo (107714,113684). Most studies were conducted in countries with high year-round ultraviolet radiation exposure, such as Australia and Brazil; results may not be readily extrapolated to populations in other geographic regions.
• Age-related cognitive decline. Although there is interest in using oral niacinamide for age-related cognitive decline, there is insufficient reliable information about the clinical effects of niacinamide for this purpose.
• Age-related macular degeneration (AMD). Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients with early-stage age-related maculopathy shows that taking a combination of niacinamide 18 mg, vitamin E 20 mg, and lutein 15 mg daily for nearly a year improves retinal function when compared with no treatment (60134). It is unclear if this effect is due to niacinamide, other ingredients, or the combination.
• Aging skin. It is unclear if topical niacinamide improves symptoms of aging skin. Details: A small study in females with signs of facial photo-aging shows that applying niacinamide 5% cream to half of the face twice daily for 12 weeks improves blotchiness, the appearance of wrinkles, skin elasticity, and skin pigmentation when compared with applying placebo cream to the other half of the face (25551).
• Atopic dermatitis (eczema). It is unclear if topical niacinamide improves eczema symptoms. Details: A small clinical study in patients with atopic dermatitis and dry skin shows that applying niacinamide 2% cream twice daily for 8 weeks decreases skin water loss and improves skin hydration when compared with using a white petrolatum moisturizer (25560). A moderate-sized clinical study in adults with mild atopic dermatitis (AD) shows that applying a specific niacinamide containing body emollient (Bioderma Atoderm PP Baume, Bioderma Cosmetics Trading Co., Ltd.) 250 grams weekly, applied twice daily for 28 days with or without pre-cleansing with a specific niacinamide containing gel wash (Atoderm Intensive Gel Moussant, Bioderma Cosmetics Trading Co., Ltd.), improves AD severity, itching, trans-epidermal water loss, skin water content, and dermatological quality of life when compared with a control emollient and water-only skin cleansing. Additionally, using both the niacinamide containing emollient and cleansing gel improves trans-epidermal water loss and skin water content sooner when compared with niacin containing emollient only (113681). However, the study may have been inadequately powered and too short in duration to detect additional differences between the 2 niacinamide groups.
• Attention deficit-hyperactivity disorder (ADHD). Oral niacinamide has only been evaluated in combination with other vitamins; its effect when used alone is unclear. Details: A small clinical study in children with ADHD shows that taking a maximum of niacinamide 3 grams, ascorbic acid 3 grams, calcium pantothenate 1.2 grams, and pyridoxine 600 mg daily for 3 months seems to improve behavior in 29% of participants when compared with baseline (9957). The validity of this finding is limited by the lack of a comparator group.
• Bladder cancer. Oral niacinamide has only been evaluated in combination with carbogen for improving survival in advanced bladder cancer; its effect when used alone is unclear. Details: A phase II clinical study in patients with locally advanced bladder cancer shows that adding inhaled carbogen and oral niacinamide 40-60 mg/kg about 2 hours before radiotherapy shows a trend to improved survival at 3 years when compared with inhaled carbogen and radiotherapy (25558), and a larger phase III study shows that carbogen and oral niacinamide improves 3-year survival by about 13% when compared with radiotherapy alone (93366). An observational follow-up of the phase III study found a trend to increased survival at 5 years in the carbogen and niacinamide group when compared with radiotherapy alone. And in a subgroup of patients with tumor necrosis, the 5-year survival was significantly greater with carbogen and niacinamide when compared with radiotherapy alone (93356). It is unclear if these effects are due to niacinamide, carbogen, or the combination.
• Child growth. It is unclear if oral niacinamide improves child growth. Details: Preliminary clinical research in children in rural Tanzania shows that supplementing niacinamide orally from birth to 18 months of age does not improve length-for-age, weight-for-age, or head circumference when compared with control. Niacinamide was initially supplemented to breast-feeding mothers, 250 mg daily, until 6 months of age, followed by 100 mg daily taken by the child until 18 months of age (107713).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral niacinamide is beneficial for COVID-19. Details: Observational research in adults with acute kidney injury secondary to coronavirus disease-19 infection has found that taking niacinamide 1000 mg orally daily for 7 days is associated with a 55% lower risk of mortality when compared with control. However, taking niacinamide was not associated with a lower risk of renal replacement therapy (110500).
• Cutaneous lupus erythematosus (CLE). It is unclear if topical niacinamide is beneficial for CLE. Details: Preliminary clinical research in adults with discoid lupus erythematosus, a type of CLE, shows that applying topical niacinamide 2% to 4% twice daily for 12 weeks modestly improves lesion scores, but not quality of life scores, when compared with placebo. However, the study may have been inadequately powered to detect a difference between groups (110498).
• Depression. Although there is interest in using oral niacinamide for depression, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Diabetic neuropathy. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with diabetic polyneuropathy shows that taking a specific combination product (Cytoflavin, Polysan) containing niacinamide, inosine, riboflavin, and succinate daily for 12 weeks improves symptom scores, including paresthesia and numbness scores, when compared with placebo. The therapy was first administered intravenously, providing niacinamide 200 mg, inosine 400 mg, riboflavin 40 mg, and succinate 2000 mg daily for 10 days, followed by an oral formulation providing niacinamide 100 mg, inosine 200 mg, riboflavin 20 mg, and succinate 1200 mg daily for the remainder of the study (110503).
• Erythema. Topical niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: There is interest in using niacinamide to reduce the side effects of topical tretinoin, including erythema. A small preliminary clinical study in patients using isotretinoin for acne shows that applying a specific cream (Sebiaclear Hydra, SVr Laboratoire Dermatologique) containing niacinamide 5% and omega-ceramides 8% twice daily for 6 months reduces isotretinoin-induced erythema, dryness, and itching of the skin when compared with a glycerin placebo (98938). It is not clear if this effect is due to niacinamide, omega-ceramides, or the combination.
• Head and neck cancer. Oral niacinamide has only been evaluated in combination with carbogen for improving survival in laryngeal cancer; its effect when used alone is unclear. Details: A phase III clinical trial in patients with laryngeal cancer shows that treatment with accelerated radiotherapy plus carbogen and niacinamide 60 mg/kg taken orally 1-1.5 hours prior to each fraction of radiation improves local tumor control, but does not improve overall survival or 5-year disease-free survival, when compared with accelerated radiotherapy alone. In a subgroup of patients with hypoxic tumors, anemia, or high expression of epidermal growth factor receptor, receiving niacinamide and carbogen seems to improve both survival and tumor control when compared with radiotherapy alone (93358,93359,93363).
• Melasma. It is unclear if topical niacinamide improves melasma. Details: A small clinical study in female adults with melasma shows that applying a specific niacinamide 10% serum (Bo leda, Shanghai Ruizhi Medical Technology Co., Ltd) twice daily after skin cleansing for 16 weeks improves melasma area and severity, pigmented spots, and skin texture when compared with control. Both groups were also treated with salicylic acid 30% throughout the study (113683). Topical niacinamide has also been studied in patients with hyperpigmentation. A small clinical study in Japanese females with uneven facial hyperpigmentation shows that applying niacinamide 5% moisturizer to the face twice daily reduces hyperpigmentation and increases skin lightness after 4 weeks when compared with placebo moisturizer. However, further improvements are not observed after another 4 weeks of treatment (25552). Another small clinical study in Korean females with uneven facial hyperpigmentation shows that applying a moisturizer containing niacinamide 2% plus tranexamic acid 2% (Regederm RX White Project, Aestura) twice daily for 8 weeks reduces skin pigmentation by about 9% when compared with a placebo cream (93361).
• Non-Hodgkin lymphoma. It is unclear if adding oral niacinamide to chemotherapy reduces relapses of refractory lymphoma. Details: One small clinical study in patients with relapsed or refractory lymphoma shows that 24% of patients achieve complete or partial remission and 57% achieve disease stabilization when compared with baseline, following treatment with vorinostat 400 mg daily and niacinamide titrated from 20 mg/kg to 100 mg/kg over the first 14 days of a 21-day cycle for up to 18 cycles (93355). It is unclear how these outcomes compare to using vorinostat alone, or to other control treatments.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral niacinamide is beneficial for NAFLD. Details: Preliminary clinical research in adults with NAFLD and diabetes shows that taking a specific niacinamide product (Nature's Life) 1000 mg orally daily for 12 weeks does not improve liver function tests, liver steatosis, or liver fibrosis when compared with no intervention. However, some quality of life domain scores were moderately improved. However, the study may have been inadequately powered to detect a difference between groups (110502).
• Nonmelanoma skin cancer. It is unclear if oral or topical niacinamide reduces the risk of nonmelanoma skin cancer. Details: A meta-analysis of 4 clinical trials in adults shows that taking niacinamide 500 mg twice daily for 4-12 months does not reduce the risk of nonmelanoma skin cancer when compared with placebo. This analysis also shows no effect of niacinamide on the risk of basal cell carcinoma and squamous cell carcinoma (113560). However, there was high heterogeneity across the studies due to differences in patient populations and mixed results overall. Two studies included in the analysis show that niacinamide, including a specific niacinamide product (Nature's Own, Virginia), reduces the risk of nonmelanoma skin cancer in immunocompetent adults when compared with placebo (93362,93365). One was a large clinical trial that shows taking a specific niacinamide product (Insolar, Blackmores) 500 mg twice daily for 12 months reduces the rate of new nonmelanoma skin cancer by 23%, but it does not reduce the risk of not recurrent nonmelanoma skin cancers, when compared with placebo. However, this reduced risk appears to be transient. Follow up 6 months after niacinamide was discontinued showed no difference between groups (93362). The 2 other studies analyzed, including a large trial using a specific niacinamide product (Insolar, Blackmores), were conducted in transplant recipients showed no reduced risk of nonmelanoma skin cancer when compared with placebo (113560,113559). All studies were conducted in Australia; it is unclear if these results can be extrapolated to other geographical regions with different background ultraviolet radiation exposure and skin cancer rates. A previous meta-analysis of 5 clinical studies shows taking niacinamide 500-1000 mg daily for 6-12 months or applying niacinamide 1% twice daily for 6 months decreases the rate of basal cell and cutaneous squamous cell carcinomas by 54% and 52%, respectively when compared with control. Niacinamide was only administered topically in 1 of the 5 studies and only reduced risk of cutaneous squamous cell carcinoma (110497).
• Premenstrual syndrome (PMS). Although there is interest in using oral niacinamide for PMS, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Pruritus. It is unclear if oral niacinamide reduces pruritus in patients with kidney failure. Details: A small clinical study in patients with pruritus due to kidney failure shows that taking niacinamide sodium 500 mg twice daily for 4 weeks does not reduce pruritus severity when compared with placebo (93364). This study is limited due to small size and short study duration.
• Psoriasis. It is unclear if oral niacinamide is beneficial for psoriasis. Details: Preliminary clinical research in adults with mild to moderate psoriasis shows that applying niacinamide 4% cream topically twice daily for 12 weeks improves psoriasis scores by 31% when compared with baseline. The validity of these results is limited by the lack of a comparator group (110501).
• Rosacea. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that 71% of adult and adolescent patients with rosacea who take a combination product (Nicomide) containing niacinamide 750 mg, zinc 25 mg, copper 1.5 mg, and folic acid 500 mcg once or twice daily report improvement in appearance after 4 weeks when compared to baseline (25557). The validity of these findings is limited by the lack of a control group.
• Schizophrenia. Although there is interest in using oral niacinamide for schizophrenia, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Seborrheic dermatitis. It is unclear if topical niacinamide is beneficial for reducing seborrheic dermatitis symptoms. Details: One small clinical study in patients with seborrheic dermatitis shows that applying niacinamide 4% cream once daily for 12 weeks reduces the severity of symptoms such as redness and scaling by 75%, compared with a 35% reduction when using a placebo cream (93357). More evidence is needed to rate niacinamide for these uses.

(Read more about NIACINAMIDE)

EFFECTIVE

• Pantothenic acid deficiency. Taking pantothenic acid 5-10 mg daily is effective for treating and preventing pantothenic acid deficiency (15).

POSSIBLY INEFFECTIVE

• Radiation dermatitis. Topical dexpanthenol does not seem to be beneficial for preventing or treating radiation dermatitis. Details: Applying dexpanthenol, an analog of pantothenic acid, twice daily to areas of irradiated skin does not seem to reduce erythema, desquamation, itching, or pain following radiation treatment (7192). Also, applying dexpanthenol 0.5% cream (Bepanthen, Hoffmann LaRoche ) daily during radiation therapy and for 2 weeks after completing radiation therapy is less effective than methylprednisolone aceponate 0.1% cream (Advantan) at reducing radiation-induced skin irritation (67779).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Oral or topical pantothenic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In adults with mild to moderate acne, clinical research shows that taking a specific supplement (Pantothen, Avilan Marketing LLC) providing pantothenic acid 1.1 grams twice daily in addition to other B vitamins for 12 weeks modestly reduces total and non-inflammatory lesion counts when compared with placebo (105188). Also, in adolescents or young adults with mild to moderate acne, preliminary clinical research shows that topical application with a gel containing D-panthenol 4%, hydrogen peroxide 4%, and salicylic acid 0.5% once daily for 60 days modestly reduces acne lesions when compared with baseline (105189). The validity of this finding is limited by the lack of a comparator group.
• Alcoholism. Although there is interest in using oral pantothenic acid for improving recovery from alcoholism, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Allergic rhinitis (hay fever). Although there is interest in using oral pantothenic acid for allergic rhinitis, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Alopecia areata. Pantothenic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy adults with diffuse hair loss shows that intramuscular administration of dexpanthenol 250 mg and biotin 5 mg once weekly for 6 weeks reduces hair fall count at weeks 1 and 8, but only increases hair density at week 1, when compared to baseline (111366). The validity of these findings is limited by the study's small size, short duration, and lack of comparator group.
• Anxiety. Although there is interest in using oral pantothenic acid for anxiety, there is insufficient reliable information about the clinical effects of pantothenic acid for this purpose.
• Asthma. Although there is interest in using oral pantothenic acid for asthma, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Athletic performance. Although there is interest in using oral pantothenic acid to improve athletic performance, there is insufficient reliable information about the clinical effects of pantothenic acid for this purpose.
• Attention deficit-hyperactivity disorder (ADHD). Oral pantothenic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some small outdated clinical studies in children diagnosed with hyperkinesis suggest that taking calcium pantothenate 1.2 grams, alone or in combination with niacinamide, ascorbic acid, and pyridoxine, does not improve symptoms of hyperactivity when compared with placebo (3351,9957). It is unclear what effects pantothenic may have, if any, in children with a modern diagnosis of ADHD.
• Atopic dermatitis (eczema). It is unclear if topical pantothenic acid is beneficial in infants or children with atopic dermatitis. Details: One preliminary clinical trial in infants and children with stable mild atopic dermatitis shows that topical application of an emollient containing panthenol (Bepanthen, SensiDaily, Bayer Consumer Care AG) for 3 months is as effective as a reference emollient for reducing symptoms and preventing a flare. However, the efficacy of the reference emollient (Stelatopia Emollient Cream, Mustela; Laboratoires Expanscience) is unclear based on available preliminary clinical research (105190).
• Autism spectrum disorder. Although there is interest in using oral pantothenic acid for autism spectrum disorder, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Carpal tunnel syndrome. Although there is interest in using oral pantothenic acid for carpal tunnel syndrome, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Cheilitis. Topical pantothenic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small, open-label study in adults with mild-to-moderate cheilitis shows that applying a specific lip care product containing pantothenic acid and bisabolol (Eucerin Aquaphor SOS lip care) at least twice daily for 8 weeks reduces cheilitis severity scores by 5 points on a 12 point scale assessing erythema, scale, fissure, and inflammation when compared to baseline (114549). The validity of this finding is limited by the small study size and lack of a comparator group. Additionally, it is unclear if this effect is due to pantothenic acid, bisabolol, or the combination.
• Chronic fatigue syndrome (CFS). Although there is interest in using oral pantothenic acid for CFS, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Conjunctivitis. Although there is interest in using oral or ocular pantothenic acid for conjunctivitis, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Constipation. It is unclear if oral or intramuscular dexpanthenol is beneficial for constipation. Details: Preliminary clinical research shows that administering dexpanthenol (Bepanthene), an analog of pantothenic acid, 400 mg orally or 500 mg intramuscularly daily for 5 days decreases the time to a bowel movement in patients with chronic or occasional constipation when compared with an oral placebo (67822).
• Dandruff. Although there is interest in using oral or topical pantothenic acid for dandruff, is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Depression. Although there is interest in using oral pantothenic acid for depression, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Diaper rash. Although there is interest in using topical pantothenic acid for diaper rash, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Dry eye. Although there is interest in using ocular pantothenic acid for dry eye, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Dry skin. It is unclear if topical dexpanthenol is beneficial for patients with dry skin. Details: A small, open-label study in healthy adults with dry skin shows that cleansing the skin with a dexpanthenol-containing liquid cleanser (DCLC, Bepanthen SensiControl Daily Gentle Body Wash) daily for 4 weeks increases stratum corneum hydration by 17% without affecting skin barrier function, pH, or microbiome when compared to baseline (111262). The validity of these findings is limited by the lack of blinding and a comparator group.
• Epilepsy. Although there is interest in using oral pantothenic acid for epilepsy, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Eye trauma. It is unclear if ocular dexpanthenol is beneficial for eye trauma. Details: Some preliminary clinical research shows that using eyedrops containing dexpanthenol 5%, a derivative of pantothenic acid, two drops four times daily for 28 days following surgery for retinal detachment reduces eye pain and discomfort when compared with placebo drops (67783). However, using a specific dexpanthenol 5% ointment (Bepanthen) does not seem to improve corneal epithelial wound healing following phototherapeutic keratectomy when compared with placebo (67801).
• Heart failure. Although there is interest in using oral pantothenic acid for heart failure, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Herpes zoster (shingles). Although there is interest in using oral or topical pantothenic acid for shingles, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Insomnia. Although there is interest in using oral pantothenic acid for insomnia, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Laser skin resurfacing. It is unclear if topical dexpanthenol or pantothenic acid can reduce adverse effects after laser skin resurfacing procedures. Details: A preliminary clinical study shows that use of a dexpanthenol-containing ointment (Bepanthen Wound Healing Ointment, Bayer) once daily modestly reduces the diameter of lesions up to 3 days after fractional carbon dioxide laser resurfacing when compared with petroleum jelly (105743). Also, applying a specific cream (Cicaplast Baume B5 cream, L'Oreal) containing panthenol 5%, madecassoside, copper, zinc, and manganese to one side of the face for 28 days reduces decrustation time by approximately one day when compared with a control emollient. Redness and swelling were lower at 3 days, but there was no difference in pain and burning (105742). It is unclear if these effects are due to pantothenic acid, other ingredients, or the combination.
• Multiple sclerosis (MS). Although there is interest in using oral pantothenic acid for MS, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Muscular dystrophy. Although there is interest in using oral pantothenic acid for muscular dystrophy, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Nipple fissures. Although there is interest in using topical pantothenic acid for nipple fissures, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Obesity. Although there is interest in using oral pantothenic acid for obesity, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Pain (chronic). It is unclear if oral or topical pantothenic acid is beneficial for the management of various forms of chronic pain. Details: Although there is interest in using oral or topical pantothenic acid for various forms of chronic pain, including neuropathy and arthritis, there is limited information available about the clinical effects of pantothenic acid for this purpose. One review of preliminary clinical research found that calcium pantothenate does not reduce symptoms of arthritis in patients with rheumatoid arthritis or osteoarthritis (10433).
• Parkinson disease. Although there is interest in using oral pantothenic acid for Parkinson disease, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Poison oak and poison ivy dermatitis. Although there is interest in using topical pantothenic acid for poison ivy dermatitis, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Postoperative pain. It is unclear if oral pantothenic acid is beneficial for postoperative pain. Details: In post-tonsillectomy patients aged 5-12 years, preliminary clinical research shows that taking pastilles containing dexpanthenol (Bepanthene, Bayer) 100 mg three times daily reduces pain when compared with placebo. Postoperative pain was modestly reduced at 1, 3, 7, and 14 days after surgery (105191).
• Postoperative sore throat. It is unclear if pantothenic acid lozenges are beneficial for postoperative sore throat. Details: Preliminary clinical research shows that taking two lozenges containing dexpanthenol, an analog of pantothenic acid, 200 mg 30 minutes prior to general anesthesia reduces the incidence and severity of postoperative sore throat when compared with a benzydamine hydrochloride or placebo spray (67792).
• Pregnancy-related leg cramps. Although there is interest in using oral pantothenic acid for pregnancy-related leg cramps, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Premenstrual syndrome (PMS). Although there is interest in using oral pantothenic acid for PMS, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Respiratory tract infections. Although there is interest in using oral pantothenic acid for respiratory tract infections, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Rhinosinusitis. It is unclear if nasal dexpanthenol is beneficial for rhinosinusitis. Details: Preliminary clinical research shows that using a nasal spray (MarPlus) containing dexpanthenol, an analog of pantothenic acid, on the first, second, fourth, and sixth week after endoscopic sinus surgery reduces nasal discharge, but not other symptoms associated with chronic rhinosinusitis, when compared with saline nasal spray (67808).
• Skin irritation. It is unclear if topical dexpanthenol is beneficial for preventing or treating skin irritation due to sodium lauryl sulfate. Details: Preliminary clinical research shows that applying dexpanthenol (Bepanthol Handbalsam), an analog of pantothenic acid, twice daily for 26 days does not prevent sodium lauryl sulfate-induced skin irritation (67785). However, dexpanthenol may be effective for treating skin irritation caused by sodium lauryl sulfate. Use of an ointment containing dexpanthenol 1% to 5% twice daily for up to 30 days following skin exposure to sodium lauryl sulfate seems to reduce skin water loss, skin roughness, and skin inflammation when compared to control (67802,67806).
• Ulcerative colitis. Although there is interest in using oral or rectal pantothenic acid for ulcerative colitis, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Vertigo. Although there is interest in using oral pantothenic acid for vertigo, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Wound healing. Preliminary clinical research suggests that oral dexpanthenol might be beneficial for wound healing. Details: In post-tonsillectomy patients aged 5-12 years, preliminary clinical research shows that taking pastilles containing dexpanthenol (Bepanthene, Bayer) 100 mg three times daily improves wound healing when compared with placebo. Depending on the type of surgery, wound healing occurred in 2.3-2.9 times as many patients within 7 days of surgery, and in 13% to 35% more patients within 14 days, when compared with placebo (105191). More evidence is needed to rate pantothenic acid for these uses.

(Read more about PANTOTHENIC ACID)

EFFECTIVE

• Ariboflavinosis. Oral riboflavin can treat and prevent low riboflavin levels.

POSSIBLY EFFECTIVE

• Hyperhomocysteinemia. Oral riboflavin reduces homocysteine levels in individuals with the MTHFR 677 TT genotype. It does not seem to provide benefit in individuals with other genotypes. Details: Population research has found that poor riboflavin status is associated with high homocysteine levels in individuals with the 677 TT genotype for the MTHFR enzyme (71386,71403,71409). Taking riboflavin 1.6 mg daily for 12 weeks reduces homocysteine levels by 22% to 40% in individuals with the 677 TT genotype of MTHFR when compared with pretreatment. However, riboflavin supplementation does not seem to reduce homocysteine levels in individuals with the 677 CC or CT genotypes (71443).
• Migraine headache. Oral riboflavin modestly reduces migraine attack frequency and severity in adults. The benefits of oral riboflavin in children are unclear. Details: A meta-analysis of 5 small clinical trials in adults with migraine shows that taking riboflavin 100-400 mg daily, alone or in combination with other natural ingredients, for three months modestly reduces migraine duration, frequency, and pain scores when compared with control (105480). These findings are limited by significant heterogeneity. Most clinical studies compared riboflavin 400 mg daily with placebo, no treatment, or an active control (1396,1397,1398,12387,105480). Limited evidence also suggests that taking riboflavin 400 mg daily might be no different for migraine prevention than certain conventional treatments such as bisoprolol 10 mg, metoprolol 200 mg, propranolol 80 mg, or valproate 500 mg (1396,105480). These findings are limited due to small study size and a lack of power to detect a difference between groups. Limited research has also evaluated riboflavin in children. A network meta-analysis of 3 small clinical trials in children with migraine shows that taking oral riboflavin 100-200 mg daily for 4-12 months does not significantly reduce incidence of migraine when compared with placebo. However, there was a non-significant trend towards reduced migraine frequency. Furthermore, conventional treatments such as propranolol, pregabalin, valproate, and topiramate were not shown to be significantly better than riboflavin for migraine prevention (105484). These findings are limited by small population sizes and insufficient power to detect differences between groups. Although riboflavin 100-200 mg has been used in prospective clinical studies, small observational studies have found some benefit in children taking riboflavin doses as low as 10-40 mg daily and as high as 400 mg daily for 3-4 months (105481,105485). Riboflavin has also been studied in combination with other ingredients, with research suggesting potential benefit. Specifically, riboflavin 400 mg has been combined with magnesium 600 mg and coenzyme Q10 150 mg daily (Dolovent; Linpharma Inc.) (92101), and also with magnesium 300 mg and feverfew 100 mg daily (12389).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there is interest in using oral riboflavin for acne, there is insufficient reliable information about the clinical effects of riboflavin for this purpose.
• Alzheimer disease. Although there is interest in using oral riboflavin for Alzheimer disease, there is insufficient reliable information about the clinical effects of riboflavin for this condition.
• Anxiety. It is unclear if oral riboflavin is beneficial for anxiety. Details: A large observational cohort study in adults suggests that a dietary riboflavin intake above 2.1 mg daily is associated with a 5% lower prevalence of anxiety when compared with a riboflavin intake less than 1.6 mg daily. Subgroup analysis suggests that this association is especially strong in males (111209).
• Cardiovascular disease (CVD). It is unclear if oral riboflavin can prevent mortality due to CVD. Details: Epidemiological research has found that dietary and supplemental riboflavin intake in the highest quartile, around 3.4 mg daily, is associated with a 47% lower risk of CVD mortality when compared with riboflavin intake in the lowest quartile, around 1 mg daily. The reduction in CVD mortality with riboflavin was enhanced by higher folate intake (110727). The validity of this finding is limited by the fact that dietary riboflavin intake was based on 2-day dietary recall.
• Carpal tunnel syndrome. Although there is interest in using oral riboflavin for carpal tunnel syndrome, there is insufficient reliable information about the clinical effects of riboflavin for this purpose.
• Cataracts. It is unclear if oral riboflavin is beneficial in patients with cataracts. Details: Observational research has found that high dietary intake of riboflavin is associated with a reduced risk of nuclear cataracts and age-related lens opacification (6378,14301). Furthermore, a clinical study in Chinese patients with nutrient deficiencies shows that taking a combination of riboflavin 3 mg plus niacin 40 mg daily also seems to reduce the risk of developing nuclear cataracts when compared with no supplementation (4885). It is unclear if the benefit is due to riboflavin, niacin, or the combination.
• Cervical cancer. It is unclear if oral riboflavin helps to prevent cervical cancer. Details: Epidemiological evidence has found that increased riboflavin intake from dietary and supplement sources, along with other B vitamins, is associated with a reduced risk of precancerous cervical lesions (11074).
• Cognitive function. Oral riboflavin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in healthy adults aged 40-65 years shows that taking a combination supplement containing riboflavin 70 mg, other group B vitamins, ginkgo leaf, and bacopa daily for 12 weeks does not improve measures of memory, attention, cognition, mood, or stress reactivity when compared with placebo (111334).
• Colorectal cancer. It is unclear if oral riboflavin reduces colorectal cancer risk. Details: Epidemiological evidence in a Chinese population suggests that increased dietary intake of riboflavin is associated with a reduced risk of developing colorectal cancer (105482).
• Depression. It is unclear if oral riboflavin is beneficial for depression. Details: A large cross-sectional study in middle-aged adults suggests that dietary riboflavin intake above 2.1 mg daily is associated with an 8% lower prevalence of depression when compared with a riboflavin intake less than 1.6 mg daily. Subgroup analysis suggests that this association is especially strong in males (111209).
• Diabetes. It is unclear if oral riboflavin reduces the risk of developing gestational diabetes. Details: A large prospective cohort study in pregnant adults shows that supplementation with riboflavin at doses over 2.5 mg daily during the first trimester and 2.1 mg daily in the second trimester is associated with a lower risk of developing gestational diabetes when compared with riboflavin doses under 1.1 mg daily. However, this effect was not found for dietary intake of riboflavin, only supplementation. Additionally, the participants were mostly Han Chinese adults, limiting the generalizability of the findings to other populations (111680).
• Diabetic neuropathy. Intravenous and oral riboflavin have only been evaluated in combination with other ingredients; riboflavin's effect when used alone is unclear. Details: Clinical research in patients with type 2 diabetes shows that intravenous administration of a specific combination product containing succinic acid, inosine, nicotinamide, and riboflavin (Cytoflavin, Polysan) daily for 10 days followed by an oral formulation of the same product, taken daily for 76 days, reduces symptoms of diabetic neuropathy including paresthesia, numbness, and burning when compared with placebo (110503). It is unclear if these findings are due to riboflavin, other ingredients, or the combination.
• Esophageal cancer. It is unclear if oral riboflavin reduces esophageal cancer risk. Details: Population research in Iranian patients has found that low riboflavin status is associated with a two-fold increase in the risk of esophageal cancer (71439). However, not all evidence agrees. Preliminary clinical studies in Chinese individuals with esophageal dysplasia shows that taking riboflavin, alone or in combination with calcium or niacin, for 3-5 years does not seem to reduce the risk of esophageal cancer in patients when compared with baseline or control (4679,63576,71488). Taking riboflavin 200 mg weekly, in combination with retinol 15 mg and zinc 50 mg, also does not seem to be beneficial in this patient population (71501). It is unclear if these findings are generalizable to geographic locations other than China and Iran.
• Gastric cancer. It is unclear if oral riboflavin reduces colorectal cancer risk. Details: Low quality clinical research in a Chinese population shows that taking riboflavin in combination with niacin does not reduce the risk of gastric cancer when compared with control (4679).
• Hypertension. There is limited evidence on the oral use of riboflavin for reducing blood pressure in patients with the MTHFR 677 TT genotype. Details: A 677 C to T polymorphism on the MTHFR gene has been associated with hypertension. In patients with a confirmed MTHFR 677 TT genotype and premature cardiovascular disease, preliminary clinical research suggests that taking riboflavin 1.6 mg daily for 16 weeks reduces systolic blood pressure (SBP) by 9 mmHg and diastolic blood pressure (DBP) by 6 mmHg when compared with placebo. This decrease in blood pressure is larger than that reported in other trials, which may be due to the fact that only patients with the 677 TT genotype were included. These patients seem to respond to riboflavin therapy more so than patients with 677 CC or 677 CT genotype (92102). Additional clinical research in patients with the 677 TT genotype but without cardiovascular disease shows that taking riboflavin 1.6 mg daily for 16 weeks reduces SBP by 5.6 mmHg but does not reduce DBP (92103). There is also interest in using dietary riboflavin for reducing the onset of hypertension. Some epidemiological evidence in a Chinese population has found that increased dietary intake of riboflavin is associated with a reduced risk of developing hypertension (105483).
• Liver cancer. Oral riboflavin has only been evaluated in combination with niacin; its effect when used alone is unclear. Details: Preliminary clinical research in Chinese individuals older than 55 years shows that taking riboflavin in combination with niacin does not seem to prevent liver cancer mortality when compared with control. However, there was a reduced risk of liver cancer mortality in people aged less than 55 years when compared with control (63470).
• Lung cancer. Oral riboflavin has only been evaluated in combination with niacin; its effect when used alone is unclear. Details: Preliminary clinical research in Chinese individuals shows that taking riboflavin in combination with niacin does not appear to reduce the risk of lung cancer when compared with control (34539).
• Malaria. Oral riboflavin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children ages 5-14 years living in Gambia and at high risk for malaria exposure suggests that taking riboflavin, in combination with iron, thiamine, and vitamin C, for 3 months does not reduce the frequency or severity of malaria infections when compared with placebo (56730).
• Malnutrition. There is limited evidence on the oral use of riboflavin with other ingredients in children at risk for kwashiorkor. Details: A clinical study in Malawian children at risk for kwashiorkor, a severe form of malnutrition, suggests that taking riboflavin, vitamin E, selenium, and N-acetyl cysteine at a dose of three times the recommended dietary allowance does not prevent kwashiorkor, reduce edema, increase physical growth, or reduce infection when compared with placebo (71433).
• Mitochondrial myopathies. Although there is interest in using oral riboflavin for mitochondrial myopathies, there is insufficient reliable information about the clinical effects of riboflavin for this condition.
• Multiple sclerosis (MS). It is unclear if oral riboflavin slows the progression of MS-related disability. Details: A small clinical study in patients with relapsing-remitting MS or secondary progressive MS who are undergoing treatment with disease-modifying therapies suggests that taking oral riboflavin 10 mg daily for six months is no more effective for improving disability than placebo (91752). The validity of this finding is limited by the small study sample size.
• Oral leukoplakia. It is unclear if oral riboflavin prevents or slows progression of oral leukoplakia. Details: Population research in people living in Uzbekistan suggests that low blood levels of riboflavin are associated with an increased prevalence of oral leukoplakia (71502). However, clinical evidence in patients with a high occurrence of oral and esophageal cancer who are living in Uzbekistan suggests that taking riboflavin 80 mg weekly for 20 months does not improve the prevalence or progression of oral leukoplakia when compared to baseline (71565). The validity of this finding is limited by the lack of a placebo group and unusual once weekly dosing. Furthermore, it is unclear if these results are generalizable to other geographic locations.
• Pre-eclampsia. Although there is interest in using oral riboflavin for pre-eclampsia, there is insufficient reliable information about the clinical effects of riboflavin for this purpose.
• Pregnancy-related iron deficiency. It is unclear if oral riboflavin is beneficial in patients with iron deficiency due to pregnancy. Details: Preliminary clinical research in pregnant patients in China suggests that adding riboflavin 1 mg daily to supplemental iron and folic acid does not improve iron status when compared with taking iron and folic acid alone (71480).
• Sickle cell disease. It is unclear if oral riboflavin is beneficial in patients with sickle cell disease. Details: One small clinical study in patients with sickle cell disease suggests that taking riboflavin 5 mg twice daily for 8 weeks increases serum iron and transferrin saturation when compared to baseline; however, riboflavin does not seem to improve serum ferritin or circulating hemoglobin levels (71566).
• Stroke. Oral riboflavin has only been evaluated in combination with niacin; its effect when used alone is unclear. Details: Preliminary clinical research in Chinese individuals with poor nutritional status who are at risk for stroke suggests that taking riboflavin 5.2 mg daily in combination with niacin 40 mg daily does not reduce the risk of stroke-related mortality (2673). More evidence is needed to rate riboflavin for these uses.

(Read more about RIBOFLAVIN)

POSSIBLY EFFECTIVE

• Congestive heart failure (CHF). Oral taurine may improve left ventricular function, heart failure-related symptoms, and exercise capacity in patients with CHF. Details: Taking taurine 2-6 grams in two or three divided doses daily for 6-8 weeks seems to improve left ventricular function (5248,5271,8221) and symptoms of heart failure (5271,5306,8221) when compared with placebo or coenzyme Q10 in patients with New York Heart Association (NYHA) functional class II to IV. Also, taking taurine 500 mg three times daily for 2 weeks seems to improve exercise capacity when compared with placebo in patients with heart failure (77176). Some patients with severe heart failure rapidly improve from NYHA class IV to II after 4-8 weeks of treatment. Improvement seems to continue for as long as taurine treatment is continued, up to one year (5306,8217,8218,8221).
• Hepatitis. Oral taurine may improve liver function in patients with acute or chronic hepatitis. Details: Several small clinical trials show that taking taurine 1.5-4 grams daily for up to 3 months improves liver function in patients with acute and chronic hepatitis when compared with placebo (10454,77114,77147).

POSSIBLY INEFFECTIVE

• Obesity. Oral taurine does not appear to improve body weight in adults who are obese or overweight. Details: A meta-analysis of 12 small clinical trials shows that taurine supplementation does not reduce body weight or body mass index (BMI) when compared with placebo. The studies included in this analysis evaluated taurine doses of 0.5-6 grams daily for 15 days to 6 months. Most of the patient populations evaluated in the included studies had liver or metabolic disorders; three studies specifically evaluated overweight or obese adults (104166). Additionally, a more recent clinical trial in a small group of females with obesity shows that taking taurine 1 gram three times daily along with a calorie-restricted diet for 8 weeks does not reduce body weight, BMI, or waist circumference when compared with calorie restriction alone (104167). In contrast, a very small study in adults with type 2 diabetes on antidiabetes medication shows that taking taurine 500 mg twice daily for 8 weeks reduces body mass, BMI, and body fat percentage when compared with control (112271). The validity of these effects is limited by the small sample size.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Academic performance. It is unclear if oral taurine is beneficial to improve academic performance. Details: A very small clinical study in college entrance examinees over age 19 shows that taking a jelly containing taurine 3 grams daily for 14 days does not improve academic achievement when compared with baseline or placebo (110579). Due to its small size, this study may have been inadequately powered to detect a difference between groups.
• Age-related macular degeneration (AMD). Although there has been interest in using oral taurine for AMD, there is insufficient reliable information about the clinical effects of taurine for this purpose.
• Androgenic alopecia. Oral taurine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in adults with androgenic alopecia or telogen effluvium shows that taking a combination product containing taurine, cysteine, methionine, iron, selenium, and hydrolyzed collagen (GFM Oral, Cantabria Labs) along with conventional therapy, consisting primarily of finasteride or minoxidil, daily for 12 weeks improves hair loss when compared with conventional therapy alone (111636). It is unclear if this effect is due to taurine, other ingredients, or the combination.
• Athletic performance. Research on the use of taurine for improving endurance or power output is limited and conflicting; however, it may improve performance by a small amount in some athletes. Details: Research is conflicting on the effects of taurine on athletic performance. Several clinical studies in trained and untrained athletes show that taking taurine 1-6 grams as a single dose before endurance exercise, or 3 grams daily for 8 weeks after endurance exercise, does not improve endurance or aerobic capacity when compared with placebo (77159,77203,95613,98334). However, a meta-analysis of 7 small clinical trials shows that taking taurine 1-6 grams daily for up to 2 weeks slightly improves endurance when compared with control. Also, preliminary studies in male cyclists, recreationally active males, Olympic-level athletes, and female athletes habituated to caffeine show that taking taurine 50 mg/kg or 1-6 grams one time 1.5-2 hours prior to a cycling test increases the time to exhaustion and peak, mean, and minimum power output but does not improve perceived exertion, fatigue index, heart rate, or anaerobic capacity when compared with placebo (101475,103211,112265,112269). The reasons for these discrepancies are unclear; the meta-analysis did not identify a dose or duration-related benefit. One small clinical trial shows that taking taurine 40 mg/kg improves muscle power in caffeine-deprived athletes who regularly use caffeine, but actually seems to worsen muscle power in athletes who do not regularly use caffeine (98335). Overall, it is not clear which population is most likely to benefit from taurine use (98337,98338). Study results are mixed when taurine has been evaluated in combination with other ingredients. One small study shows that taking a specific product containing taurine and caffeine (AdvoCare Spark) does not improve sprint performance in college athletes when compared with placebo (77195). However, other small studies of cyclists and boxers suggest that taking taurine in combination with a variety of other ingredients including B vitamins, caffeine, and glucuronolactone (Red Bull Energy Drink) or ginseng, kudzu, and soybean, may improve measures such as endurance, power, balance, or agility (37815,57945,110577,112269). It is unclear if the benefits seen in these studies are due to taurine, other ingredients, or the combinations.
• Attention deficit-hyperactivity disorder (ADHD). Although there has been interest in using oral taurine for ADHD, there is insufficient reliable information about the clinical effects of taurine for this purpose.
• Autism spectrum disorder. Although there has been interest in using oral taurine for autism spectrum disorder, there is insufficient reliable information about the clinical effects of taurine for this purpose.
• Chemotherapy-induced nausea and vomiting (CINV). It is unclear if oral taurine is beneficial in patients with CINV. Details: One small clinical trial in patients with acute lymphoblastic leukemia receiving 6 months of chemotherapy shows that taking taurine (pure powder, Aviforme) 1000 mg twice daily, starting 6 hours after receiving chemotherapeutic agents, significantly improves CINV in 87.5% of patients. Other symptoms, such as reduced appetite and smell and taste impairment, are also improved in some patients (91512).
• Chemotherapy-induced nephrotoxicity. It is unclear if oral taurine is beneficial for preventing or treating chemotherapy-induced nephrotoxicity. Details: One small clinical trial in patients with acute lymphoblastic leukemia receiving 6 months of chemotherapy shows that taking taurine (pure powder, Aviforme) 1000 mg twice daily reduces plasma creatinine, urea, bilirubin, and liver enzymes after 4 months when compared with placebo. This suggests a protective effect against chemotherapy-induced nephrotoxicity and hepatotoxicity. A reduction in overall fatigue is also observed (95616).
• Cirrhosis. It is unclear if oral taurine is beneficial in patients with cirrhosis. Details: One small, uncontrolled clinical study in patients with cirrhosis shows that taking taurine 1 gram three times daily for 4 weeks reduces the severity and frequency of muscle cramps when compared to baseline (104165). Another small clinical trial in patients with cirrhosis shows that taking taurine 6 grams daily for 4 weeks reduces portal hypertension by 12%, compared with a 2% increase in the placebo group (98336). However, it is unclear if this is associated with a reduced risk for complications such as variceal bleeding and ascites.
• Cognitive function. It is unclear if oral taurine is beneficial for improving cognitive function; however, taking an energy drink (Red Bull Energy Drink) containing taurine and other ingredients may modestly improve some measures of cognitive function. Details: Levels of taurine decrease with age, but supplementation does not seem to have neuroprotective effects or cognitive benefits in the elderly (101471,110574,110578). In one small crossover study, taurine alone did not reduce errors in sleep-deprived individuals when compared with placebo (38154). However, taurine taken as part of an energy drink formulation containing taurine, caffeine, glucuronolactone, and B vitamins (Red Bull Energy Drink) improves focused and sustained attention, wakefulness, verbal reasoning, driving ability and quality, and reaction speed when compared with placebo (9899,38117,77088,77202). Preliminary clinical research in young adults also shows that consuming the Red Bull Energy Drink might improve attention and verbal reasoning, but does not seem to improve memory, when compared with placebo (9899,77088).
• Cystic fibrosis. Oral taurine may reduce steatorrhea in children with cystic fibrosis, but it does not seem to improve other measures of nutritional status. Details: Some small clinical studies in children with cystic fibrosis show that taking taurine 30-40 mg/kg daily for 7 days to 6 months might be useful as adjunctive therapy to reduce steatorrhea when compared with baseline or placebo (10455,77227,77231). However, it does not seem to improve growth, lung function, muscle protein breakdown, or other symptoms of cystic fibrosis (77224,77228). Also, adding taurine 500-1500 mg daily to treatment with ursodeoxycholic acid for up to one year does not improve liver function tests, fat absorption, or nutritional status in patients with cystic fibrosis and associated liver disease when compared with ursodeoxycholic acid alone (77246,77256).
• Delirium. It is unclear if oral taurine prevents delirium in patients in the intensive care unit. Details: A large clinical study of hospitalized adults in Iran who underwent liver transplantation shows that taking a specific taurine powder product (100% Taurine Amino Acid, MyProtein) 2 grams daily for 30 days post-transplant reduces the risk of delirium by 73% when compared with placebo. These results also suggest that for every four patients treated with taurine over placebo, one additional case of delirium is prevented. Patients who took taurine also had less time on the ventilator and shorter intensive care and hospital stays (110575). However, it is unclear if these effects are due to taurine or other factors since ventilator time and intensive care length of stay are risk factors for delirium.
• Diabetes. It is unclear if oral taurine is beneficial in patients with diabetes. Details: Plasma levels of taurine are reported to be lower in patients with diabetes than in healthy controls (101473). However, clinical research evaluating taurine for glycemic control is mixed (77074,103212). One small clinical trial in patients with type 2 diabetes shows that taking taurine 1 gram three times daily for 8 weeks reduces blood glucose, insulin resistance, total cholesterol, and low-density lipoprotein (LDL) cholesterol when compared with placebo (103212). Although there was no improvement in glycated hemoglobin (HbA1c), the study was not long enough to detect a meaningful reduction in HbA1c. Other preliminary clinical research shows that taking taurine 1-1.5 grams twice daily for 2-4 months does not affect fasting blood glucose, HbA1c, or insulin but may improve measures of insulin resistance in patients with type 2 diabetes when compared with placebo (77074,112271). However, taking taurine while following an exercise program 3 times weekly does appear to reduce fasting blood sugar and HbA1c when compared with exercise plus placebo (112271). The reasons for these discrepant findings are unclear; however, all the included studies were small and potentially inadequately powered to detect a difference in outcomes.
• Epilepsy. Although there has been interest in using oral taurine for epilepsy, there is insufficient reliable information about the clinical effects of taurine for this condition.
• Exercise-induced muscle soreness. Small clinical studies suggest that oral taurine may modestly improve exercise-induced muscle soreness. Details: One small clinical trial in healthy, untrained adults shows that taking taurine 2 grams in combination with branched chain amino acids (BCAAs) three times daily for 2 weeks reduces subjective muscle soreness by 37% when compared with placebo (77212). Another small clinical trial in young, untrained males shows that taking taurine (Taisho Pharmaceutical Co., LTD.) 2 grams three times daily after meals before exercise, and continuing for three days after exercise, reduces delayed onset muscle soreness (DOMS), but not creatine kinase levels, when compared with placebo (91513).
• Fatigue. It is unclear if oral taurine is beneficial for improving fatigue. Details: One small clinical trial shows that taurine seems to reduce fatigue when taken alone, but increases fatigue when taken in combination with caffeine (77202). However, an observational study in young adults has found that subjective scores for physical and mental fatigue do not seem to correlate with dietary taurine intake (101472). One small clinical trial shows that drinking 500 mL of an energy drink providing taurine 1 gram plus other ingredients including caffeine and B vitamins decreases measures of driving-related fatigue in a driving simulation when compared with placebo (91075).
• Helicobacter pylori. It is unclear if oral taurine can aid in the eradication of helicobacter pylori (H. pylori). Details: One clinical trial shows that taking taurine 500 mg twice daily in combination with conventional treatment for 6 weeks increases H. pylori eradication and shortens duodenal ulcer scarring time in patients with confirmed H. pylori infection when compared with conventional treatment alone (77145).
• Hyperlipidemia. It is unclear if oral taurine is beneficial for lowering lipid levels. Details: A meta-analysis of 12 small clinical trials in adults with various liver or metabolic disorders, but without a specific diagnosis of hyperlipidemia, shows that taurine supplementation reduces total cholesterol by 11 mg/dL and triglycerides by 13 mg/dL, but does not seem to improve low-density lipoprotein (LDL) cholesterol or high-density lipoprotein (HDL) cholesterol levels, when compared with placebo. The studies included in this analysis evaluated doses of 0.5-6 grams daily for 15 days to 6 months (104166). The benefits of taurine in adults with hyperlipidemia are unclear. The effect of taurine has also been investigated in combination with exercise. A very small study in adults with type 2 diabetes on antidiabetes medication shows that taking taurine 500 mg twice daily while participating in an exercise program 3 times weekly for 8 weeks reduces triglycerides, total cholesterol, and LDL cholesterol and increases HDL cholesterol when compared with exercise plus placebo (112271).
• Hypertension. Oral taurine may modestly reduce blood pressure in patients with hypertension; however, the long-term antihypertensive effects of taurine are unclear. Details: One clinical study in patients with elevated blood pressure or stage 1 hypertension shows that taking taurine 1.6 grams daily for 12 weeks reduces systolic blood pressure (SBP) by 5 mmHg and diastolic blood pressure (DBP) by 3 mmHg when compared with placebo. The benefit is seen after 8 weeks of continued supplementation (95614). A small clinical trial in patients with stage 2 hypertension (previously classified as borderline hypertension) shows that taking taurine 6 grams daily for 7 days reduces both SBP and DBP when compared to baseline (77229). The long-term effects of taurine on blood pressure are unclear. A meta-analysis of 12 small clinical trials in adults with various liver or metabolic disorders, but without a specific hypertension diagnosis, shows that taurine supplementation reduces SBP by 5 mmHg and DBP by 3 mmHg when compared with placebo. The studies included in this analysis evaluated doses of 0.5-6 grams daily for 15 days to 6 months (104166). Taurine is commonly found in energy drinks, and its effect on blood pressure when used in combination with other ingredients in the form of an energy drink has been evaluated. A small observational study in young adults suggests that drinking a specific combination product containing taurine 100 mg, caffeine, and group B vitamins (Redbull Energy Drink) reduces heart rate but does not change SBP or DBP when compared to baseline (112266). However, another small observational study in young healthy adults suggests that drinking a specific combination product containing taurine 2000 mg, caffeine, ginseng, glucuronolactone, inositol, guarana, L-carnitine, and B vitamins (Monster Energy Drink) increases both SBP and DBP by about 16 mmHg and raises heart rate by 17 beats per minute 15 minutes after consumption when compared to baseline. However, 90 minutes after consumption only DBP and heart rate remain elevated (112268). In both studies, the validity of the effects is limited by a lack of a comparator group. Additionally, it is unclear if the effects are due to taurine, other ingredients, or the combination.
• Infant development. Higher maternal intake of taurine from the diet may be linked to increased newborn length and weight; however, feeding taurine-containing formula to newborns does not appear to improve infant development. Details: One observational study has found a positive correlation between maternal dietary taurine intake and newborn length. In pregnant patients with high taurine intake (>120 mg/day), neonatal birth weight and length were significantly higher when compared with groups with lower taurine intake (101474). However, clinical research shows that administering infant formula containing taurine 45 mg/L for up to 12 weeks does not affect weight, length, head circumference, or behavior in preterm and full-term infants when compared with formula without taurine (77119,77216,77218,77239,77260).
• Iron deficiency anemia. It is unclear if oral taurine is beneficial in patients with iron deficiency anemia. Details: One small clinical trial in females with iron deficiency anemia shows that taking taurine 1000 mg plus ferrous sulfate 325 mg daily for 20 weeks improves hemoglobin concentrations, red blood cell counts, and serum ferritin levels when compared with ferrous sulfate plus placebo (77070).
• Muscular dystrophy. It is unclear if oral taurine is beneficial in patients with muscular dystrophy. Details: One very small crossover trial in patients with muscular dystrophy shows that taking taurine 100-150 mg/kg for 6 months improves the ability to relax muscles after voluntary use when compared with placebo (77235).
• Physical performance. It is unclear if oral taurine improves physical performance in older adults. Details: A small study in elderly females living in a care facility shows that taking taurine powder 1.5 grams daily for 14 weeks in addition to standardized exercise training may modestly improve some measures of physical fitness (i.e. agility, endurance) when compared to baseline. These measures were not improved in patients who took taurine but did not participate in exercise training or who participated in exercise training but did not take taurine (110574). The validity of these findings is limited by lack of randomization, blinding, and statistical comparison between groups.
• Postoperative recovery. It is unclear if oral taurine is beneficial for improving postoperative recovery. Details: One small clinical trial in patients recovering from surgery after a hip fracture shows that taking taurine 6 grams daily for 7 days after surgery does not improve morbidity and mortality outcomes after 1 year when compared with placebo (95615).
• Psychosis. It is unclear if oral taurine is beneficial in patients with psychosis. Details: One small clinical trial in adults up to 25 years of age with first-episode psychosis shows that taking taurine 4 grams daily for 12 weeks in combination with prescribed antipsychotics reduces positive psychotic symptoms, but not negative or cognitive symptoms, when compared with placebo (95612).
• Sleep deprivation. Oral taurine 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 product containing taurine, caffeine, glucuronolactone, and B vitamins (Red Bull Energy Drink) reduces lane drifting and sleepiness and improves driving quality and reaction time during a car-driving simulator exercise in sleep-deprived individuals when compared with placebo (38117,77066). Other preliminary clinical research in sleep-deprived surgical trainees shows that taking taurine 2 grams in addition to caffeine 150 mg improves reaction time during performance of simulated laparoscopic surgery when compared with placebo, although error-making is not reduced (38154).
• Tourette syndrome. Oral taurine may improve tic severity in children with Tourette syndrome who are taking tiapride at a dose of 300 mg or less. Taurine may not be effective in children taking higher doses of tiapride. Details: One clinical trial in children 6-16 years of age with Tourette syndrome or other tic disorders shows that taking taurine along with tiapride reduces the severity of tics when compared with tiapride alone. For every 6 children taking taurine, one additional child saw a 60% or greater reduction in tic severity as measured on the Yale Global Tic Severity Scale when compared with placebo. However, taurine did not improve tic severity in children taking tiapride at a dose greater than 300 mg daily (103210). Taurine was taken in age-dependent doses of 2.4 grams daily in those 6-8 years, 3.6 grams daily in those 9-13 years, and 4.8 grams daily in those 14-16 years.
• Traumatic brain injury (TBI). It is unclear if oral taurine is beneficial in patients with a TBI. Details: A small clinical study of adults in Iran receiving treatment in the intensive care unit (ICU) following TBI shows that adding a specific taurine powder product (Nutricost) 30 mg/kg/day up to 3 grams daily to enteral nutrition for 14 days may modestly improve disease severity scores, but does not reduce days on the ventilator, ICU length of stay, or mortality at 30 days when compared with usual enteral nutrition (110573). Due to its small size, this study may have been underpowered to detect differences between groups. More evidence is needed to rate taurine for these uses.

(Read more about TAURINE)

EFFECTIVE

• Imerslund-Grasbeck disease. Intramuscular vitamin B12 is effective for patients with this condition. Details: Administering intramuscular vitamin B12 (hydroxocobalamin) 1 mg daily for 10 days, followed by monthly injections for the remainder of a patient's life, is effective for treating familial selective vitamin B12 malabsorption (Imerslund-Grasbeck disease) (15,82862).
• Vitamin B12 deficiency. Administering vitamin B12 orally, intramuscularly, or intranasally is effective for preventing and treating vitamin B12 deficiency. Details: Vitamin B12 deficiency has varying definitions but is often defined as vitamin B12 (cobalamin) levels less than 180-200 pmol/L (or 240 pg/mL). Some believe that only intramuscular vitamin B12 is effective for treating vitamin B12 deficiency. However, clinical research shows that oral therapy increases cobalamin levels similarly to intramuscular administration, even in patients with pernicious anemia or malabsorption, if a high enough dose is given (2909,2911,2915,9335,82832) (82836,82949,82860,103976,103972,107141,107144). Some evidence suggests that the most effective oral dose is between 647-1032 mcg daily (13106). However, in certain situations, intramuscular treatment might be more appropriate. Guidelines by the British Committee for Standards in Hematology recommend only intramuscular vitamin B12 for initial treatment of severe vitamin B12 deficiency in patients with pernicious anemia, malabsorption disorders, or neurological involvement (94722). Intramuscular vitamin B12 is also appropriate in patients with diarrhea or vomiting and those likely to be nonadherent (103972). Vitamin B12 deficiency is especially common in older adults, primarily due to lack of intrinsic factor and malabsorption (2915,2919,9335). Daily supplementation with vitamin B12 50-100 mcg might be needed to correct deficiency (10126), while daily doses of 25-37.5 mcg help to maintain normal levels over time (9335). In addition to supplements, foods such as milk and bread fortified with vitamin B12 can be used and are approximately 55% to 60% absorbed by people over 60 years of age (10124). Vitamin B12 deficiency is also common in patients that have had gastric surgery, including gastrectomy and bariatric surgery (107144,107145). Taking vitamin B12 in the doses found in multivitamins or generic vitamin B supplements does not seem to prevent vitamin B12 deficiency following bariatric surgery (107145). However, taking methylcobalamin 500 mcg daily is beneficial for treating vitamin B12 deficiency associated with a total gastrectomy and taking cyanocobalamin 5000 mcg daily is beneficial for preventing vitamin B12 deficiency following gastric bypass (107144). Other people at risk for vitamin B12 deficiency include strict vegetarians who eat no animal products (vegans) and people with increased vitamin B12 requirements associated with pregnancy, thyrotoxicosis, hemolytic anemia, hemorrhage, malignancy, and hepatic and kidney disease. Moderate consumption of animal products may not be sufficient to restore and maintain vitamin B12 levels, especially in adolescents who had consumed macrobiotic (vegan type) diets for the first 6 years of life. High dietary intake of vitamin B12 or supplements is usually needed in order to restore and maintain optimal vitamin B12 levels in these adolescents (10125).

LIKELY EFFECTIVE

• Cyanide poisoning. Intravenous hydroxocobalamin (Cyanokit) is likely effective as an antidote for patients with suspected or known cyanide toxicity due to inhalation, ingestion, or skin exposure. Details: Treatment of cyanide poisoning with hydroxocobalamin (Cyanokit) up to 10 grams has been approved by the US Food and Drug Administration (FDA) and recommended by the Australian Resuscitation Council (82870,82905,82906). Hydroxocobalamin is also FDA-approved for treating cyanide toxicity during pregnancy (82904).

POSSIBLY EFFECTIVE

• Canker sores. Sublingual or topical vitamin B12 seems to reduce canker sore symptoms. Details: Clinical research in patients with canker sores shows that applying a topical ointment containing vitamin B12 500 mcg in four divided doses daily for 2 days reduces pain levels by 80% when compared with a control ointment not containing vitamin B12 (96176). Other preliminary clinical research shows that taking vitamin B12 1000 mcg sublingually daily for 6 months reduces the duration of canker sore outbreaks, the number of ulcers, and level of pain when compared with placebo in patients with normal vitamin B12 levels (17242).
• Hyperhomocysteinemia. Oral vitamin B12 in combination with folic acid, and sometimes with vitamin B6, reduces homocysteine levels. Details: While folic acid 0.5-5 mg daily lowers fasting homocysteine levels by an average of 25%, adding vitamin B12 0.5 mg daily produces an additional decrease of about 7% on average (6883,9400,9401,9405,9409,50145,107136). Vitamin B12 in combination with folic acid and other vitamins also reduces homocysteine levels in patients with kidney failure, sickle cell disease, and those receiving nitrous oxide general anesthesia (1489,6883,6884,7289,7881,9324,9414,9415,9416,9481,82941). Some researchers recommend routine use of vitamin B12 with homocysteine-lowering regimens to avoid the risk of neuropathy in people with undetected vitamin B12 deficiency (9405). Using vitamin B12 alone has a limited effect on homocysteine levels, and probably only in those people with vitamin B12 deficiency (2147,9410,9512). Hyperhomocysteinemia is considered by some to be an independent risk factor for atherosclerosis, recurrent thromboembolism, deep vein thrombosis, myocardial infarction, and ischemic stroke (1899,2147,3323,9402,9405,9408,9409). Clinical research suggests that supplementation with folic acid, pyridoxine, and vitamin B12 decreases homocysteine levels and reduces the atherosclerosis progression in patients at risk for atherosclerosis when compared with placebo (50133,50056,82806). However, other research suggests that elevated homocysteine levels may be a marker, as opposed to a cause, of vascular disease (11387,11388). A 5 µmol/L increase in plasma homocysteine increases the risk of cerebrovascular disease by 50%, and the odds of coronary heart disease by 60% and 80% in males and females, respectively (9407,9411). However, it is not clear if reducing homocysteine levels results in reduced cardiovascular morbidity and mortality (1489,6883,6884,9400,9405,9409,96417). Folic acid, vitamin B6, and vitamin B12 supplementation can reduce total homocysteine from 13.4 to 11 µmol/L. However, this reduction does not seem improve endothelial function or help with secondary prevention of death or myocardial infarction, and some research even suggests an increase in cardiovascular disease (CVD) risk (11387,13482,50373,50314,97619). There is also some debate about whether supplementation with homocysteine-lowering B vitamins can reduce the risk of stroke. A number of large clinical studies and meta-analyses show that supplementation with folic acid, vitamin B6, and vitamin B12, alone or in combination, does not reduce the risk of stroke in patients with CVD or impaired kidney function (11387,13482,50423,83050,96150). However, a more recent meta-analysis of 10 clinical trials including over 44,000 patients shows that B vitamin supplementation reduces the relative risk of stroke by 10% when compared with placebo in patients at risk or with a history of CVD (97619). Also, a meta-analysis in adults with a history of stroke shows that B vitamin supplementation modestly reduces the relative risk of stroke recurrence by 13% and vascular death by 11% when compared with placebo (107136).
• Postherpetic neuralgia. Subcutaneous injections of vitamin B12 seem to reduce postherpetic neuralgia symptoms. Details: Clinical research in patients with subacute herpetic neuralgia shows that subcutaneous injection of vitamin B12 (methylcobalamin) 1000 mcg six times weekly for 4 weeks reduces pain when compared with oral vitamin B12 or subcutaneous lidocaine (90394). Another clinical study shows that administering local subcutaneous injections of methylcobalamin 1000 mcg plus lidocaine up to 20 mg daily for 12 injections over 14 days, starting within 7 days of the onset of subacute ophthalmic herpetic neuralgia, decreases the mean pain score by 63% to 79% when compared with intravenous lidocaine and intramuscular methylcobalamin. Less than 2 patients need to be treated to achieve a pain reduction to ≤3 out of 10. Healing of rash, itching, numbness, and tingling were also improved (96175). Additional clinical research in patients with postherpetic pain and itching shows that this same dosing regimen of subcutaneous vitamin B12 reduces pain and analgesic requirements when compared to baseline (90396).

POSSIBLY INEFFECTIVE

• Age-related cognitive decline. Oral vitamin B12 does not seem to improve cognitive function in older adults when used alone or in combination with other B vitamins. Details: Taking vitamin B12 100-1000 mcg plus folic acid 400-2000 mcg, with or without vitamin B6 3-50 mg, daily for up to about 2 years does not seem to improve tests of cognitive function in adults aged 65 or older, most of whom do not report cognitive impairment at baseline (14392,50225,50510,90392,107140). Also, supplementation with vitamin B12 does not seem to improve cognitive function in elderly individuals with low vitamin B12 levels (12305).
• Alzheimer disease. Oral vitamin B12, when used in combination with other B vitamins, does not seem to improve cognitive function in patients with Alzheimer disease. Details: Clinical research in patients with probable Alzheimer disease using routine medication shows that taking vitamin B12 1 mg, folic acid 5 mg, and vitamin B6 25 mg daily for 18 months does not have a beneficial effect on cognitive function or the severity of disease when compared with placebo. In this study, all patients were consuming a folate-fortified diet (50319). Also, a meta-analysis of clinical research in elderly adults with mild cognitive impairment or dementia shows that taking vitamin B12, usually with other B vitamins, does not improve cognitive function (50510). Observational research has also found that higher vitamin B12 intake over 3 years in a population consuming a folate-fortified diet is not associated with a decreased risk of developing Alzheimer disease (15270). In contrast, preliminary clinical research in patients with probable Alzheimer disease who are not consuming a folate-fortified diet shows that taking vitamin B12 50 mcg daily plus folic acid 1.2 mg daily for 6 months modestly improves some measures of cognitive performance and decreases levels of homocysteine when compared with placebo (107150). More research is needed to determine if any changes in this latter study are clinically relevant.
• Cataracts. Oral vitamin B12 does not seem to reduce cataract development. Details: Clinical research in women with existing cardiovascular disease (CVD) or at increased risk of CVD shows that taking a combination of folic acid 2.5 mg daily, vitamin B6 50 mg daily, and vitamin B12 1 mg daily for an average of 7.3 years does not reduce the risk of cataracts and seems to increase the risk of cataract extraction by 28% when compared with placebo (96149).
• Circadian rhythm sleep disorders. Oral vitamin B12 does not seem to improve sleep disorders. Details: Oral vitamin B12 (methylcobalamin) does not seem to be effective for treating delayed sleep phase syndrome. Methylcobalamin 0.5-1 mg three times daily, with or without bright light therapy, also does not seem to help people with primary circadian rhythm sleep disorders (1344,1345,1346,1347,1348).
• Cognitive impairment. Oral vitamin B12 does not seem to be beneficial for older adults with cognitive impairment. Details: A meta-analysis of clinical research in elderly adults with mild cognitive impairment or dementia shows that taking vitamin B12, usually with other B vitamins, does not improve cognitive function (50510). One clinical trial in elderly people with memory complaints shows that taking a combination of B vitamins, including folic acid 0.8 mg, vitamin B12 0.5 mg, and vitamin B6 (form not specified) 20 mg daily for 24 months reduces cerebral atrophy in the gray matter regions associated with Alzheimer disease by up to seven-fold when compared with placebo. However, this protection does not occur in patients with the lowest average blood levels of homocysteine (90374).
• Fall prevention. Oral vitamin B12 does not seem to reduce the risk of falls. Details: Clinical research shows that taking B vitamins, including folic acid 400 mcg and vitamin B12 500 mcg, daily for 2 years does not prevent falls when compared with placebo in elderly individuals also taking vitamin D (96148).
• Osteoporosis. Oral vitamin B12 does not seem to reduce the risk of osteoporotic fractures. Details: Clinical research in elderly patients or patients with a history of cerebrovascular disease shows that taking vitamin B12 500 mcg and folic acid 0.4-2 mg, with or without vitamin B6 25 mg, daily for 2-3 years does not seem to reduce the risk for osteoporotic fractures when compared with placebo (90377,90393). A 5-7 year follow-up of this research has also found no benefit (103981).
• Physical performance. Oral vitamin B12 does not seem to improve physical performance in older adults. Details: Clinical research shows that taking B vitamins, including folic acid 400 mcg and vitamin B12 500 mcg, daily for 2 years does not increase hand strength or improve performance such as walking when compared with placebo in elderly individuals also taking vitamin D (96148).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large-scale clinical study shows that taking vitamin B12 1000 mcg, folic acid 2.5 mg, and vitamin B6 50 mg daily, reduces the risk of developing AMD in females over 40 years of age with a history of cardiovascular disease (CVD) or at least three risk factors for CVD. Those who took this combination for an average of 7.3 years had a 34% reduced risk of developing AMD and a 41% reduced risk of visually significant AMD when compared with placebo (14620). It is unclear if this effect is due to vitamin B12, other ingredients, or the combination.
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). It is unclear if high-dose intramuscular vitamin B12 improves the prognosis of ALS. Details: A clinical study in patients with ALS symptoms for 3 years or less shows that intramuscular vitamin B12 (methylcobalamin) 25-50 mg twice weekly for 3.5 years does not slow functional decline or increase the time until ventilation or death when compared with placebo. However, other clinical research in patients with early-stage ALS shows that intramuscular methylcobalamin 50 mg twice weekly for 16 weeks is associated with slower functional decline and a longer period of time until death or full ventilation when compared with placebo (104947,111556). These effects seem to be particularly notable in fine and gross motor skills, but not bulbar or respiratory functions. Furthermore, vitamin B12 and riluzole slowed clinical progression of ALS more than riluzole alone (111556).
• Angioplasty. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some evidence suggests that vitamin B12 400 mcg, folic acid 1 mg, and vitamin B6 10 mg daily can decrease the rate of restenosis in patients treated with balloon angioplasty (8009,9412,34540). However, this combination does not seem to be as effective for reducing restenosis in patients after coronary stenting (8009). An intravenous loading dose of folic acid, pyridoxine, and vitamin B12 followed by oral administration of folic acid 1.2 mg, pyridoxine 48 mg, and vitamin B12 60 mcg daily after bare metal coronary stenting also does not seem to reduce restenosis and might actually increase restenosis (12150,12151,34540). Due to the lack of evidence of benefit and potential for harm, this combination of vitamins should not be recommended for patients receiving coronary stents (12151). It is unclear if any effects are due to vitamin B12, other ingredients, or the combination.
• Anxiety. Although there is interest in using oral vitamin B12 for anxiety and panic attacks, there is insufficient reliable information about the clinical effects of vitamin B12 for these uses.
• Asthma. Although there is interest in using oral vitamin B12 for asthma, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Atherosclerosis. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients with intermediate risk for coronary heart disease shows that taking vitamin B12 100 mcg, aged garlic extract 250 mg, folic acid 300 mcg, vitamin B6 12.5 mg, and L-arginine 100 mg daily for 12 months reduces coronary artery calcium progression when compared with placebo (88385). It is unclear if this effect is due to vitamin B12, other ingredients, or the combination.
• Atopic dermatitis (eczema). It is unclear if topical vitamin B12 reduces the severity of eczema. Details: Preliminary clinical research shows that applying a specific topical vitamin B12 0.07% cream (Regividerm) twice daily reduces the extent and severity of atopic dermatitis when compared with placebo (15765).
• Attention. Although there is interest in using oral vitamin B12 for improving attention and focus, there is insufficient reliable information about the clinical effects of vitamin B12 for this use.
• Cancer. It is unclear if oral vitamin B12 reduces overall cancer risk when used in combination with other B vitamins. Details: An ancillary clinical study in middle-aged and elderly adults with cardiovascular disease shows that taking a combination of vitamin B12 (cyanocobalamin) 0.02 mg, folic acid 0.56 mg, and vitamin B6 3 mg, with or without eicosapentaenoic acid (EPA) 400 mg plus docosahexaenoic acid (DHA) 200 mg, for a median of 4.7 years does not reduce the risk of cancer when compared with placebo (90666). An additional secondary analysis of clinical research in patients recovering from stroke or transient ischemic attack shows that taking vitamin B12 500 mcg, folic acid 2 mg, and vitamin B6 25 mg daily for around 3.4 years does not reduce the risk of cancer when compared with placebo (90378). The validity of these findings is limited because the studies were not designed nor adequately powered to test for cancer risk.
• Cardiovascular disease (CVD). Oral vitamin B12, taken along with other B vitamins, does not seem to improve secondary prevention of death or myocardial infarction in patients with CVD. However, it might slightly reduce the risk of stroke. Details: Overall evidence from clinical research and meta-analyses shows that taking vitamin B12 in combination with folic acid and/or vitamin B6 does not seem to reduce the risk for secondary death or myocardial infarction in patients with or at risk for CVD (11387,13482,34540,50423,83050,90379,97619). In fact, some research suggests that long-term supplementation with vitamin B6, folic acid, and vitamin B12 for secondary prevention increases the risk of CVD by 20% despite lowering homocysteine levels by 30% (13482). However, other research shows that taking vitamin B12 in combination with other B vitamins modestly reduces the risk of stroke, although results are conflicting (11387,13482,50423,83050,96150,96165,97619,107136). It is unclear which specific combination of B vitamins, if any, might be optimal for reducing stroke risk and which patients are most likely to benefit. In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) approved a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368).
• Cervical cancer. It is unclear if oral vitamin B12 reduces cervical cancer risk. Details: Some epidemiological evidence has found that increasing vitamin B12 intake from dietary and supplement sources, along with folic acid, thiamine, and riboflavin, might decrease the risk of precancerous cervical lesions (11074). Also, an analysis of two case control studies has found that increased intake of vitamin B12 is associated with a 75% reduced odds of cervical cancer (34609).
• Chemotherapy-induced peripheral neuropathy. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients receiving chemotherapy shows that a combination of B vitamins that includes vitamin B12 (cyanocobalamin) 1000 mcg, taken daily starting one week prior to treatment and finishing 12 weeks after treatment is completed, does not prevent peripheral neuropathy when compared with placebo (96173).
• Child development. It is unclear if oral vitamin B12 is beneficial for child development. Details: Population research has found that daily dietary intake of less than 2.26 mcg vitamin B12 in the third trimester of pregnancy is associated with an increased risk of poorer outcomes in the offspring for some measures of speech and mathematics ability, including vocabulary at 24 months, combining words at 38 months, speech intelligibility at 6 years, and math comprehension between ages 8-11 years, when compared with dietary intakes of at least 2.26 mcg daily. There was no association between prenatal vitamin B12 intake and reading or spelling abilities, vocabulary at other ages, or full-scale Intelligence Quotient (IQ) at ages 8 or 15 (107143). Furthermore, a very large clinical study in infants of pregnant adults, 71% of whom were deficient in vitamin B12 at baseline, shows that taking vitamin B12 50 mcg daily starting in early pregnancy (<15 weeks gestation) until 6 months postpartum does not improve neurodevelopment as measured by language, motor, socioemotional, or cognitive scores at 12 months old and may worsen early motor performance at 8-12 weeks when compared with placebo. However, the negative effects on motor performance resolved by 6 and 12 months of age (112431).
• Child growth. Oral vitamin B12 taken by pregnant adults does not seem to be beneficial for infant growth. Details: A very large clinical study in infants of pregnant adults, 71% of whom were deficient in vitamin B12 at baseline, shows that taking vitamin B12 50 mcg daily starting in early pregnancy (<15 weeks gestation) until 6 months postpartum does not improve the infant's linear growth, length, or weight at 12 months of age (112431).
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral vitamin B12 reduces the risk of COPD. Details: Clinical research in patients with COPD shows that taking vitamin B12 500 mg daily for 8 weeks modestly improves endurance on the cycle ergometer, but does not improve oxygen consumption, when compared with placebo (96172).
• Cognitive function. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in healthy, middle-aged adults shows that taking a combination product containing vitamin B12, other B vitamins, bacopa, and gingko biloba twice daily for 12 weeks does not improve measures of memory, attention, cognition, mood, or stress reactivity when compared with placebo (111334).
• Colorectal cancer. It is unclear if oral vitamin B12 reduces colorectal cancer risk. Details: Some epidemiological evidence has found that increased dietary intake of vitamin B12 is associated with a reduced risk of developing colorectal cancer (90383). However, preliminary clinical research shows that taking vitamin B12 1 mg, folic acid 2.5 mg, and vitamin B6 50 mg daily for up to 7.3 years does not reduce the risk of colorectal adenoma in females at high risk for cardiovascular disease (90389). Furthermore, a secondary analysis of clinical research in elderly patients suggests that taking vitamin B12 500 mcg and folic acid 400 mcg daily for 2 years might increase the risk of colorectal cancer when compared with placebo (90393).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral vitamin B12 is beneficial for patients with COVID-19. Details: A small observational study in hospitalized patients with COVID-19 pneumonia has found that higher plasma vitamin B12 levels may be associated with an increased risk of transfer to intensive care or death than lower plasma levels. However, when multivariate regression was conducted, only patient age was associated with worsened outcomes. Additionally, the total study population was small, with only nine of 49 patients experiencing the worsened outcomes (107138).
• Dementia. It is unclear if oral vitamin B12 reduces the risk of developing dementia. Details: A large cohort of Danish adults has found that vitamin B12 levels or intake does not seem to impact the risk of developing Alzheimer disease or other dementias (104922). However, vitamin B12 might be beneficial in specific patient populations. A small observational study in patients with Parkinson disease has found that higher vitamin B12 levels (648.5 ng/L) are associated with a lower risk of developing dementia when compared with lower vitamin B12 levels (452 ng/L) (103975). It is not yet known if supplementation with vitamin B12 reduces the risk for dementia in these patients.
• Depression. It is unclear if oral vitamin B12 is beneficial for reducing depression risk. Details: A meta-analysis of epidemiological research has found that the highest dietary intake of vitamin B12 is associated with a 14% reduced risk of depression. However, in a sub-analysis, this association was not significant in males (107133). In contrast, one epidemiological study in older males included in the analysis has found that daily dietary intake of at least 4.79 mcg vitamin B12 is linked with a 58% lower risk of depression when compared with daily intake of less than 3.16 mcg. In this study, this inverse association was not observed in females (96168). Other observational research has found that low-normal serum vitamin B12 levels are associated with a 3.8 times increased risk for depression during pregnancy when compared with normal vitamin B12 levels (102384). It is unclear if increased intake of vitamin B12 through the diet or supplements reduces the risk for depression or is beneficial for treating symptoms of depression in any population. However, a meta-analysis of clinical research in elderly populations shows that supplementation with vitamin B12 100-1000 mcg daily, usually in combination with folic acid 400-2000 mcg daily, does not reduce symptoms of depression. Most individuals in these studies were not specifically diagnosed with depression (107140).
• Diabetes. It is unclear if oral vitamin B12 improves glycemic indices or prevents loss of skeletal muscle in patients with diabetes. Details: A small clinical study in patients with diabetes in India who are stabilized on metformin and/or a sulfonylurea shows that taking vitamin B12 (methylcobalamin) 500 mcg with or without folic acid 5 mg daily for 8 weeks seems to reduce glycated hemoglobin (HbA1C) by 1.3% to 1.5%, compared with a 0.3% increase with placebo (104917). This study is limited due its small sample size and lack of blinding. In elderly adults with type 2 diabetes, population research has found a lower dietary intake of vitamin B12 (average of 11.2 mcg daily) in individuals with a loss of skeletal muscle mass of at least 1.2%, compared with an average intake of 13.4 mcg daily in those with a skeletal muscle mass loss of less than 1.2%. However, further analysis determined that any relationship between vitamin B12 intake and loss of skeletal muscle mass was only significant in individuals with insufficient energy intake overall (107151).
• Diabetic neuropathy. Small clinical studies suggest that oral vitamin B12 may modestly improve pain in patients with diabetic neuropathy. Details: Two small clinical studies in patients with diabetic peripheral neuropathy show that taking vitamin B12 (methylcobalamin) 1-1.5 mg for 4-12 months modestly improves pain when compared with baseline or placebo (82841,104923). Some research also shows that vitamin B12 may be beneficial in combination with other ingredients. Studies have evaluated products containing vitamin B12 (methylcobalamin or cyanocobalamin), benfotiamine, and vitamin B6 daily for 9-12 weeks (82931,82939); and vitamin B12 (methylcobalamin) 2 mg, folic acid (L-methylfolate) 3 mg, and vitamin B6 (pyridoxal-5'-phosphate) 35 mg (Metanx; Pamlab) daily for 24 weeks (90375).
• Diarrhea. It is unclear if oral vitamin B12 is beneficial for reducing diarrhea in children. Details: Preliminary clinical research in children aged 6-30 months from low- and middle-income countries shows that taking vitamin B12 at twice the recommended dietary allowance, with or without folic acid, does not reduce the risk for diarrhea when compared with placebo (90391).
• Fatigue. It is unclear if intramuscular vitamin B12 is beneficial for improving well-being in those with fatigue or tiredness. Details: A small crossover trial in patients complaining of tiredness or fatigue shows that receiving intramuscular injections of vitamin B12 (hydroxocobalamin) 5 mg twice weekly for 2 weeks seems to improve general well-being and happiness, and has a trend toward improving fatigue, when compared with placebo (10127). The validity of this study is limited by a large drop-out rate and unstandardized outcome measures.
• Hearing loss. Oral vitamin B12 has only been evaluated in combination with adenosine triphosphate; its effect when used alone is unclear. Details: A small observational study in adults with idiopathic sudden sensorineural hearing loss has found that taking vitamin B12 1.5 mg with adenosine triphosphate 300 mg daily for 8-16 weeks is associated with modestly reduced hearing loss at 4-6 months after starting treatment when compared with taking the combination for less than 8 weeks (104924). This finding is limited due to its observational nature and lack of a control group.
• Hepatitis C. It is unclear if intramuscular vitamin B12 is beneficial for sustaining viral response in patients with chronic hepatitis C infection. Details: A small clinical study in patients with chronic hepatitis C infection shows that intramuscular vitamin B12 (cyanocobalamin) 5000 mcg every 4 weeks along with standard care improves sustained viral response when compared with standard of care alone (90386).
• Hypertriglyceridemia. It is unclear if oral vitamin B12 is beneficial for reducing triglyceride levels. Details: Some evidence shows that taking vitamin B12 7.5 mcg with fish oil 5 grams might be superior to fish oil alone when used daily to reduce total serum cholesterol and triglycerides. This suggests vitamin B12 might have an independent effect in lowering serum cholesterol and triglycerides, but further investigation is needed to confirm this effect (8694).
• Hypotension. It is unclear if oral vitamin B12 is beneficial for treating hypotension. Details: A meta-analysis of 3 observational studies in patients hospitalized with hypotension secondary to cardiac surgery vasoplegia suggests that administration of intravenous vitamin B12 (hydroxocobalamin) is associated with an 8 mmHg higher mean arterial pressure (MAP) at 1 hour but no change in vasopressor dosage at 1 hour or mortality rate when compared with methylene blue (112264). The validity of these findings is limited by the inclusion of only retrospective studies.
• Infant development. It is unclear if taking oral vitamin B12 during pregnancy is beneficial for improving infant development. Giving oral vitamin B12 to infants does not seem to be beneficial. Details: Clinical research shows that supplementation with vitamin B12 50 mcg daily from less than 14 weeks gestation until 6 weeks postpartum does not improve cognitive development in infants by 9 months of age when compared with placebo (96174). When these children were evaluated at 30 months of age, a very small benefit of vitamin B12 on expressive language was identified; however, there was no effect on cognition, receptive language, fine motor skills, or gross motor skills (100169). It is unknown whether a longer duration of postpartum supplementation or supplementation in specific populations might be beneficial. Vitamin B12 supplementation in infants has also been evaluated. A large clinical trial in marginally stunted Nepalese infants aged 6-11 months shows that giving vitamin B12 (cyanocobalamin) 2 mcg daily for 12 months reduces homocysteine levels, but does not improve motor or cognitive development, when compared with placebo (104926).
• Inflammatory bowel disease (IBD). Although there is interest in using oral vitamin B12 for IBD, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Lung cancer. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: The association between vitamin B12 and lung cancer is unclear. Some population research found no relationship between blood levels of vitamin B12 and lung cancer (9454). However, other observational research involving over 5,000 case-control pairs found that higher vitamin B12 levels are linked with an increased risk for lung cancer (102383). It is unclear if increased intake of vitamin B12, either through the diet or supplementation, directly affects the risk of lung cancer.
• Male infertility. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A retrospective study in adult males with idiopathic and varicocele-related infertility suggests that taking a combination product containing vitamin B12 1.5 mcg, L-carnitine, acetyl L-carnitine, citric acid, selenium, coenzyme Q10, vitamin C, zinc, and folic acid (Proxeed Plus) twice daily for 6 months is associated with improvements in ejaculate volume, sperm count, sperm concentration, total motility, and progressive motility in patients with idiopathic infertility when compared to baseline. However, improvement in sperm morphology was lacking. Furthermore, patients with more severe varicocele seem to benefit most, especially with regard to progressive motility (111296). The validity of these findings is limited by a lack of comparator group. Further, it is unclear if these effects are due to vitamin B12, other ingredients, or the combination.
• Mastalgia. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in patients with mastalgia shows that taking a combination of vitamin B12 as methylcobalamin 100 mg, gamma-linolenic acid, and vitamin C daily for 12 weeks does not improve the proportion of patients with minimal or no pain when compared with placebo (111059).
• Multiple sclerosis (MS). Although there is interest in using oral vitamin B12 for MS, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral vitamin B12 is beneficial for NAFLD. Details: A small clinical study in adults with NAFLD shows that taking vitamin B12 1000 mcg daily for 12 weeks reduces serum levels of homocysteine but has no effect on serum aminotransferases, measures of steatosis, fibrosis scores, fasting blood glucose, serum insulin, measures of insulin resistance, triglycerides, low-density lipoprotein (LDL) cholesterol, or high-density lipoprotein (HDL) cholesterol when compared with placebo (111555).
• Pancreatic cancer. It is unclear if oral vitamin B12 is beneficial for reducing the risk of pancreatic cancer. Details: Most population research has found that increased intake of vitamin B12, as a supplement or in the diet, is not associated with a reduced risk of pancreatic cancer (9327,104927). However, a small, retrospective population study in which smoking and non-smoking adults recalled past eating habits found that increased dietary intake of vitamin B12 is associated with a 33% reduction in pancreatic cancer risk (97976). These conflicting findings may be related to study methodology, as well as the age, gender, or smoking status of the included patients.
• Periodontitis. Although there is interest in using oral vitamin B12 for periodontitis, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Peripheral neuropathy. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific product containing vitamin B12 3 mcg, folic acid 400 mcg, and uridine monophosphate 50 mg (Keltican) daily for 60 days reduces pain by 44% and decreases analgesic use by over 75% when compared to baseline in patients with peripheral neuropathy, including those with lumbar/lumbosacral radiculopathy, sciatic pain, and cervical radiculopathy (90384). The validity of this finding is limited by the lack of a control group. Furthermore, it is unclear if the benefits are due to vitamin B12, other ingredients, or the combination.
• Psoriasis. Topical vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that a specific cream containing vitamin B12 and avocado oil (Regividerm, Regeneratio Pharma AG) reduces symptoms of psoriasis as effectively as calcipotriol ointment (Psorcutan) after 12 weeks of therapy. The vitamin B12 combination cream also causes less irritation than calcipotriol (14909). It is unclear if the benefits are due to vitamin B12, other ingredients, or the combination.
• Respiratory tract infections. A small study suggests that oral vitamin B12 does not reduce the rate of respiratory tract infections in children. Details: Preliminary clinical research in children aged 6-30 months from low-and middle-income countries suggests that taking vitamin B12 at twice the recommended dietary allowance with or without folic acid does not reduce the risk for lower respiratory tract infections when compared with placebo (90391).
• Schizophrenia. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a combination of vitamin B12 400 mcg and folic acid 2 mg daily for 16 weeks improves negative symptoms when compared with placebo in patients with schizophrenia who have persistent symptoms and a specific genetic variant of the folate transporter gene FOLHI. This variant normally results in reduced folate absorption. However, in patients without this genetic variant, folate is not beneficial with respect to negative symptom improvement (90387).
• Sickle cell disease. Oral vitamin B12 has only been evaluated in combination with other B vitamins; its effect when used alone is unclear. Details: Preliminary clinical research in adults with sickle cell disease shows that taking vitamin B12 4.2-6 mcg, folic acid 700 mcg, and vitamin B6 4.2-6 mg daily might lower homocysteine levels. However, it is unknown if this will reduce the risk of endothelial damage in these patients (9324).
• Stroke. It is unclear if oral vitamin B12, either alone or with other B vitamins, is beneficial for stroke prevention. Details: Epidemiological research has found that people with a higher intake of vitamin B12 from dietary sources do not have a reduced risk of ischemic or hemorrhagic stroke (14316). A number of clinical studies and meta-analyses show that supplementation with folic acid, vitamin B6, and vitamin B12, alone or in combination, does not reduce the risk of stroke in patients with cardiovascular disease (CVD) or impaired kidney function (11387,13482,50420,50423,83050,90379,90380,96150). However, a more recent meta-analysis of 10 clinical trials including over 44,000 patients shows that B vitamin supplementation modestly reduces the relative risk of stroke by 10% when compared with placebo in patients at risk or with a history of CVD (97619). This meta-analysis differed from some of the earlier analyses due to the inclusion of several additional clinical trials. Also, a meta-analysis in adults with a history of stroke shows that B vitamin supplementation modestly reduces the relative risk of stroke recurrence by 13% and vascular death by 11% when compared with placebo (107136). In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) allowed a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368). Unfortunately, even after the publication of higher quality research, it is still unclear which specific combination of B vitamins is optimal and which patients are most likely to benefit. One network meta-analysis suggests that a combination of folic acid and vitamin B6 lowers the risk of stroke more effectively than B vitamin mixtures that include vitamin B12 (96165). However, this analysis is limited because it didn't account for dosing. Another meta-analysis suggests that exposure to low, but not high, amounts of vitamin B12 (cyanocobalamin) seems to reduce stroke risk (96150).
• Tinnitus. It is unclear if intramuscular vitamin B12 is beneficial in patients with tinnitus. Details: A small clinical study shows that intramuscular vitamin B12 2500 mcg weekly for 6 weeks reduces tinnitus severity by 22% when compared to baseline in patients with chronic tinnitus and vitamin B12 deficiency, but not in patients with normal levels of vitamin B12. Vitamin B12 does not improve pitch or volume in either group of patients (96170). The validity of this finding is limited by the lack of a control group.
• Venous thromboembolism (VTE). It is unclear if oral vitamin B12 is beneficial for preventing VTE. Details: Epidemiological research has found that low levels of vitamin B12 are associated with an increased risk for VTE. However, clinical trials evaluating the use of B vitamins for prevention of VTE have shown conflicting results (90398). More evidence is needed to rate vitamin B12 for these uses.

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EFFECTIVE

• Pyridoxine-dependent epilepsy. Intravenous vitamin B6 is effective for controlling pyridoxine-dependent seizures. Details: Pyridoxine-dependent seizures are a rare type of refractory seizures in neonates that do not respond to anticonvulsant drugs. These seizures are typically controlled within minutes of intravenous administration of pyridoxine, a form of vitamin B6. Pyridoxine-dependent seizures can be due to genetic (autosomal recessive) pyridoxine dependency, or more commonly, a result of the use of high-dose pyridoxine during pregnancy (8197,8198).
• Sideroblastic anemia. Oral vitamin B6 is effective for treating hereditary sideroblastic anemia. Details: Taking vitamin B6 (pyridoxine) orally is effective for treating hereditary sideroblastic anemia (15,9518). Taking the active form of vitamin B6 (pyridoxal-5'-phosphate) also seems to be effective in cases in which the patient does not respond to pyridoxine (93049).
• Vitamin B6 deficiency. Oral vitamin B6 is effective for preventing and treating vitamin B6 deficiency. Details: Taking oral vitamin B6 can prevent and treat vitamin B6 deficiency (15).

LIKELY EFFECTIVE

• Hyperhomocysteinemia. Taking vitamin B6 orally, alone or in combination with folic acid, is effective for reducing hyperhomocysteinemia. Details: Vitamin B6 (pyridoxine) seems to lower homocysteine concentrations when folic acid and vitamin B12 are at physiologic levels or when given with folic acid and vitamin B12 supplements (9451,83042,107136). A combination of vitamin B6 100 mg and folic acid 0.5 mg daily seems to lower homocysteine levels by about 35% and is recommended for people with postprandial hyperhomocysteinemia (1489,9406). Other research shows that taking pyridoxine 50-200 mg daily reduces postprandial homocysteine levels by 32% to 35% (9406,10350). Pyridoxine also seems to reduce homocysteine levels in patients with kidney failure, kidney transplant patients (1489,6884,9414,9415), or patients who receive general anesthesia with nitrous oxide (9481). However, some research in healthy adults suggests that adding pyridoxine to folic acid might not provide any additional benefit over folic acid alone (9400,9405,9409,50145). Hyperhomocysteinemia is considered by some to be an independent risk factor for atherosclerosis, recurrent thromboembolism, deep vein thrombosis, myocardial infarction, and ischemic stroke (1899,3323,9402,9405,9408,9409). However, elevated homocysteine levels may be a marker, as opposed to a cause, of vascular disease (11387,11388). A 5 µmol/L increase in plasma homocysteine increases the risk of cerebrovascular disease by 50% and the odds of coronary heart disease by 60% and 80% in males and females, respectively (9407,9411). However, it is not clear if reducing homocysteine levels results in reduced cardiovascular morbidity and mortality (1489,6883,6884,9308,9400,9405,9409). Folic acid, vitamin B6, and vitamin B12 supplementation can reduce total homocysteine from 13.4 to 11 µmol/L. However, this reduction does not seem to help with secondary prevention of death or myocardial infarction, and some research even suggests an increase in cardiovascular disease (CVD) risk (11387,13482,50423,83050,97619). There is also debate about whether supplementation with homocysteine-lowering B vitamins can reduce the risk of stroke. A number of large clinical studies and meta-analyses show that supplementation with folic acid, vitamin B6, and vitamin B12, alone or in combination, does not reduce the risk of stroke in patients with CVD or impaired renal function (11387,13482,50423,83050,96150). However, a more recent meta-analysis shows that B vitamin supplementation modestly reduces the relative risk of stroke by 10% when compared with placebo in patients at risk for or with a history of CVD (97619). Also, a meta-analysis in patients with a history of stroke shows that B vitamin supplementation modestly reduces the relative risk of stroke recurrence by 13% and the risk of vascular death by 11% when compared with placebo (107136).

POSSIBLY EFFECTIVE

• Antipsychotic-induced hyperprolactinemia. It is unclear if oral vitamin B6 is beneficial for patients with antipsychotic-induced hyperprolactinemia. Details: Clinical research in male patients with hyperprolactinemia who are on a consistent antipsychotic dose shows that taking vitamin B6 300 mg twice daily for 16 weeks reduces serum prolactin levels by 68%, compared with 37% in patients taking aripiprazole 5 mg twice daily. Also, 67% of patients taking vitamin B6 had prolactin levels less than 40 mcg/mL versus 2% of those taking aripiprazole (107128).
• Kidney stones (nephrolithiasis). Oral vitamin B6 seems to decrease urinary oxalate levels and decrease the risk of kidney stone formation in some patients. Details: There is some evidence that taking vitamin B6 (pyridoxine) orally, alone or in combination with magnesium, can decrease urinary oxalate levels in people with type I primary hyperoxaluria, a hereditary disorder (1201,6437,6438,6439,6440,8548,8549,8550). Additionally, a small clinical study in this population suggests that intravenous pyridoxine hydrochloride can reduce urinary oxalate by 25.5% when compared to baseline (90796). In patients with idiopathic hyperoxaluria, taking a combination of pyridoxine 25mg and magnesium oxide 400 mg for 3 months decreases urinary oxalate by approximately 16%, with 68% of patients experiencing a reduction. However, supplementation is less effective than following a low-oxalate diet, which reduces urinary oxalate in 91% of patients by an average of 31% (107127). There is also preliminary evidence that higher pyridoxine intake in females with no history of kidney stones is associated with decreased risk of kidney stone formation (6441), but this association has not been found in males (6442).
• Pregnancy-induced nausea and vomiting. Oral vitamin B6 may reduce nausea and vomiting in some pregnant patients and is sometimes used in combination with doxylamine. Details: While some conflicting evidence exists, most small clinical studies suggest that oral vitamin B6 is effective for improving nausea and vomiting associated with pregnancy when compared with baseline or placebo. However, vitamin B6 may not be as effective as ginger (110459). Two small clinical studies show that taking vitamin B6 (pyridoxine) 25 mg every 8 hours for 3-4 days decreases pregnancy-induced nausea severity and vomiting incidence when compared with placebo (6168,16306). A larger clinical trial shows that taking lower doses of vitamin B6, 10 mg every 8 hours over 5 days, improves pregnancy-induced nausea, but not vomiting, when compared with placebo (6167). A small clinical study in patients with mild to moderate nausea and vomiting shows that taking a higher dose of 40 mg twice daily for 4 days is more effective than placebo, but no better than ginger 500 mg twice daily (99404). The American College of Obstetrics and Gynecology (ACOG) considers vitamin B6 at a dose of 10-25 mg 3 to 4 times daily a first-line treatment for pregnancy-induced nausea and vomiting due to its benign safety profile (111601). However, it is not effective for all patients, such as those with hyperemesis gravidarum, a severe form of pregnancy-induced nausea and vomiting. Adding vitamin B6 20 mg three times daily for 2 weeks to intravenous rehydration, metoclopramide, and thiamine seems to be no more effective than placebo for reducing vomiting in hyperemesis gravidarum (99405). Vitamin B6 is also sometimes used in combination with doxylamine. In fact, a combination of vitamin B6 plus doxylamine (Diclegis or Bonjesta, Duchesnay Inc., and various generics) has been approved by the US Food and Drug Administration (FDA) as a prescription product111601). ACOG recommends vitamin B6 in combination with doxylamine as another first-line treatment option (111601). However, the clinical trial used to obtain FDA approval has some methodological problems, and the significance of the results has been questioned. The improvement in symptom scores seen with Diclegis was less than one point on a 13-point scale, which is unlikely to be clinically significant (97998). Also, some clinical research shows that taking pyridoxine 25 mg and doxylamine 12.5 mg is less effective than ondansetron 4 mg when taken every 8 hours for 5 days. Only 41% of the patients using pyridoxine and doxylamine had a clinically significant reduction in nausea, compared to 92% of patients using ondansetron (90797). The combination of vitamin B6 and doxylamine is also studied with acupuncture. A large clinical study in patients with moderate to severe pregnancy-induced nausea and vomiting conducted in China shows that taking vitamin B6-doxylamine (Diclegis, Duchesnay, Inc) 20 to 40 mg each at bedtime for 14 days in combination with daily acupuncture modestly improves patient-reported nausea and vomiting scores when compared with either intervention alone (111820). However, it is unclear whether this improvement is clinically significant.
• Premenstrual syndrome (PMS). Oral vitamin B6 seems to reduce PMS symptoms. Details: There is some evidence that taking vitamin B6 (pyridoxine) orally can improve symptoms of PMS such as breast pain or tenderness (mastalgia) and depression in some patients. Pyridoxine in doses of at least 50 mg daily, plus magnesium oxide 200 mg daily, seems to relieve PMS-related anxiety and other symptoms (8555,39007,82962). Although some clinicians advocate doses of pyridoxine 200-500 mg daily for PMS, doses of 50-100 mg daily seem to work just as well. There is no apparent dose-response curve for PMS, so the lowest effective dose should be used. Higher doses might increase the risk of side effects (3093).

POSSIBLY INEFFECTIVE

• Age-related cognitive decline. Oral vitamin B6 does not seem to slow age-related cognitive decline. Details: One clinical trial in elderly people with memory complaints shows that taking a combination of B vitamins, including folic acid 0.8 mg, vitamin B12 0.5 mg, and vitamin B6 (form not specified) 20 mg daily for 24 months reduces cerebral atrophy in the gray matter regions associated with Alzheimer disease by up to seven-fold when compared with placebo. However, this protection does not occur in patients with the lowest average blood levels of homocysteine (90374). Furthermore, other clinical research shows that taking vitamin B6 (pyridoxine) 3-75 mg daily in combination with folic acid and vitamin B12 does not improve cognitive function in elderly adults (14392,50225,50510).
• Alzheimer disease. Oral vitamin B6 does not seem to improve cognitive function in patients with Alzheimer disease when used in combination with other B vitamins. Also, oral vitamin B6 does not seem to reduce the risk of developing this condition. Details: Clinical research in patients with probable Alzheimer disease taking routine medications shows that taking vitamin B6 25 mg with folic acid 5 mg and vitamin B12 1 mg daily for 18 months does not have a beneficial effect on cognitive function or the severity of disease when compared with placebo. In this study, all patients were consuming a folate-fortified diet (50319). Also, population research in elderly adults has found that a high intake of vitamin B6 from dietary or supplemental sources is not associated with a decreased risk of Alzheimer disease when compared to lower vitamin B6 intake (13165,15270).
• Carpal tunnel syndrome. Oral vitamin B6 does not seem to reduce symptoms of carpal tunnel syndrome. Details: Most research shows that people with carpal tunnel syndrome are not generally deficient in vitamin B6 and do not benefit from taking vitamin B6 supplements (8203,8937,9448,9450,9478,9482). Although early studies by a single group of researchers, as well as anecdotal reports, suggest that taking vitamin B6 may relieve carpal tunnel symptoms, more reliable research has not supported these findings (8202,9445,9447,9449,9483,15955,83086). Vitamin B6 has also been evaluated in combination with other ingredients. A moderate-sized clinical study in adults with mild to moderate carpal tunnel syndrome shows that taking a combination product containing vitamin B6, alpha-lipoic acid, acetyl-L-carnitine, phosphatidylserine, turmeric, and vitamins C, E, B1, B2, and B12 twice daily for 60 days reduces symptom severity and pain but does not improve measures of hand and wrist function when compared with a control (111702). The dose of vitamin B6 was not provided. The validity of this study is limited by the lack of blinding and placebo. Additionally, it is unclear if the effects are due to vitamin B6, other ingredients, or the combination.
• Cataracts. Oral vitamin B6 does not seem to slow cataract development. Details: Clinical research in females with existing cardiovascular disease (CVD) or at increased risk of CVD shows that taking a combination of folic acid 2.5 mg, vitamin B6 (form not specified) 50 mg, and vitamin B12 1 mg daily for an average of 7.3 years does not reduce the risk of cataracts when compared with placebo. Furthermore, the risk of cataract extraction was increased by 28% (96149).
• Chemotherapy-induced acral erythema. While some conflicting evidence exists, most research suggests that oral or topical vitamin B6 does not seem to prevent or reduce the severity of acral erythema induced by chemotherapy. Details: A meta-analysis of 10 clinical trials and 4 observational studies shows that taking vitamin B6 60-500 mg daily for up to 8 chemotherapy cycles does not prevent chemotherapy-induced acral erythema or reduce the incidence of severe cases when compared with control. Most studies used capecitabine chemotherapy alone or in combination, and one study used pegylated liposomal doxorubicin; however, no subgroup analysis was conducted to differentiate chemotherapy regimens. Results did not seem to vary based on study location, study design, or vitamin B6 dose (104930). However, a more recent preliminary clinical study in patients receiving doxorubicin for multiple myeloma shows that taking vitamin B6 100 mg on the first day of chemotherapy then twice daily for 7 days with each cycle reduces the risk of developing acral erythema by 72%, but does not improve the severity of acral erythema, when compared with no vitamin B6 supplementation (110458). Also, one small, low-quality clinical study suggests that taking vitamin B6 400 mg daily reduces the risk of moderate or severe chemotherapy-induced acral erythema when compared with vitamin B6 200 mg daily; however, the higher dose also seems to be associated with worsened tumor response and increased treatment failure (97620). Topical vitamin B6 has also failed to show benefit. A small clinical study in patients with acral erythema from capecitabine or pegylated liposomal doxorubicin shows that applying vitamin B6 1% cream to affected areas three times daily for 6 weeks does not improve symptoms when compared with placebo (104929).
• Colorectal adenoma. Oral vitamin B6 does not seem to reduce the risk of developing colorectal adenomas. Details: Clinical research shows that taking a combination of B vitamins, including folic acid 2.5 mg, vitamin B6 (pyridoxine) 50 mg, and vitamin B12 1 mg, daily for up to 9.2 years does not reduce the risk of colorectal adenoma in females at high risk of cardiovascular disease when compared with placebo (90389).
• Eclampsia. Oral or intramuscular vitamin B6 does not seem to reduce the risk of eclampsia. Details: Meta-analyses of limited clinical research in pregnant patients show that taking vitamin B6 (pyridoxine), either as 25 mg daily or a single dose of 100 mg orally or intramuscularly, does not reduce the risk of eclampsia when compared with control (83046,96166).
• Osteoporosis. Oral vitamin B6 does not seem to reduce the risk of osteoporotic fractures. Details: Clinical research in patients with cerebrovascular disease shows that taking a combination of B vitamins, including folic acid 2 mg, vitamin B6 (form not specified) 25 mg, and vitamin B12 500 mcg daily for up to 10.5 years does not prevent osteoporotic fractures when compared with placebo (90377). Furthermore, a secondary analysis of two large studies in patients with cardiovascular disease has found that taking vitamin B6 (pyridoxine) 40 mg daily in addition to folic acid and vitamin B12 for 1-3 years is associated with a 42% increased risk of hip fracture over an 11-year period when compared with only folic acid and vitamin B12 (96163). This finding is limited because these studies were not designed to assess the effects of vitamin B6 on fracture risk and the analyses were not adjusted for baseline bone health or fall risk.
• Pre-eclampsia. Oral or intramuscular vitamin B6 does not seem to reduce the risk of pre-eclampsia. Details: Meta-analyses of limited clinical research in pregnant patients show that taking vitamin B6 (pyridoxine), either as 25 mg daily or a single dose of 100 mg orally or intramuscularly, does not reduce the risk of pre-eclampsia when compared with placebo (83046,96166).
• Preterm labor. Oral or intramuscular vitamin B6 does not seem to reduce the risk of preterm labor. Details: Meta-analyses of limited clinical research in pregnant patients shows that taking vitamin B6 (pyridoxine), either as 25 mg daily or a single dose of 100 mg orally or intramuscularly, does not reduce the risk of preterm labor when compared with placebo (83046,96166).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults and children with inflammatory acne shows that taking 1-4 tablets of a specific product (NicAzel, Elorac Inc.) containing vitamin B6 (pyridoxine), nicotinamide, azelaic acid, zinc, copper, and folic acid for 8 weeks reduces inflammatory lesions and improves appearance in 88% and 81% of patients, respectively, when compared to baseline (90800). The validity of these findings is limited by the lack of a comparator group.
• Age-related macular degeneration (AMD). Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large-scale clinical study shows that taking vitamin B6 (pyridoxine) 50 mg, vitamin B12 1000 mcg, and folic acid 2.5 mg daily reduces the risk for AMD in females over 40 years of age with a history of cardiovascular disease (CVD) or with risk factors for CVD. Those who took this combination for an average of 7.3 years had a 34% reduced risk of developing AMD and a 41% reduced risk of visually significant AMD when compared with placebo (14620). It is unclear if this effect is due to vitamin B6, other ingredients, or the combination.
• Angioplasty. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some evidence suggests that vitamin B6 (pyridoxine) 10 mg, folic acid 1 mg, and vitamin B12 400 mcg daily can decrease the rate of restenosis in patients treated with balloon angioplasty (8009,9412). However, this combination does not seem to be as effective for reducing restenosis in patients after coronary stenting (8009). An intravenous loading dose of folic acid, vitamin B6 (pyridoxine), and vitamin B12 followed by oral administration of folic acid 1.2 mcg, vitamin B6 (pyridoxine) 48 mg, and vitamin B12 60 mcg daily after bare metal coronary stenting also does not seem to reduce restenosis and might actually increase restenosis (12150,12151). Due to the lack of evidence of benefit and potential for harm, this combination of vitamins should not be recommended for patients receiving coronary stents (12151). It is unclear if any effects are due to vitamin B6, other ingredients, or the combination.
• Antipsychotic-induced metabolic side effects. It is unclear if oral vitamin B6, as an adjunct to progesterone, is beneficial in patients with antipsychotic-induced amenorrhea. Details: A small clinical study in females with antipsychotic-induced amenorrhea shows that taking vitamin B6 80 mg three times daily for 1 month plus intramuscular progesterone daily for 5 days increases levels of estradiol and follicle stimulating hormone, reduces prolactin levels, and increases the rate of clinical efficacy, defined as the normalization of menstruation and improvement in endocrine indicators, by 14% when compared with progesterone alone (110457).
• Anxiety. It is unclear if oral vitamin B6 is beneficial in patients with anxiety. Details: Clinical research in college students shows that taking vitamin B6 100 mg daily for one month does not reduce anxiety scores when compared with placebo (110453). However, because a diagnosis of anxiety was not a requirement for study participation, it is unclear if these findings can be generalized to patients diagnosed with anxiety.
• Asthma. It is unclear if oral vitamin B6 is beneficial in patients with asthma. Details: Preliminary clinical studies show that taking vitamin B6 (pyridoxine) 200-300 mg daily may improve symptoms of asthma in some patients, but not others, when compared with placebo (7064,7065). Studies have yielded conflicting results, with some research suggesting that it may only be beneficial in children with severe asthma (7065). Additionally, some research suggests that theophylline may lower vitamin B6 levels, although it is unclear if vitamin B6 supplementation is beneficial (4522,7066,9503).
• Atherosclerosis. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with intermediate risk for coronary heart disease shows that taking a specific supplement (Kyolic, Total Heart Health, Formula 108, Wakunga) containing vitamin B6 12.5 mg, aged garlic extract 250 mg, vitamin B12 100 mcg, folic acid 300 mcg, and L-arginine 100 mg daily for 12 months reduces coronary artery calcium progression when compared with placebo (88385). It is unclear if this effect is due to vitamin B6, other ingredients, or the combination.
• Atopic dermatitis (eczema). It is unclear if oral vitamin B6 is beneficial in patients with eczema. Details: A small clinical study in children with eczema shows that taking vitamin B6 (pyridoxine hydrochloride) 50 mg daily for 4 weeks does not reduce symptoms such as redness and itchiness when compared with placebo (83090).
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral vitamin B6 is beneficial for ADHD. Details: A small crossover study in children with ADHD shows that taking vitamin B6 600 mg, niacinamide and ascorbic acid 3 grams, and calcium pantothenate 1.2 grams daily for 6 weeks does not improve behavior scores when compared with placebo (9957).
• Autism spectrum disorder. Although there is interest in using oral vitamin B6 for autism, there is insufficient reliable information about the clinical effects of vitamin B6 for this condition.
• Bipolar disorder. It is unclear if oral vitamin B6 is beneficial in patients with bipolar disorder. Details: A small clinical trial in patients with type 1 bipolar disorder who are taking lithium and experiencing an acute episode of mania shows that taking vitamin B6 80 mg daily for 8 weeks does not improve cognitive function or the severity of mania when compared with placebo. Cognitive function was reduced in patients taking vitamin B6; any effect on sleep was unclear (107132).
• Cancer. It is unclear if oral vitamin B6 reduces overall cancer risk. Details: Population research has found that higher dietary intake of vitamin B6 is associated with a 22% reduced risk of cancer, including esophageal, pancreatic, gastric, colorectal, and breast cancer. However, when dietary and supplemental vitamin B6 intake is considered, the inverse association between vitamin B6 and cancer risk is weaker and limited to fewer tumor sites. Furthermore, a meta-analysis of 9 clinical studies shows that taking vitamin B6 3-100 mg orally daily for 2-7.3 years, in combination with vitamin B12 and folate, does not reduce the risk of cancer in patients with cardiovascular disease or kidney failure (96164).
• Cardiovascular disease (CVD). Oral vitamin B6, taken along with other B vitamins, does not seem to improve secondary prevention of death or myocardial infarction in patients with CVD. However, it might slightly lower the risk of stroke. Details: Overall evidence from clinical research and meta-analyses shows that taking vitamin B6 in combination with folic acid and/or vitamin B12 does not seem to help with secondary prevention of death or myocardial infarction in patients with or at risk for CVD (11387,13482,34540,50423,83050,90379,97619). In fact, some research suggests that long-term supplementation with vitamin B6, folic acid, and vitamin B12 for secondary prevention increases the risk of CVD by 20% despite lowering homocysteine levels by 30% (13482). However, some research shows that taking vitamin B6 in combination with other B vitamins modestly reduces the risk of stroke, although results are conflicting (11387,13482,50423,83050,96150,96165,97619,107136). Additionally, it is unclear which specific combination of B vitamins is optimal for reducing stroke risk and which patients are most likely to benefit. In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) approved a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368).
• Cognitive function. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in healthy adults aged 40-65 years shows that taking a supplement containing vitamin B6, ginkgo leaf, bacopa, and other B vitamins twice daily for 12 weeks does not improve memory or attention when compared with placebo (111334).
• Colorectal cancer. It is unclear if oral vitamin B6 reduces the risk of colorectal cancer. Details: A meta-analysis of observational studies suggests that the highest dietary intake of vitamin B6 is associated with a 20% reduced risk of colorectal cancer when compared with the lowest dietary intake. However, this association was not shown in subgroup analyses of studies conducted in Australia, Europe, or North America (111600). The validity of this analysis is limited by the heterogeneity of the included studies.
• Dental caries. There is limited evidence on the oral use of vitamin B6 for dental decay during pregnancy. Details: Meta-analyses of limited clinical research show that taking vitamin B6 (pyridoxine), 25 mg daily or a single dose of 100 mg orally or intramuscularly, may reduce the risk of dental decay during pregnancy when compared with placebo (83046,96166).
• Depression. It is unclear if oral vitamin B6 reduces the risk of developing depression or improves symptoms of depression. Details: Clinical research in healthy college students shows that taking vitamin B6 100 mg daily for one month does not reduce depression scores when compared with placebo (1104453). However, because a diagnosis of depression was not a requirement for study participation, it is unclear if these findings can be generalized to patients diagnosed with depression. Whether vitamin B6 reduces the risk of developing depression is also unclear. A meta-analysis of population research has found that the highest dietary intake of vitamin B6 is associated with a 19% lower risk of depression when compared with the lowest intake. However, sub-analyses suggest that this association is only relevant in females and not males (107133). In one individual population study in community dwelling older adults included in the analysis, the consumption of at least 1.71 mg of vitamin B6 daily from food was associated with a 43% reduction in the likelihood of becoming depressed when compared with the consumption of 1.33 mg or less daily in females. However, there was no association between vitamin B6 levels and risk of depression in males, and the finding in females was no longer significant when adjusted for total energy intake, since foods rich in vitamin B6 are energy-dense (96168). Another observational longitudinal study in healthy adults starting oral contraceptives containing ethinyl estradiol and levonorgestrel has found that taking vitamin B6 25 mg daily for 6-12 months is associated with a 40% lower risk of depression when compared with no supplementation (90789). Most available studies are cross-sectional in nature, making any conclusions related to causation difficult.
• Diabetes. It is unclear if oral vitamin B6 is beneficial in patients with type 2 diabetes or gestational diabetes. Details: Observational research in Chinese adults with type 2 diabetes has found that dietary intake of vitamin B6 in the highest quartile is associated with 53% lower odds of developing cardiovascular disease, defined as a non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina, when compared with vitamin B6 intake in the lowest quartile (110452). Small clinical studies in patients with gestational diabetes and vitamin B6 deficiency shows that taking vitamin B6 (pyridoxine) 100 mg daily for 2 weeks improves glucose tolerance and blood glucose levels when compared with baseline (82967,83088). However, there is concern that these findings were confounded by dietary alterations. This benefit was not observed in a subsequent small case series in patients with gestational diabetes (22380).
• Diabetic neuropathy. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research suggests that taking a combination of B vitamins, including folic acid (L-methylfolate), vitamin B12 (methylcobalamin), and vitamin B6 (pyridoxal-5'-phosphate) for 24 weeks does not improve neural dysfunction based on vibration perception when compared with placebo in patients with diabetic neuropathy. However, taking this combination appears to modestly improve neuropathy symptoms and quality of life related to mental functioning when compared with placebo (90375).
• Dysmenorrhea. It is unclear if oral vitamin B6 is beneficial in patients with dysmenorrhea. Details: Preliminary clinical research shows that taking vitamin B6 (form not specified) 200 mg daily reduces pain associated with dysmenorrhea when compared with placebo. However, taking vitamin B6 in combination with magnesium does not reduce pain when compared with placebo (77388).
• Fibromyalgia. It is unclear if oral vitamin B6 is beneficial in patients with fibromyalgia. Details: A small clinical study in patients with fibromyalgia shows that taking vitamin B6 80 mg daily for 8 weeks does not improve pain, disease severity, anxiety, depression, or quality of life when compared with placebo (110454).
• Gastroenteritis-associated nausea and vomiting. It is unclear if oral vitamin B6 is beneficial in children with gastroenteritis. Details: A small clinical study in children aged 6 months to 12 years with acute viral gastroenteritis shows that taking vitamin B6 (form not specified) does not improve symptoms of dehydration or the frequency of vomiting when compared with placebo (90793).
• Helicobacter pylori. It is unclear if oral vitamin B6 is beneficial for Helicobacter pylori. Details: A large clinical study in adults with Helicobacter pylori infection shows that taking vitamin B6 20 mg twice daily for 2 weeks alongside conventional quadruple therapy does not improve eradication rates when compared with a control group not receiving vitamin B6 (113551). Conventional therapy consisted of a proton pump inhibitor, bismuth, minocycline, and metronidazole. The validity of this study is limited by the lack of placebo and inadequate blinding.
• Hypertension. It is unclear if oral vitamin B6 reduces blood pressure. Details: One small clinical study in patients with essential hypertension shows that taking vitamin B6 (pyridoxine hydrochloride) 5 mg/kg daily for 4 weeks can reduce systolic and diastolic blood pressure when compared with baseline (83091). The validity of this finding is limited by the lack of a control group.
• Hypertriglyceridemia. It is unclear if oral vitamin B6 reduces triglyceride levels. Details: Preliminary clinical research shows that vitamin B6 (form not specified) 50 mg daily for 12 weeks does not reduce triglyceride levels in people with hypertriglyceridemia when compared with placebo. However, vitamin B6 appears to decrease total cholesterol and high-density lipoprotein (HDL) cholesterol by approximately 9% in these patients (59028).
• Infertility. Although there is interest in using oral vitamin B6 for infertility, there is insufficient reliable information about the clinical effects of vitamin B6 for this condition.
• Insomnia. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in healthy adults with self-reported sleep difficulty shows that taking a specific product (LZ Complex3, Sanofi Consumer Healthcare Pty Ltd.) containing vitamin B6, zizyphus extract, hops extract, hydrolyzed milk protein (Lactium), and magnesium oxide nightly, 30 minutes before bed, for 2 weeks does not improve sleep quality, daytime functioning, or physical fatigue when compared with placebo. However, due to the large improvement seen in both the treatment and placebo groups, the effectiveness of this product is unclear (95971).
• Isoniazid-induced neuropathy. It is unclear if oral vitamin B6 prevents the development of neuropathy in patients taking isoniazid. Details: Preliminary clinical research in patients taking isoniazid for tuberculosis shows that taking vitamin B6 (pyridoxine) 6 mg daily reduces the development of neuropathy when compared with control (83068).
• Lactation. It is unclear if oral vitamin B6 helps to suppress postpartum lactation. Details: A meta-analysis of two small clinical trials shows that taking vitamin B6 (pyridoxine) 400-600 mg daily for 6-7 days postpartum does not suppress lactation when compared with no treatment (83047).
• Levetiracetam-induced side effects. While some conflicting evidence exists, several small, low-quality studies suggest that oral vitamin B6 (pyridoxine) may reduce some neuropsychiatric adverse effects related to the use of levetiracetam. Details: In an analysis of case reports, retrospective studies, and a single low-quality prospective study, improvement in levetiracetam-associated neuropsychiatric symptoms occurred in approximately 73% of patients taking pyridoxine (107137). A more recent preliminary clinical trial in children ages 1-17 years shows that taking pyridoxine 10 or 15 mg/kg daily as needed based on symptoms improves behavioral side effects associated with levetiracetam by a small amount when compared with low-dose pyridoxine 0.5 mg/kg daily used as placebo (107124). Also, observational research in children ages 9 months to 14 years has found that taking vitamin B6 is associated with improved behavior and a 44% lower risk of levetiracetam discontinuation when compared with no vitamin B6 supplementation (110455). Some observational research in adults with levetiracetam-associated irritability has found that taking vitamin B6 is associated with an improvement in irritability in 45% of patients when compared to baseline (107129). However, a small clinical trial in adults with epilepsy shows that taking pyridoxine 40 mg daily for 3 weeks does not improve levetiracetam-related psychiatric adverse effects when compared with placebo (110456). This study may have been underpowered to detect differences between groups. Pyridoxine doses used in the studies above have ranged from 50-400 mg daily in children and 40-600 mg daily in adults (107124,107129,107137,110456).
• Lung cancer. It is unclear if dietary or oral vitamin B6 reduces lung cancer risk. Details: Epidemiological research has found that higher serum levels of vitamin B6 in male smokers is associated with a lower risk of lung cancer (9454). Also, people with blood levels of vitamin B6 in the top quartile have a modestly lower risk of lung cancer when compared with those whose levels are in the lowest quartile. The association is stronger for males and for people who have smoked (97999). However, other epidemiological research found that increased dietary intake of vitamin B6 is not associated with a reduced risk of lung cancer (96164).
• Menopausal symptoms. Although there is interest in using oral vitamin B6 for menopausal symptoms, there is insufficient reliable information about the clinical effects of vitamin B6 for this condition.
• Motion sickness. Although there is interest in using oral vitamin B6 for motion sickness, there is insufficient reliable information about the clinical effects of vitamin B6 for this condition.
• Nausea and vomiting. It is unclear if oral vitamin B6 is beneficial for nausea and vomiting in patients taking oral contraceptives or antibiotics for Helicobacter pylori. Details: A large clinical study in adults with Helicobacter pylori infection shows that taking vitamin B6 20 mg twice daily for 2 weeks alongside conventional quadruple therapy reduces the incidence and severity of gastrointestinal adverse effects when compared with a control group not receiving vitamin B6 (113551). Conventional therapy consisted of a proton pump inhibitor, bismuth, minocycline, and metronidazole. The validity of this study is limited by the lack of placebo and inadequate blinding. An observational longitudinal study in healthy females taking oral contraceptives containing ethinyl estradiol and levonorgestrel has found that taking vitamin B6 25 mg daily for 6-12 months is associated with a 43% reduced risk of nausea when compared with no supplementation (90789).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral vitamin B6 for patients with NAFLD. Details: A small clinical trial in patients with NAFLD shows that taking vitamin B6 (pyridoxine) 30 mg three times daily for 12 weeks does not reduce levels of liver transaminases or plasma lipids when compared with baseline. However, hepatic fat accumulation was modestly reduced (107130). The validity of this study is limited by the lack of a comparator group.
• Obesity. It is unclear if oral vitamin B6 in beneficial in overweight or obese individuals. Details: A small clinical trial in females with a body mass index (BMI) of at least 25 kg/m² shows that taking vitamin B6 as pyridoxine 80 mg daily for 8 weeks reduces fat mass and improves insulin resistance and triglyceride levels by a small amount when compared with placebo. Although some other anthropometric and metabolic indices were improved when compared with baseline, there was no effect of pyridoxine on body weight, visceral adiposity, or other endpoints when compared with placebo (107131).
• Overall mortality. It is unclear if oral vitamin B6 reduces the risk of overall mortality. Details: Observational research in US adults has found that dietary intake of vitamin B6 in the highest quintile is associated with a 12% to 21% lower risk of all-cause mortality and a 31% to 44% lower risk of cardiovascular mortality when compared with the lowest quintile of dietary vitamin B6 intake (110451).
• Pancreatic cancer. It is unclear if oral vitamin B6 reduces the risk of pancreatic cancer. Details: Observational research has found that higher dietary intake of vitamin B6 is associated with a 37% lower risk of developing pancreatic cancer when compared with lower intake (104927).
• Postpartum depression. It is unclear if oral vitamin B6 is beneficial in patients with postpartum depression. Details: Preliminary clinical research in individuals considered at increased risk for postpartum depression, but without clinical depression, shows that taking vitamin B6 80 mg daily from the 28th week of pregnancy until birth, and then 40 mg daily for one month, reduces symptoms of depression 1.5 months after birth when compared with baseline (measured during the third trimester) and when compared with placebo. However, it is unclear if any of the patients included in the study developed postpartum depression, as there were no changes in overall symptoms in patients taking placebo (107126).
• Proton pump inhibitor-induced gastrointestinal (GI) symptoms. It is unclear if oral vitamin B6 is beneficial for proton pump inhibitor-induced GI symptoms. Details: A large clinical study in adults with Helicobacter pylori infection shows that taking vitamin B6 20 mg twice daily for 2 weeks alongside conventional quadruple therapy reduces the incidence and severity of gastrointestinal adverse effects when compared with a control group not receiving vitamin B6 (113551). Conventional therapy consisted of a proton pump inhibitor, bismuth, minocycline, and metronidazole. The validity of this study is limited by the lack of placebo and inadequate blinding.
• Restless legs syndrome (RLS). It is unclear if oral vitamin B6 is beneficial in patients with RLS. Details: A small clinical study in adults with RLS who are beginning treatment with pramipexole shows that also taking vitamin B6 40 mg daily for 2 months moderately improves RLS scores and sleep quality scores when compared with pramipexole and placebo (110052).
• Schizophrenia. It is unclear if oral vitamin B6 is beneficial for patients with treatment-resistant schizophrenia. Details: Clinical research in male patients with treatment-resistant schizophrenia who are on a consistent antipsychotic dose shows that adding vitamin B6 300 mg twice daily for 16 weeks modestly improves psychotic symptoms and some measures of cognitive performance when compared with adding aripiprazole 5 mg twice daily (107128). More research is needed to determine if these benefits are clinically relevant.
• Seizures. It is unclear if oral vitamin B6 is beneficial for preventing seizures in patients with glycosylphosphatidylinositol (GPI) deficiency. Details: Observational case series in a small number of children and young adults with GPI deficiency has found that taking vitamin B6 20-30 mg/kg daily for 3-12 months is associated with some reduction in seizure frequency in 9 of 13 patients. However, no patient reached seizure freedom (107125,107135). In one case series, treatment for 12 months was associated with modest developmental improvements in almost all patients (107135). The study patient populations were slightly different in terms of age and underlying genetic causes for GPI deficiency.
• Sickle cell disease. Oral vitamin B6 has only been evaluated in combination with other B vitamins; its effect when used alone is unclear. Details: Preliminary clinical research in adults with sickle cell disease shows that taking vitamin B6 4.2-6 mg, vitamin B12 4.2-6 mcg, and folic acid 700 mcg daily might lower homocysteine levels. However, it is unknown if this will reduce the risk of endothelial damage in these patients (9324).
• Stroke. It is unclear if oral vitamin B6, either alone or with other B vitamins, is beneficial for stroke prevention. Details: There is some debate about whether supplementation with homocysteine-lowering B vitamins, including vitamin B6, can reduce the risk of stroke. A number of clinical studies and meta-analyses show that supplementation with folic acid, vitamin B6, and vitamin B12, alone or in combination, does not reduce the risk of stroke in patients with cardiovascular disease (CVD) or impaired kidney function (11387,13482,50423,83050,96150). However, a more recent meta-analysis of 10 clinical trials, including over 44,000 patients at risk for or with a history of CVD, shows that B vitamin supplementation reduces the relative risk of stroke by 10% when compared with placebo (97619). This meta-analysis differed from some of the earlier analyses due to the inclusion of several additional clinical trials. Also, another meta-analysis of three clinical trials including 9900 patients with a history of stroke shows that B vitamin supplementation reduces the relative risk of stroke recurrence by 13% when compared with placebo, although this finding was determined to have a low level of certainty. Based on two clinical trials, there was also a 17% reduced risk of vascular death and an 11% reduction in the combined risk of stroke, myocardial infarction, and vascular death (107136). In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) allowed a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368). Unfortunately, even after the publication of higher quality research, it is still unclear which specific combination of B vitamins is optimal and which patients are most likely to benefit. One network meta-analysis shows that a combination of folic acid and vitamin B6 lowers the risk of stroke more effectively than B vitamin mixtures that include vitamin B12 (96165). However, this analysis is limited because it didn't account for dosing. Exposure to low, but not high amounts, of vitamin B12 (cyanocobalamin) seems to reduce stroke risk (96150).
• Tardive dyskinesia. It is unclear if oral vitamin B6 prevents tardive dyskinesia in patients taking neuroleptic drugs. Details: A small clinical study in patients taking neuroleptic drugs for schizophrenia shows that taking vitamin B6 (form not specified) 400 mg daily seems to improve Parkinsonian, dystonic, and dyskinetic symptoms when compared with placebo (8558).
• Tourette syndrome. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small, nonblinded clinical study in children aged 4-17 years with untreated Tourette syndrome or with chronic tic disorder and associated symptoms of anxiety shows that taking a liquid nutritional supplement providing vitamin B6 2.8 mg and L-theanine 200 mg daily for 2 months improves scores on the Yale Global Tic Severity Scale, but does not reduce anxiety, when compared with patients receiving psychoeducation (108555). This study may have been inadequately powered to detect a difference between groups.
• Vincristine-induced neuropathy. Oral vitamin B6 has only been evaluated in combination with pyridostigmine; its effect when used alone is unclear. Details: A small clinical study in children ages 11 months to 13 years with neuropathy due to vincristine treatment for acute lymphoblastic leukemia, shows that taking vitamin B6 150 mg/m2 and pyridostigmine 3 mg/kg twice daily for 3 months is associated with reduced severity of sensory and motor neuropathy when compared with baseline (104928). The validity of this finding is limited by the lack of a control group. More evidence is needed to rate vitamin B6 for these uses.

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EFFECTIVE

• Vitamin C deficiency. Oral or intramuscular vitamin C is effective for preventing or treating vitamin C deficiency. Details: Administering vitamin C orally or intramuscularly prevents and treats vitamin C deficiency, including scurvy. Vitamin C administration can reverse complications of scurvy within 2 days to 3 weeks (4844). In newborns with transient tyrosinemia due to vitamin C deficiency, oral or intramuscular vitamin C can correct this condition (15).

POSSIBLY EFFECTIVE

• Anemia of chronic disease. Oral vitamin C seems to improve markers of anemia in patients on hemodialysis. Details: Meta-analyses of clinical research in hemodialysis patients with anemia shows that treatment with vitamin C 200-300 mg three times weekly for 3-6 months increases hemoglobin levels by approximately 0.9 grams/dL, increases transferrin saturation by about 8%, and decreases the required recombinant human erythropoietin dose by 17 U/kg weekly when compared with standard care (83447,83475).
• Atrial fibrillation. Oral and intravenous vitamin C seems to help prevent atrial fibrillation after cardiac surgeries. Details: Meta-analyses of clinical research show that taking vitamin C prior to and after cardiac surgery reduces the risk of postoperative atrial fibrillation by 27% to 53%. Most studies administered vitamin C at doses of 1-2 grams orally daily for 1-3 days prior to cardiac surgery, followed by 1-2 grams in two divided doses daily for 4-5 days after cardiac surgery. Some studies provided vitamin C intravenously at similar doses, but oral vitamin C seems to be more effective (91233,96703,96705). Despite these findings, a meta-analysis of clinical research conducted only in the U.S. does not support the benefit of vitamin C for reducing postoperative atrial fibrillation (96703). These differences may be related to lifestyle factors such as nutrition, as well as differences in hospital treatments. Vitamin C has also been studied in combination with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) with evidence of benefit (90701).
• Bowel preparation. Powdered vitamin C is approved for use as part of a polyethylene glycol-based bowel preparation for colonoscopy. Details: Clinical research shows that treatment with 2 liters of oral solution containing polyethylene glycol (PEG) plus vitamin C achieves a similar quality of bowel cleansing as treatment with 4 liters of PEG when administered on the evening prior to colonoscopy or when administered in a split-dose regimen. Patients given 2 liters of PEG plus vitamin C solution also have better adherence and experience fewer adverse events, such as nausea, vomiting, or abdominal bloating, compared to patients treated with 4 liters of PEG solution without vitamin C (90413,90415,90420,90424,90428). This treatment also appears to be effective and tolerable in elderly patients aged 60-79 years, including those with poor bowel habits and a high number of comorbidities (108085). Other clinical research in older adults undergoing bowel preparation for colonoscopy also shows that taking 1 liter of PEG plus vitamin C (CleanViewAL, Taejoon Pharm) results in similar quality of bowel cleansing overall and per segment with similar tolerability and adverse effects as sodium picosulfate 170 mL plus magnesium citrate or oral sulfate solution alone (111297,112476). The most common PEG plus vitamin C preparation used in clinical research is MoviPrep (Norgine BV), which contains macrogol 3350 100 grams, sodium sulfate 7.5 grams, sodium chloride 2.7 grams, potassium chloride 1 gram, vitamin C 4.7 grams, and sodium ascorbate 5.9 grams per liter of solution (90413,90415,90424). In the U.S., MoviPrep is approved by the Food and Drug Administration (FDA) for bowel preparation prior to a colonoscopy.
• Cataracts. Dietary and supplemental intake of vitamin C may reduce the risk of developing cataracts. Details: Population research suggests that people with the highest total intake of vitamin C have about a 19% reduced risk of developing cataracts when compared with those with the lowest total intake, with the most benefit observed for nuclear cataracts (96711). Additionally, another observational study shows that higher supplemental intake of vitamin C over 10 years is associated with a 60% reduction in the incidence of nuclear and cortical cataracts (4208). Other population research suggests that individuals with the highest blood levels of vitamin C have a 33% lower odds of developing age-related cataract, but any benefit is limited to Asian populations (90944). An umbrella review of meta-analyses also shows that dietary intake of vitamin C is associated with a 27% lower odds of cataract development (112095). However, a prospective clinical study shows that a combination of vitamin C, vitamin E, and beta-carotene does not prevent age-related loss of vision from cataracts in well-nourished people with an average supplementation duration of 6.3 years (7304).
• Common cold. Oral high-dose vitamin C might modestly shorten and reduce cold symptoms; however, taking vitamin C prophylactically does not seem to prevent the development of a cold. Details: There is substantial controversy about the effectiveness of vitamin C for treating the common cold (1969,1989,7100,9835,9836). The majority of evidence shows that taking high doses of vitamin C orally might decrease the duration of cold symptoms by 1-1.5 days in some patients (1966,1967,1968,1987,6458,7102,9832,83487). However, other studies have found no effect with doses up to 3 grams daily (9833). A meta-analysis of clinical research in healthy children and adults shows that taking vitamin C 1-4 grams daily for one week to 5 months reduces cold severity by 13%, limits absences from daily activities, and improves the duration of severe symptoms, but does not reduce the duration of mild symptoms, when compared with placebo (113665). Vitamin C has also been investigated for preventing the common cold. A meta-analysis of clinical research suggests that vitamin C supplementation decreases the incidence of cold in individuals exposed to physical stress, but not in the general population (83487). Other research suggests vitamin C may be more effective for treating cold symptoms in children than in adults. Also, there may be a dose-dependent response; doses of at least 2 grams daily seem to work better than 1 gram doses (9834). Taking vitamin C supplements prophylactically does not decrease the risk of catching a cold (1966,1967,1968,1987,3042,6458,7101,9832). Dietary intake of vitamin C also does not seem to affect the risk of getting a cold (10780).
• Complex regional pain syndrome. Most research shows that taking oral vitamin C after a distal radius (i.e. wrist) fracture or surgery seems to reduce the risk of developing complex regional pain. However, it is unclear if oral vitamin C is beneficial in reducing the risk of complex regional pain in other orthopedic surgeries. Details: Although some research has found no benefit in patients with distal radius (i.e. wrist) fractures (90411,96702), most clinical research shows that taking vitamin C 500 mg daily, and possibly doses of up to 1500 mg daily, for 45-50 days beginning immediately after fracture can reduce the risk of developing complex regional pain syndrome (2045,16302,96700,96706). Reasons for discrepancies are unclear but might relate to differences in diagnostic criteria for complex regional pain syndrome (96702). Research in patients undergoing various orthopedic surgeries has also shown benefit with the use of vitamin C for the prevention of complex regional pain syndrome; however, some findings are conflicting. (90422,108076,115613). One meta-analysis of clinical research in patients undergoing ankle, foot, or wrist surgery shows that taking vitamin C 500-1000 mg for 42-50 days following surgery reduces the rate of complex regional pain syndrome, and may improve pain following ankle or foot surgery, when compared with placebo (108076). The validity of these findings is limited by the high heterogeneity of included trials. An additional meta-analysis of clinical research in patients undergoing a broader variety of orthopedic surgery types (i.e., ankle, foot, knee, shoulder, wrist) shows that taking vitamin C 500 to 1500 mg does not reduce the incidence of complex regional pain syndrome (115613). The reasons for these discrepant findings are unclear but may relate to the inclusion of a wide range of orthopedic surgeries.
• Exercise-induced respiratory infections. High-dose oral vitamin C seems to reduce the risk of respiratory infections associated with strenuous exercise. Details: Some preliminary clinical research suggests that prophylactic use of vitamin C in doses of 600 mg to 1 gram daily for 3-8 weeks before heavy physical exercise, such as a marathon, might prevent upper respiratory infections that sometimes follow heavy exercise (9831,83370). More recently, high doses of vitamin C have been studied. A large clinical study in army recruits undergoing basic military training shows that taking vitamin C 6 grams daily for one month reduces the odds of getting a cold by 20% when compared with placebo (102975).
• Hypercholesterolemia. Oral vitamin C seems to reduce lipid levels in patients with hypercholesterolemia. Details: A meta-analysis of clinical research in patients with hypercholesterolemia shows that taking vitamin C 500 mg daily for at least 4 weeks reduces low-density lipoprotein (LDL) cholesterol by about 8 mg/dL and reduces triglycerides by about 20 mg/dL when compared with control (83445).
• Hypertension. Oral vitamin C seems to modestly reduce blood pressure in patients with hypertension, but some evidence is conflicting. Details: Vitamin C seems to modestly reduce systolic blood pressure (SBP), without meaningful effects on diastolic blood pressure (DBP) (2044,9822,13162,83483,102974). A meta-analysis of 13 clinical trials in patients with hypertension, with or without other comorbidities, shows that taking a median dose of vitamin C 500 mg daily for 8 weeks reduces SBP but not DBP by about 5 mmHg. Some of the studies used vitamin C in combination with other supplements, such as vitamin E and magnesium. When studies assessing vitamin C alone were analyzed, the magnitude of reduction in SBP decreased (83483). A newer meta-analysis of small clinical studies in patients with essential hypertension shows that taking vitamin C 200 mg or more daily reduces SBP by about 4 mmHg and DBP by about 2 mmHg (102974). However, this newer analysis omitted numerous relevant studies and included studies with normotensive patients and those without an adequate control, limiting the validity of its findings. In contrast, a network meta-analysis of small, low-quality clinical studies comparing five different vitamins in adults with essential hypertension shows that vitamin C does not reduce SBP, DBP, mean 24-hour SBP, mean 24-hour DBP, or heart rate when compared with placebo and when indirectly compared with vitamin B2, vitamin D, vitamin E, and folic acid. However, the included studies were of low quality and high heterogeneity, particularly in dosing, limiting the validity of the results (113668).
• Laser skin resurfacing. Topical vitamin C seems to reduce erythema occurring after cosmetic laser skin resurfacing procedures intended to reduce scars and wrinkles. Details: There is some evidence that an aqueous formulation of topical vitamin C can decrease the degree and duration of erythema following cutaneous carbon dioxide laser resurfacing for scar and wrinkle removal (1959).
• Lead toxicity. Dietary vitamin C seems to lower concentrations of lead in the blood. Details: Observational research has found that consuming more vitamin C from dietary sources is associated with lower blood concentrations of lead. People who consumed at least 340 mg of vitamin C daily as part of the diet had lower blood lead levels than those who consumed less than 100 mg vitamin C daily (3097,3098,3099).
• Nitrate tolerance. Oral vitamin C might prevent nitrate tolerance in some patients. Details: Small clinical studies show that taking vitamin C orally seems to prevent the development of nitrate tolerance in patients taking sublingual nitroglycerin. There is some evidence that short-term vitamin C supplementation can prevent tolerance to the vasodilatory effects of nitrates (1441,1961).
• Postoperative pain. Oral or intravenous vitamin C might prevent acute postoperative pain following certain surgeries. It is unclear if vitamin C reduces chronic postoperative pain. Details: A meta-analysis of 7 small clinical studies in adults undergoing elective surgery shows that receiving perioperative vitamin C, either as 1 gram orally, 2-3 grams intravenously, or 50 mg/kg intravenously, modestly reduces acute pain and opioid requirements for up to 24 hours when compared with control (105457). Most surgeries were laparoscopic and included cholecystectomy, colectomy, hysterectomy; two non-laparoscopic surgeries included uvulopalatopharyngoplasty with tonsillectomy and major abdominal surgery (90418,99840,105457). A meta-analysis of clinical trials in adults undergoing noncardiac surgery (i.e., orthopedic, abdominal, gynecologic, kidney transplantation) shows that administering perioperative vitamin C, either orally or intravenously, reduces postoperative intravenous morphine requirements at 2, 24, and 48 hours after surgery and improves pain scores at 2, 6, and 24 hours after surgery when compared with placebo. The dose of vitamin C did not appear to impact outcomes. However, when only laparoscopic surgeries are included, perioperative vitamin C does not improve pain or morphine use when compared with placebo (108087). Use of vitamin C perioperatively has also been evaluated in other surgery types with generally similar outcomes. A moderate-sized clinical study in adults undergoing total hip arthroplasty shows that intravenous vitamin C 3 grams perioperatively reduces 24-hour post-operative morphine use and subjective pain scores when compared with placebo; however, these improvements do not appear to be clinically significant (115500). The validity of these results is limited by a short follow-up period. Additionally, a small observational study in adults undergoing surgery for wisdom tooth extraction shows that taking vitamin C 500 mg three times daily for 7 days in addition to standard treatment reduces pain 24, 48, and 72 hours after surgery when compared with control (113664). However, a moderate-sized clinical study in adults undergoing transurethral resection of a bladder tumor under general anesthesia shows that administering intravenous vitamin C 1 gram after induction of anesthesia reduces the incidence and severity of catheter-related bladder discomfort immediately after surgery and at 1 and 2 hours postoperatively, but not 6 hours, when compared with placebo. Further, vitamin C does not reduce postoperative pain scores or analgesic requirements when compared with placebo (111645). Vitamin C has also been evaluated for reducing chronic pain after surgery. Clinical research in patients undergoing surgery for foot or ankle trauma shows that taking vitamin C 500 mg orally twice daily postoperatively for 6 weeks reduces pain scores when compared with placebo at 2 weeks and 6 weeks. The mean total amount of diclofenac used for pain relief over the 6-week period is also reduced, from 5.7 grams with placebo to 3.4 grams with vitamin C (102131).
• Wrinkled skin. Topical vitamin C might reduce the appearance of existing wrinkles. Details: Topical preparations containing vitamin C seem to improve the appearance of wrinkled skin. Some evidence shows that vitamin C 3% applied for 12 weeks might reduce facial wrinkles (14008). A small clinical study shows that applying a dissolving microneedle patch containing vitamin C 5.6% every 4 days for 12 weeks to crow's feet on one side of the face reduces wrinkles when compared to control treatment applied on the other side of the face (98780). Other clinical research in females aged 30-60 years shows that applying an oil-soluble cream containing the vitamin C derivative tetra-isopalmitoyl ascorbic acid 1%, 2%, or 3% to the periorbital area twice daily for 8 weeks reduces visual wrinkle grading when compared with placebo. A dose analysis shows greater improvements in wrinkle parameters, average wrinkle depth, and mean depth with the lower concentration, while greater improvements in maximum roughness and maximum depth are observed with the higher concentration (108072). This study only included individuals defined as having Fitzpatrick skin type III or IV; it effects on other skin types is unclear. Preparations containing vitamin C in combination with other ingredients have also been investigated. A small low-quality trial in females with moderately photodamaged and hyperpigmented facial skin shows that applying a moisturizer with vitamin C 30%, vitamin E, and coenzyme Q10 once daily in the morning, along with applying retinol 0.5% once daily or once every other day for 12 weeks, seems to improve skin tone, photodamage, and wrinkles when compared to baseline (99085). In another small trial, a topical preparation containing vitamin C 10% as L-ascorbic acid along with acetyl tyrosine, zinc sulfate, sodium hyaluronate, and bioflavonoids (Cellex-C High Potency Serum) applied to photo-aged facial skin for 3 months improves fine and coarse wrinkling, yellowing and sallowness, roughness, and skin tone when compared with placebo (6155). It is unclear if the beneficial effects of these products are due to vitamin C, other ingredients, or the combination.

POSSIBLY INEFFECTIVE

• Acute bronchitis. Oral vitamin C doesn't seem to improve symptoms of acute bronchitis. Details: A clinical study in adults with acute bronchitis shows that taking vitamin C orally 500 mg on day 1, then 250 mg on days 2 through 5 (similar to an azithromycin regimen) doesn't seem to have any effect on quality of life or bronchitis duration when compared with azithromycin (9827).
• Asthma. Oral vitamin C doesn't seem to prevent asthma or improve lung function. Details: Although some observational research has found that some patients with asthma might have lower serum vitamin C levels (5873), other observational research found that increased dietary vitamin C intake is not associated with a reduced risk of asthma or improved lung function (15006,34567). In addition, clinical research shows that supplemental intake of vitamin C does not reduce asthma symptoms, improve lung function, or reduce the use of inhaled steroids in asthma patients (90409).
• Atherosclerosis. Oral vitamin C does not seem to reduce the progression of atherosclerosis. Details: A clinical study shows that taking a specific combination product containing slow-release vitamin C 250 mg and vitamin E 136 IU (CellaVie, Ferrosan A/S) twice daily modestly slows the 3-year progression of atherosclerosis of the carotid artery in males, but not females. This result persisted at a 6-year follow-up of this study (1918,10473). However, when this form of vitamin C is used alone, it does not slow the 3-year progression of atherosclerosis of the carotid artery (1918).
• Bladder cancer. Oral vitamin C does not reduce the risk of bladder cancer or mortality from bladder cancer. Details: Epidemiological research has found that supplemental vitamin C intake is not associated with mortality rate in patients with bladder cancer (9839). A secondary analysis of a large clinical trial, the Physicians' Health Study II, in healthy men aged at least 50 years also shows that taking vitamin C 500 mg daily alone or with vitamin E 400 IU daily for up to 10 years does not reduce the risk of developing bladder cancer or bladder cancer-related deaths when compared with placebo (90097).
• Cardiovascular disease (CVD). Oral vitamin C does not seem to be beneficial for either primary or secondary CVD prevention. Details: Vitamin C does not seem to be beneficial for primary prevention of CVD. Some population research has found that higher supplemental vitamin C or dietary vitamin C has been associated with a reduced risk of developing CVD (10358,14108,109779), while other observational research has found no benefit (34566,10358,14108). However, meta-analyses of clinical research in healthy patients show that vitamin C supplementation does not prevent CVD or coronary heart disease when compared with control (97308,104025). In 2004, the American Heart Association stated that current evidence does not justify use of antioxidants such as vitamin C for reducing the risk of CVD (12142). Evidence is also negative for secondary prevention in people with coronary heart disease. Population studies have found that higher serum vitamin C was associated with no effect or decreased CVD mortality from CVD (3910,5878). A meta-analysis of two large clinical trials shows that vitamin C supplementation does not reduce CVD events or CVD mortality when compared with control (97308).
• Colorectal cancer. Oral vitamin C does not seem to prevent colorectal cancer. Details: Population research has found that dietary vitamin C intake is not associated with a reduced risk of developing colon cancer. When total vitamin C intake from food and supplements is considered, there is a modest association (34600). However, most clinical trials show that supplemental vitamin C, alone or along with other antioxidants, does not reduce the risk of colorectal cancer development, colorectal cancer or adenoma recurrence, or colorectal cancer-related mortality (34580,34581,34594,90097,90089,92903).
• Fetal and premature infant mortality. Oral vitamin C does not seem to prevent neonatal death. Details: Meta-analyses of clinical research show that taking vitamin C alone or with other supplements does not reduce the risk of neonatal death (83472,96707).
• Fractures. Oral vitamin C does not seem to improve fracture healing. Details: Clinical research shows that taking vitamin C 500 mg daily for 50 days following an acute distal radial fracture does not improve physical function, symptoms, or healing rates when compared with placebo (90411).
• Helicobacter pylori. Oral vitamin C does not seem to improve eradication of H. pylori. Details: Most clinical research shows that treatment with vitamin C, alone or in combination with vitamin E, does not improve the eradication rate of H. pylori when taken with a standard eradication regimen when compared with the eradication regimen alone (83476,90094).
• Hereditary motor and sensory neuropathy. Oral vitamin C does not seem to improve neuropathy in these patients. Details: In a meta-analysis of five studies in patients with Charcot-Marie-Tooth disease type 1A, taking vitamin C 1-4 grams orally daily for 1 year did not improve neuropathy when compared with placebo (99084). Continuing vitamin C 4 grams daily for 2 years also does not improve neuropathy in these patients (90419).
• Interferon-related retinopathy. Oral vitamin C does not seem to improve retinopathy associated with interferon therapy. Details: A small clinical study in patients with chronic hepatitis C receiving interferon therapy shows that taking vitamin C 600 daily orally does not seem to reduce the risk of retinopathy from interferon therapy when compared with control (10355).
• Leukemia. Oral vitamin C does not seem to reduce the risk of leukemia or mortality from leukemia. Details: A large clinical trial in men aged at least 50 years shows that taking vitamin C 500 mg daily, alone or along with vitamin E 400 IU daily, for up to 10 years does not reduce the risk of developing leukemia or leukemia-related deaths when compared with placebo (90097).
• Low birth weight. Oral vitamin C does not seem to reduce the risk of infants being born with a low birth weight. Details: Meta-analyses of clinical research show that maternal use of oral vitamin C alone or with other supplements does not reduce the risk of giving birth to infants with low birth weight when compared with control (83450,83472).
• Lung cancer. Oral vitamin C does not seem to reduce the risk of lung cancer. Details: Two meta-analyses of clinical research suggest that taking vitamin C, alone or in combination with vitamin E, does not reduce the incidence of lung cancer or lung cancer-related mortality (34528,34632). Also, a clinical study in females shows that taking supplemental vitamin C 500 mg daily, with or without vitamin E and beta carotene, is associated with an INCREASED risk of lung cancer when compared with placebo (34580). However, another large epidemiological cancer screening trial with a mean follow-up of over 12 years suggests that moderate dietary intake of vitamin C around 500 mg daily is protective against lung cancer, but higher doses of vitamin C might increase the risk of lung cancer (112096).
• Melanoma. Oral vitamin C does not seem to reduce the risk of melanoma. Details: Clinical research shows that taking vitamin C 500 mg daily, alone or along with vitamin E 400 IU daily, for up to 10 years does not reduce the risk of developing melanoma or melanoma-related deaths when compared with placebo in men aged at least 50 years (90097).
• Miscarriage. Oral vitamin C does not seem to reduce the risk of miscarriage. Details: A meta-analysis of clinical research shows that taking vitamin C alone or with other supplements does not reduce the risk of miscarriage when compared with control (94820).
• Overall mortality. Oral vitamin C does not reduce overall mortality. Details: Although population research suggests that higher dietary intake and higher plasma vitamin C levels are associated with a reduced risk of mortality from all causes (3910,109779), vitamin C supplementation does not seem to affect overall mortality. Meta-analyses of clinical research show that taking vitamin C supplements does not reduce overall mortality when compared with control (34622,111641). Clinical studies of vitamin C used in combination with vitamin E, beta carotene, and/or selenium and zinc, also show no benefit for overall mortality (9817,14109).
• Pancreatic cancer. Oral vitamin C does not seem to prevent pancreatic cancer. However, it is unclear if intravenous vitamin C is beneficial for treatment of pancreatic cancer. Details: Observational research has found that increased dietary vitamin C intake is associated with up to a 30% reduced risk of pancreatic cancer (99083,99086). However, clinical research shows that supplemental vitamin C 500 mg daily does not reduce the risk of pancreatic cancer in females (34580). Also, taking vitamin C in combination with beta-carotene plus vitamin E does not reduce the risk of pancreatic cancer (12185,34581). While research suggests oral vitamin C may not prevent pancreatic cancer, intravenous vitamin C is being explored in the treatment of pancreatic cancer. A small, open-label clinical study in adults with stage IV pancreatic ductal adenocarcinoma shows that administration of intravenous vitamin C 75 grams three times weekly throughout each cycle of chemotherapy increases median overall survival and progression free survival by approximately 8 months and 2 months, respectively, when compared with chemotherapy alone (115499). The validity of these results is limited by potential overestimation of treatment effects, influenced by small sample size, differences in chemotherapy doses, and early study termination.
• Pre-eclampsia. Oral vitamin C does not seem to prevent pre-eclampsia. Details: Despite some early positive research in high-risk pregnancies, the majority of meta-analyses and clinical studies show that taking vitamin C alone or with vitamin E or other supplements does not reduce the risk of pre-eclampsia when compared with control. There is even some concern that vitamin C supplementation may increase the risk of gestational hypertension (3236,83450,83472,83474,96707).
• Preterm labor. Oral vitamin C does not seem to prevent preterm labor. Details: Meta-analyses of clinical research show that taking vitamin C alone or with other supplements does not reduce the risk of preterm labor when compared with control (83450,83472,96707).
• Prostate cancer. Oral vitamin C does not seem to prevent prostate cancer. However, it is unclear if intravenous vitamin C is beneficial for the treatment of prostate cancer. Details: A large-scale clinical study (The SU.VI.MAX study) shows that a combination of vitamin C 120 mg, vitamin E (alpha-tocopherol) 30 mg, beta-carotene 6 mg, selenium 100 mcg, and zinc 20 mg, taken daily for an average of 8 years, does not reduce the risk of prostate cancer overall. However, it might reduce the risk of prostate cancer in those who have normal PSA levels. It does not seem to be beneficial for reducing the risk of prostate cancer in patients with PSA levels above 3 mcg/L (14135). Another large scale study (Physician's Health Study II) shows that taking vitamin C 500 mg daily for an average of 8 years does not significantly reduce the risk of prostate cancer when compared with placebo (16708). Similarly, results from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial seem to show that supplemental or dietary intake of vitamin C does not reduce the risk of prostate cancer when compared to individuals not taking vitamin C (14124). While research suggests oral vitamin C may not prevent prostate cancer, intravenous vitamin C is being explored in the treatment of prostate cancer. A small clinical study in adults with metastatic castration-resistant prostate cancer shows that administration of intravenous vitamin C 1 gram/kg twice weekly in combination with docetaxel for up to 24 weeks does not reduce prostate-specific antigen (PSA) by 50% or more when compared with docetaxel alone (115611). This study may have been underpowered to show a difference between groups.
• Radiation dermatitis. Topical vitamin C does not seem to prevent radiation dermatitis in cancer patients. Details: A small clinical study shows that applying a 10% vitamin C solution does not appear to protect from radiation dermatitis when applied to the scalps of patients treated with radiation for intracranial tumors (789).
• Small for gestational age (SGA). Oral vitamin C does not seem to reduce SGA. Details: Meta-analyses of clinical research show that taking vitamin C alone or with other supplements does not reduce the risk of small for gestational age birth when compared with control (83450,83472).
• Stillbirth. Oral vitamin C does not seem to prevent stillbirth. Details: Meta-analyses of clinical research show that maternal use of vitamin C alone or with other supplements does not reduce the risk of stillbirth when compared with control (83472,96707).

LIKELY INEFFECTIVE

• Coronavirus disease 2019 (COVID-19). Oral vitamin C, even at high doses, does not seem to speed recovery from COVID-19 in non-hospitalized patients. Most studies show that oral or intravenous vitamin C given to patients hospitalized with COVID-19 does not improve organ function or survival, but the evidence is conflicting. It is unclear whether vitamin C is beneficial for long COVID. Details: A clinical study in adult outpatients with confirmed COVID-19 shows that taking oral vitamin C (ascorbic acid) 8000 mg in 2-3 divided doses daily, alone or with zinc gluconate 50 mg daily, for 10 days does not reduce symptom severity when compared with standard care (104450). The study was terminated prior to complete enrollment due to futility and apparent lack of effect from vitamin C and/or zinc supplementation. Limitations of this study include a lack of placebo control and blinding. Additionally, this study has been criticized for methodologic concerns (106624). Another small clinical trial in adult outpatients with confirmed COVID-19 shows that taking vitamin C 1000 mg daily for 14 days does not improve symptoms or quality of life when compared with placebo (109462). Vitamin C has also been evaluated in patients hospitalized with COVID-19. A very large analysis of two multinational clinical studies in critical and non-critical adults hospitalized with COVID-19 shows that administering intravenous vitamin C 50 mg/kg every 6 hours for 96 hours does not improve organ support-free days or survival and has a high probability of futility and worsened outcomes when compared with placebo (113666). Individual prospective and retrospective studies in critically ill patients hospitalized with COVID-19 in various countries have found that administering vitamin C, either enterally as 500-1000 mg daily or intravenously as 8-24 grams daily or 50 mg/kg daily, does not significantly reduce in-hospital or short-term mortality, hospital length of stay, or end-organ failure when compared with control groups receiving standard care alone. Additionally, all but one study found no change in the need for mechanical ventilation (105458,105465,106937,106938,108075,108079,108081). However, a meta-analysis and some small individual studies have found that vitamin C is modestly beneficial for patients hospitalized with COVID-19. A meta-analysis of 10 clinical trials and 9 observational studies in patients hospitalized with COVID-19 shows that receiving oral or intravenous vitamin C daily reduces the odds of in-hospital mortality by 41% when compared with control. When only clinical trials were considered, the odds of in-hospital mortality were decreased by 56%; however, this reduction was only identified in studies using vitamin C 10 grams daily or less. Conversely, supplementation with vitamin C increased the length of intensive care unit (ICU) stay by nearly 2 days and did not impact length of hospital stay or reduce the need for mechanical ventilation, liver injury, or cardiac injury (109955). Similarly, a meta-analysis of 8 clinical studies in primarily hospitalized patients with moderate to severe COVID-19 shows that vitamin C administered orally or intravenously decreases the risk of all-cause mortality by 16% when compared with control (114488). Additionally, a small study found a small improvement in survival when compared with standard care; however, the overall survival rate in this study was low (108075). Another clinical study in patients hospitalized in Turkey with COVID-19 shows that adding high-dose intravenous sodium ascorbate 50 mg/kg to a treatment regimen of hydroxychloroquine, azithromycin, and zinc may improve recovery time, with 57% and 39% of patients achieving total recovery at day 15 in the vitamin C and control groups, respectively (108071). However, the validity of this trial is limited due to unclear reporting. Vitamin C has also been evaluated in combination with other ingredients in patients with long COVID. Preliminary clinical research in adults with long COVID and persistent fatigue shows that taking a specific combination product containing vitamin C 500 mg and L-arginine 1.66 grams (Bioarginina C, Farmacetici Damor) for 28 days increases 6-minute walk test distance by 10% and reduces self-reported fatigue when compared with placebo (110390). However, it is unclear whether these effects are due to vitamin C, L-arginine, or the combination.
• Sepsis. Intravenous vitamin C, alone or in combination with thiamine and/or hydrocortisone, does not prevent organ failure, reduce intensive care or hospital length of stay, or reduce mortality in sepsis or septic shock. Details: Observational research suggests that patients with septic shock are more likely to have low plasma levels of vitamin C (100317). However, three randomized clinical trials in patients with sepsis or septic shock show no benefit with intravenous vitamin C, with or without thiamine, for improving organ function and preventing organ failure when compared with control treatment (102130,104027,114489). A small clinical study in patients with septic shock shows that intravenous vitamin C 50 or 150 mg/kg daily for 4 days does not improve organ dysfunction or failure rates, duration of hospital or intensive care unit (ICU) length of stay, duration of mechanical ventilation, or mortality rate when compared with placebo (114489). Another clinical study in patients with septic shock shows that administering an intravenous bolus of vitamin C 1000 mg followed by a continuous infusion of 250 mg/hour for 96 hours, starting within 24 hours of vasopressor initiation, does not improve 28-day or ICU mortality when compared with placebo. A subgroup analysis shows that the addition of corticosteroids does not affect outcomes in either group (108078). This study may have been inadequately powered to detect a difference between groups. Also, a larger clinical trial in adults with sepsis receiving vasopressor therapy in the ICU shows that intravenous administration of vitamin C 50 mg/kg every 6 hours for up to 4 days increases the risk of death or persistent organ dysfunction at day 28 by 14% to 21% when compared with placebo. There were no differences in mortality at 6 months (109459,111643). Vitamin C has also been frequently studied in patients with sepsis and septic shock in a specific combination regimen (HAT therapy) which includes intravenous vitamin C 1.5-2 grams with hydrocortisone 50 mg every 6 hours and thiamine 200 mg every 12 hours. While some retrospective research has found HAT therapy to be beneficial in sepsis (100315,102980), high quality, prospective clinical research has not confirmed these findings (105447,106620,109956). Several meta-analyses of randomized controlled trials and small clinical studies in patients with sepsis or septic shock show that intravenous vitamin C, either alone, as a component of HAT therapy, or in combination with thiamine, does not reduce short- or long-term mortality, ICU or hospital length of stay, kidney injury, or duration of mechanical ventilation, but modestly improves duration of vasopressor use and procalcitonin clearance, when compared with placebo or standard care. These analyses also show mixed results with respect to improvement in sequential organ failure assessment (SOFA) scores within 72 hours (105447,106620,106935,108073,109460,111298,111300,111301,111642,112479). Most studies included in the analyses administered HAT therapy for 2-10 days and compared it with normal saline control or with hydrocortisone alone (102129,102998,104027,104028,104032,105446). Although some subgroup analyses suggests that intravenous vitamin C alone in patients with sepsis may improve short-term mortality (106620,111298), other meta-analyses have not shown this benefit in subgroup analyses (111300). In addition, meta-analyses have identified significant publication bias (111298,111300). Long-term follow up from a study in patients with sepsis-induced respiratory and/or cardiovascular dysfunction shows that receiving HAT therapy does not improve cognitive, psychological, or functional status after 6 months and, for some domains, HAT therapy was worse when compared with placebo (111299). Studies evaluating intravenous vitamin C, either alone, as a component of HAT therapy, or in combination with thiamine, in mixed critically ill populations have also shown mixed findings. Four meta-analyses of randomized controlled trials and observational studies show that intravenous vitamin C does not have a significant effect on the length of hospital stay, mortality at 1 month, ICU mortality, use of invasive ventilation, use of renal replacement therapy, organ function, or incidence of kidney injury when compared with placebo or standard care. The meta-analyses reach conflicting conclusions on whether intravenous vitamin C reduces the risk of in-hospital mortality, 30-day mortality, and the duration of ICU stay. When only data from low risk-of-bias clinical trials are considered, the effects of intravenous vitamin C on mortality at any point are no longer significant (106933,106934,109957,113663). However, a subgroup analysis in one of these analyses suggests that intravenous vitamin C as monotherapy, or in doses of at least 10 grams daily, may improve overall mortality (106934). Vitamin C also does not appear to benefit complications from sepsis, such as vasoplegic shock. A small clinical study in adults in the ICU with vasoplegic shock mostly secondary to sepsis and requiring moderate vasopressor support shows that administering intravenous vitamin C as sodium ascorbate 1.5 grams every 6 hours for 5 days or until cessation of vasoactive therapy does not reduce the duration of vasopressors, vasopressor dose, hospital or ICU length of stay, or mortality outcomes when compared with placebo (112475).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Atrophic acne scars. It is unclear if applying topical vitamin C after microblading improves atrophic acne scars. Details: A clinical study in adults with mild to severe atrophic acne scarring shows that applying a serum containing vitamin C 17% to the face after a once-monthly home microblade treatment for 4 months improves the appearance of acne scars at month 5 when compared with baseline (108086). Although this study enrolled a control group that used topical insulin in place of vitamin C, no between-group statistical comparisons were conducted, limiting the validity of this study.
• Age-related macular degeneration (AMD). It is unclear if dietary vitamin C or oral vitamin C taken in combination with other ingredients prevents AMD. Details: An umbrella review of meta-analyses shows that increased dietary intake of vitamin C is associated with 21% higher odds of developing AMD (112095). A population study suggests that vitamin C intake is associated with increased odds of developing age-related maculopathy (9823). However, other population studies have found no association between dietary or supplemental vitamin C intake and the risk of developing AMD (14007,14257). When taken in combination with other ingredients, most clinical and population research shows that taking vitamin C 500 mg along with other antioxidants such as vitamin E 400 IU, beta-carotene 15 mg, and/or elemental zinc 80 mg reduces the risk of visual acuity loss by 23% to 27%, progression to advanced AMD at 5 years by 25% to 32%, and AMD overall (7303,7304,11326,14257,90069). The antioxidant plus zinc combination seems to reduce the risk of progression to advanced AMD in these patients more than taking the antioxidants without zinc (7303,90069). More evidence is needed to determine what role, if any, vitamin C intake has on the risk of developing AMD.
• Aging skin. Topical vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in females aged 30-65 years shows that applying a specific liquid (Antioxidant and Collagen Booster Serum, Max Biocare Pty Ltd.) containing vitamin C 20%, red raspberry leaf cell culture extract 0.0005%, and vitamin E 1% to the face nightly for 8 weeks, in addition to regular facial skin products, improves skin color, elasticity, radiance, smoothness, and appearance of wrinkles when compared with regular facial skin products alone (102355).
• Albuminuria. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study shows that taking vitamin C 1250 mg plus vitamin E 680 IU daily for 4 weeks can reduce the excretion of albumin by about 19% when compared with placebo in patients with type 2 diabetes (10434).
• Allergic rhinitis (hay fever). It is unclear if oral vitamin C is beneficial in patients with hay fever. Details: Epidemiological research has found that higher vitamin C plasma levels are not associated with a decreased risk of allergic rhinitis (15200). However, clinical research shows that some forms of vitamin C might help. In one small clinical study, intranasal vitamin C administered three times daily for 2 weeks reduces nasal secretions, nasal blockage, and edema in up to 74% of patients with perennial allergic rhinitis (15201). Another small clinical study in patients with seasonal allergic rhinitis shows that taking a single oral dose of vitamin C 2 grams reduces bronchial responsiveness to histamine at one hour after ingestion (15202). However, in another small study in patients with seasonal allergic rhinitis taking vitamin C orally in doses up to 4 grams daily for 3 days does not appear to suppress cutaneous or nasal response to histamine when compared to placebo (15203).
• Alzheimer disease. It is unclear if dietary vitamin C helps to prevent this condition. Details: Most epidemiological research has found that dietary intake of vitamin C is associated with a 17% reduced risk of developing Alzheimer disease (4636,9824,10131,13165,90082).
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). It is unclear if oral vitamin C helps to prevent ALS. Details: Observational research has found that increased dietary or supplemental intake of vitamin C is not associated with risk of developing ALS (90412).
• Anthracycline cardiotoxicity. Although there is interest in using oral vitamin C for anthracycline-induced cardiac toxicity, there is insufficient reliable information about the clinical effects of vitamin C for this condition.
• Aspirin-associated gastric damage. It is unclear if oral vitamin C helps to prevent gastric damage caused by aspirin. Details: Some clinical research shows that vitamin C 480 mg might prevent gastric damage associated with taking aspirin 400 mg by decreasing blood loss and preventing decreased gastric blood flow (10357). However, a small clinical study in healthy patients shows that taking vitamin C 500 mg as ascorbic acid with aspirin 600 mg actually increases gastrointestinal permeability to a greater extent than either ingredient taken alone (98781).
• Athletic performance. It is unclear if oral vitamin C improves athletic performance. Details: Although some small preliminary clinical studies suggest that vitamin C might improve certain biomarkers during exercise (82922), a meta-analysis of small clinical trials in older and younger adults shows that taking vitamin C 500-1000 mg daily, with or without vitamin E, does not improve endurance, lean mass, or muscle strength when compared with placebo (102973). A more recent, small clinical study in recreationally trained males shows that taking vitamin C 1000 mg and vitamin E (as alpha-tocopherol) 235 mg daily for 10 weeks while participating in a resistance training program does not improve measures of muscle strength when compared with placebo (109959).
• Atopic disease. It is unclear if dietary vitamin C helps to prevent atopic disease. Details: Population research has found that higher intake of vitamin C is not associated with a reduced risk of eczema, wheeze, IgE-mediated food allergy, or allergic sensitization (90098).
• Attention deficit-hyperactivity disorder (ADHD). Small clinical studies suggest that high-dose oral vitamin C may not improve symptoms in patients with ADHD. Details: Some research suggests that taking megadose vitamins, including vitamin C, does not improve ADHD symptoms (9957,9958,9959). However, other preliminary clinical research shows that taking 25 mg of vitamin C in combination with flaxseed oil providing alpha-linolenic acid 200 mg twice daily might improve measures of attention, impulsivity, restlessness, and self-control in children with ADHD when compared with baseline (14443). It is not clear if these effects are due to vitamin C, flaxseed oil, or the combination.
• Autism spectrum disorder. It is unclear if oral vitamin C is beneficial in patients with autism spectrum disorder. Details: One small clinical study shows that taking vitamin C 8 grams per 70 kg daily for 10 weeks modestly reduces autism symptom severity in school children when compared with placebo (83604).
• Bleeding. It is unclear if intravenous vitamin C can reduce bleeding after total abdominal hysterectomy. Details: A small clinical study in patients undergoing total abdominal hysterectomy shows that administration of intravenous vitamin C 1 gram the night before surgery and 1 gram during surgery reduces postoperative hemorrhage volume by around 40 mL when compared with placebo (109465).
• Brain tumor. It is unclear if oral vitamin C helps to prevent brain tumors. Details: Population research has found that vitamin C intake is associated with a 14% reduced risk of glioma. This risk reduction was more prevalent in America compared to other geographic locations (98782).
• Breast cancer. It is unclear if oral vitamin C helps to prevent breast cancer, its recurrence, or breast cancer-related mortality. Details: Some epidemiological research has found that dietary vitamin C is associated with a reduced risk of breast cancer (1444,10823,10824). However, other epidemiological research has found no association with dietary or supplemental vitamin C (10825,10826,108080). One cohort study found no association between breast cancer risk and total, dietary, or supplemental vitamin C, regardless of dose, treatment duration, or formulation (single ingredient or combination product). Additionally, hormone and menopausal status did not appear to impact risk. Vitamin C intake might be associated with a reduced risk in individuals with a family history of breast cancer in first-degree relatives (108080). In patients with breast cancer, supplemental or dietary intake of vitamin C might be associated with a reduced risk of mortality. A meta-analysis of results from population research shows that vitamin C supplementation following breast cancer diagnosis is associated with a 15% lower risk of breast cancer-related mortality when compared with no supplementation (90416). A large, observational study in patients with breast cancer undergoing radiation therapy has found that vitamin C supplementation does not reduce the risk of breast cancer recurrence over a period of 5 years when compared with no supplementation. Although the vitamin C group had notably less aggressive tumor types, recurrence-free survival was similar in both vitamin C and control groups (108082). The validity of these findings is limited due to unknown doses of vitamin C and the inclusion of various breast cancer subtypes.
• Burns. Small studies suggest that intravenous vitamin C may modestly improve symptoms in patients with severe burns. Details: A small clinical study in patients with severe burns shows that administering vitamin C intravenously (IV) 66 mg/kg hourly over 24 hours, as part of fluid resuscitation using lactated ringer solution, reduces wound edema and the volume of fluid needed when compared with fluid resuscitation alone (83145). A retrospective review of adults hospitalized with severe burns has found that those who receive a continuous IV infusion of at least 10 grams of vitamin C within 2 days of admission have an in-hospital mortality rate of 46%, compared with 58% for those who do not receive vitamin C (102128).
• Cancer. It is unclear if oral or intravenous vitamin C helps to prevent cancer or cancer-related mortality. Details: Some population research has found that DIETARY intake of vitamin C is linked with a lower risk of cancer and cancer-related mortality (3910,5878,10819,109779). However, clinical research shows that taking vitamin C SUPPLEMENTS does not reduce the risk for cancer (10819,14109,34580,90097). In people with cancer, although some clinical research has shown that taking high-dose vitamin C supplements can improve survival rates (9809,96704), other clinical research has not shown this benefit (4842,4843). In 2003, the US Food and Drug Administration (FDA) determined that it would allow a qualified health claim stating that some scientific evidence suggests that antioxidant vitamins, such as vitamin C, may reduce the risk of certain forms of cancer. However, the FDA has determined that there is little scientific evidence supporting this claim (102334). Preliminary clinical research has also evaluated vitamin C supplements in patients with cancer. High-dose oral vitamin C, 10 grams daily, in patients with advanced cancer does not seem to improve survival or decrease disease progression (4842,4843,106617). However, preliminary clinical research suggests high doses of vitamin C, given intravenously, might have a beneficial effect on some outcomes, including survival rate in some patients with cancer (9809,96704,106617). However, there is no benefit to other patients studied in the case reports and this has not been tested in well-designed clinical trials (9809,96704).
• Cardiac arrest. It is unclear if intravenous vitamin C is beneficial for patients after cardiac arrest. Details: A small clinical study conducted in Slovenia in adult survivors of out-of-hospital cardiac arrest shows that administering intravenous vitamin C 1.5 grams every 12 hours for 8 consecutive doses, with the first dose administered within 6 hours of resuscitation, in addition to standard care protects against arrhythmias and reduces the length of intensive care unit (ICU) stay when compared with placebo and standard care. However, intravenous vitamin C does not appear to protect against neurological or myocardial injury, reduce the need for mechanical ventilation, reduce the duration of hospital stay, or increase survival when compared with placebo (113667).
• Carpal tunnel syndrome. Vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in adults with mild to moderate carpal tunnel syndrome shows that taking a combination product containing vitamins C, E, B1, B2, B6, and B12, alpha-lipoic acid, acetyl-L-carnitine, phosphatidylserine, and turmeric twice daily for 60 days reduces symptom severity and pain but does not improve measures of hand and wrist function when compared with control (111702). The validity of these effects is limited by a lack of blinding. The study may also be inadequately powered to detect a difference between groups. Additionally, it is unclear if the effects are due to vitamin C, other ingredients, or the combination.
• Cervical cancer. It is unclear if oral vitamin C helps to prevent cervical cancer. Details: Observational research has found that higher vitamin C intake is associated with a 33% to 42% reduced odds of cervical neoplasm. Increasing vitamin C intake by 50 mg daily is associated with an 8% reduced odds of cervical neoplasm (34609,98771).
• Child growth. Some clinical research in pregnant smokers suggests that taking vitamin C during pregnancy may improve pulmonary function in the offspring from birth to 6 years of age. Details: A meta-analysis of 4 data sets from one large clinical study in pregnant adults who smoke at least one cigarette daily shows that taking supplemental vitamin C 500 mg daily during pregnancy reduces lower airway resistance and improves lung capacity of the offspring at 0, 3, 12, and 60 months of age, but does not improve airway obstruction, when compared with control (113670). Additionally, one of the clinical studies included the meta-analysis shows that taking vitamin C during pregnancy lowers the occurrence of wheezing in offspring at 4-6 years of age (114496,114497).
• Chronic fatigue syndrome (CFS). Although there is interest in using oral vitamin C for CFS, there is insufficient reliable information about the clinical effects of vitamin C for this condition.
• Colistin-induced nephrotoxicity. It is unclear if intravenous vitamin C helps to prevent nephrotoxicity from colistin. Details: A small clinical study shows that intravenous administration of vitamin C 2 grams every 12 hours along with colistin for around 9-10 days does not prevent nephrotoxicity when compared with colistin therapy alone (99839). However, this study was limited by a lack of statistical power to detect differences between the study groups.
• Contrast induced nephropathy. It is unclear if oral vitamin C helps to prevent contrast-induced nephropathy (CIN). Details: Some clinical research shows that taking vitamin C before and after coronary angiography reduces the risk of developing CIN by 33% to 55% when compared with placebo in patients with renal dysfunction (12234,90421). However, other clinical evidence published since 2012 suggests that vitamin C given orally and/or intravenously before and after angiography does not reduce the risk of CIN compared with control in high-risk patients with chronic renal insufficiency or diabetes (91232,91236,90410,90425). Reasons for the discrepancies are not entirely clear. However, it is possible that the lack of significant benefit from vitamin C in the latter studies results from the fact that incidences of CIN have become less common than in the past due to avoidance of dehydration, use of smaller catheters, and use of contrast agents with reduced nephrotoxicity (90429).
• Coronary artery bypass graft (CABG) surgery. It is unclear if intravenous vitamin C helps to improve patient outcomes after CABG surgery. Details: A small clinical study shows that giving vitamin C 5 grams intravenously (IV) before anesthesia induction and 5 grams in the cardioplegia solution used during surgery shortens the length of stay in the intensive care unit (ICU) by about 8 hours (102127). However, some limited research suggests that IV vitamin C does not resolve cardiac surgery complications. A small clinical study in patients with vasoplegia after receiving CABG and other cardiac surgeries shows that receiving IV vitamin C 1.5 grams every 6 hours after being admitted to the ICU does not improve vasoplegia when compared with control (102981).
• Delirium. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Observational research in adults with septic shock has found that receiving intravenous thiamine 400 mg daily with vitamin C 6 grams daily, both in divided doses, is not associated with reduced delirium when compared with control (103001).
• Dental plaque. It is unclear if vitamin C in a chewing gum helps to reduce dental plaque formation. Details: A small clinical study in patients with calculus shows that chewing 10 pieces of gum, each containing 60 mg of vitamin C, daily for 3 months reduces the formation of dental calculus, visible plaque, and the number of bleeding sites when compared not chewing gum (83303). The validity of this finding is limited by a lack of placebo group.
• Depression. It is unclear if oral vitamin C is beneficial for the treatment or prevention of depression. Details: A small clinical study in children and adolescents shows that taking vitamin C 500 mg orally twice daily in combination with fluoxetine 10-20 mg daily for 6 months reduces most symptoms of major depressive disorder when compared with taking fluoxetine alone (90404). However, a small clinical study in adults shows that taking vitamin C up to 1000 mg daily for 2 months does not improve the response rate or decrease symptoms of depression in adults also taking citalopram when compared with citalopram alone (96708). Reasons for these conflicting results may relate to the age of the patients, study duration, or differences in antidepressant medication being taken. One clinical guideline also provisionally recommends against the use of oral vitamin C to treat patients with depression based on low-quality evidence (110318). Some research has also evaluated vitamin C intake for the prevention of depression. A secondary analysis of pre- and peri-menopausal adults enrolled in the Study of Women's Health Across the Nation (SWAN) program suggests that vitamin C intake is inversely associated with depressive symptoms. This association persisted regardless of age, race, physical activity, body mass index, antidepressant use or menopausal status (108083). The validity of these findings is limited due to the secondary nature of this study; additionally, follow-up time is unclear.
• Diabetes. It is unclear if oral vitamin C prevents diabetes. Some low-quality research suggests that vitamin C might improve glycemic control in patients with diabetes. Details: Population research has not found a link between dietary vitamin C and the risk of developing type 2 diabetes (14004). However, low certainty clinical research has found some benefit of taking vitamin C supplements for glycemic control. Two meta-analyses of several small, heterogeneous clinical studies in patients with type 2 diabetes show that taking vitamin C 200-3000 mg daily for 2-48 weeks reduces fasting blood glucose by approximately 11 mg/dL (112478) and glycated hemoglobin (HbA1c) by an average of 0.5% when compared with placebo, standard treatment, or no treatment (105461,112478). Subgroup analyses suggest that durations of supplementation longer than 12 weeks show greater glycemic benefit, and although one meta-analysis suggests there is no dose-response relationship (105461), another meta-analysis suggests that doses of vitamin C 1000 mg and higher are most beneficial for improving glycemic indices (112478). Some research has evaluated the effects of vitamin C supplementation on the lipid profile in patients with diabetes, with mixed findings. One meta-analysis of 17 small clinical studies shows that taking vitamin C 200-3000 mg daily for 2 to 48 weeks improves levels of triglycerides and total cholesterol, but not low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol. Subgroup analysis suggests that study durations of at least 12 weeks show greater benefit (106621). However, two other meta-analyses in patients with diabetes, one of 16 small heterogenous clinical studies and one of 11 small clinical studies, show no clinically important improvement in lipid levels after vitamin C supplementation (105461,105464).
• Dry mouth. Oral vitamin C has only been evaluated in combination with vitamin E; its effect when used alone is unclear. Details: A small clinical trial in patients receiving radiotherapy for head and neck cancer shows that taking vitamin E 100 IU and vitamin C 500 mg twice daily for an average of 3 months improves dry mouth when compared to baseline (99080). The validity of these results is limited by the lack of comparison with a control group.
• Endometrial cancer. Increased dietary vitamin C has been linked to reduced risk of endometrial cancer. Details: Population research has found that intake of vitamin C from dietary sources is associated with a slightly decreased risk of endometrial cancer when compared with control. However, this benefit is not observed when results from a prospective cohort study are assessed (34578).
• Endometriosis. Oral vitamin C has only been evaluated in combination with vitamin E; its effect when used alone is unclear. Details: A small clinical study in patients with endometriosis and pelvic pain shows that taking vitamin C 1000 mg and vitamin E 800 IU daily for 8 weeks improves dysmenorrhea, dyspareunia, and chronic pelvic pain scores when compared with placebo. Vitamin C and vitamin E supplementation also reduces some biochemical markers of oxidative stress when compared with placebo (106622). Additionally, a meta-analysis of 4 other, mostly small clinical studies in patients with endometriosis shows that taking vitamin C 1000 mg and vitamin E 800-1200 IU daily for 6-8 weeks reduces chronic pelvic pain and improves dysmenorrhea and dyspareunia when compared with placebo (114491).
• Endoscopy-associated adverse effects. It is unclear if a topical vitamin C spray reduces mucosal irritation in patients undergoing Lugol chromoendoscopy. Details: A small clinical trial in patients receiving a Lugol chromoendoscopy shows that spraying a vitamin C 2% solution after the application of the Lugol iodine 2% solution reduces the severity of mucosal irritation, heartburn, and pain when compared with using a normal saline spray after the Lugol iodine 2% solution (104030).
• Esophageal cancer. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Population research has found that higher dietary intake of vitamin C is associated with reduced odds of esophageal adenocarcinoma. A 50 gram increase in dietary vitamin C intake is associated with a 13% reduced odds of esophageal cancer (34551,98770). However, a meta-analysis of clinical research shows that taking a vitamin C supplement in combination with beta-carotene and vitamin E does not reduce the risk of esophageal cancer (34581).
• Exercise-induced asthma. Small clinical studies suggest that oral vitamin C may modestly improve symptoms in patients with exercise-induced asthma. Details: A meta-analysis of the available clinical research shows that vitamin C supplementation might reduce exercise-induced breathlessness when compared with placebo or control. However, the available research is of poor quality, and no clear conclusions can be drawn regarding its benefits for exercise-induced asthma (90409).
• Exercise-induced muscle damage. It is unclear if oral vitamin C is beneficial in exercise-induced muscle damage. Details: A small clinical study in healthy females shows that taking vitamin C 1000 mg before moderate intensity cycling does not prevent muscle damage when compared with placebo (99837). Another small clinical study in endurance-trained runners shows that taking vitamin C 1000 mg and vitamin E (as alpha-tocopherol) 235 mg 2 hours prior to an exercise protocol does not reduce delayed onset muscle soreness or improve other markers of exercise-induced muscle damage when compared with placebo (109961).
• Gallbladder disease. It is unclear if oral vitamin C reduces the risk of gallbladder disease. Details: Cross-sectional epidemiological evidence has found that vitamin C supplementation and increased vitamin C serum levels are associated with a decreased risk of developing gallbladder disease in females, but not males (5877).
• Gastric cancer. It is unclear if dietary or supplemental vitamin C reduces the risk of gastric cancer. Details: Most population research has not found an association between DIETARY intake of vitamin C and gastric cancer risk (9194,10822,10819,90083). Also, clinical research shows that taking vitamin C supplements in combination with other antioxidants does not reduce the risk of gastric cancer or precancerous gastric lesions (14447,34581,90085). However, some research suggests that it might be associated with a reduced risk for specific forms of gastric cancer (9838,90083). One clinical study shows that taking vitamin C orally 500 mg daily for 6 months after eradication of Helicobacter pylori infection decreases the incidence of precancerous changes in stomach tissue when compared with no treatment (10359). Also, other clinical research shows that taking vitamin C orally 1 gram daily helps promote the regression of precancerous gastric lesions in people at high risk for gastric cancer (2579). In 2009, the US Food and Drug Administration (FDA) determined that it would allow a qualified health claim stating that vitamin C supplements may reduce the risk of gastric cancer. However, the FDA has concluded that it is highly uncertain that vitamin C supplements actually reduce the risk of gastric cancer (102332).
• Gastritis. There is limited evidence on the oral use of vitamin C in omeprazole-induced corpus gastritis. Details: A small clinical study shows that taking vitamin C orally 1200 mg daily along with omeprazole decreases corpus gastritis associated with omeprazole therapy in patients with H. pylori infection (10360).
• Gout. It is unclear if oral vitamin C helps to prevent or manage gout. Details: Population research in men has found that taking vitamin C 500-1500 mg daily from the diet and/or supplements is associated with up to a 34% reduced risk of gout when compared with less than 250 mg daily (16755). Also, men who ingest over 500 mg of vitamin C daily from the diet and supplements have serum uric acid levels that are slightly lower than men who consume less than 90 mg daily (16820). However, taking supplemental vitamin C 500 mg daily for 8 weeks does not seem to lower serum uric acid levels in patients who already have gout (90423).
• Hearing loss. There is limited evidence on the intravenous use of vitamin C in idiopathic sudden sensorineural hearing loss. It is unclear if dietary vitamin C intake can affect the risk of hearing loss. Details: A small clinical study in patients with idiopathic sudden sensorineural hearing loss shows that receiving intravenous high-dose vitamin C 200 mg/kg daily in combination with steroid therapy for 10 days, followed by oral vitamin C 2000 mg daily for 30 days, increases recovery rate two-fold and modestly improves hearing threshold levels when compared with receiving steroid therapy only (90417). In addition, population research in females has found that high dietary intake of vitamin C is associated with a 22% increased risk of developing self-reported hearing loss over a 22-year period when compared with low intake (109807).
• Heart transplant complications. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial shows that a combination of vitamin C 500 mg and vitamin E 400 IU, taken twice daily for 1 year starting within the first 2 years after cardiac transplant, reduced the progression of vasculopathy as measured by intravascular ultrasonography (IVUS) when compared with placebo. This suggests that the combination may help slow the progression of CAV (82826).
• Hepatitis C. It is unclear if oral vitamin C is beneficial in patients with hepatitis C. Details: A small clinical study in patients with confirmed hepatitis C shows that taking vitamin C 1000 mg daily with conventional therapy (sofosbuvir plus daclatasvir) for 4 weeks improves serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and albumin when compared with conventional therapy alone (109463).
• HIV/AIDS. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small, low-quality study in men with HIV shows that taking vitamin C 250 mg daily in combination with vitamin A, beta-carotene, vitamin E, selenium, and coenzyme Q10 does not improve viral load, although it seems to improve markers of oxidative stress when compared to baseline. However, a 1000 mg dose of vitamin C, as well as higher doses of the other antioxidants, do not seem to provide any additional effect (9830).
• HIV transmission. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in HIV-positive mothers shows that taking vitamin B, vitamin C, and vitamin E daily during pregnancy and while breast-feeding for 20 weeks seems to reduce child mortality and HIV transmission through breast milk when compared with taking vitamin A (9801).
• Hyperphosphatemia. Intravenous vitamin C might be beneficial for reducing phosphate levels in patients with end-stage renal disease. Details: A small clinical study in hemodialysis patients with elevated phosphorus levels suggests that administering vitamin C 500 mg intravenously three times weekly for 8 weeks reduces phosphorus levels about seven-fold when compared with placebo (90414).
• Idiopathic interstitial pneumonia. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with idiopathic pulmonary fibrosis, a form of idiopathic interstitial pneumonia, shows that taking a combination of vitamin C 250 mg every other day, vitamin D 50,000 IU daily, and vitamin E 200 IU daily for 12 weeks improves some, but not all, measures of lung function and reduces markers of inflammation and oxidative stress when compared to baseline (109464). The validity of these findings is limited by a lack of placebo control group.
• Infertility. It is unclear if oral vitamin C is beneficial in anovulatory females. Details: A very small clinical study suggests that taking vitamin C 400-1000 mg daily might improve fertility, resulting in ovulation and pregnancy in some anovulatory females, when compared to baseline (14018). The validity of these findings is limited by the small study size and lack of a comparator group. However, a very large observational study suggests that there is no association between dietary vitamin C intake and in-vitro fertilization (IVF) outcomes including good oocyte quality, embryo transfer success rates, clinical pregnancy rates, and successful term pregnancy rates in subfertile couples who are candidates for IVF (112097).
• Male infertility. It is unclear if oral or intravenous vitamin C is beneficial in males with infertility. Details: A meta-analysis of three small, low-quality clinical trials in males with infertility shows that taking vitamin C up to 1000 mg daily for up to 12 weeks can improve sperm count, motility, and vitality, but does not seem to increase semen volume or sperm concentration, when compared with control (109461). It is unclear if vitamin C can increase pregnancy rates, as these studies did not assess this outcome. A retrospective study in males with or without varicocele-related infertility has found that taking a specific combination product containing vitamin C 90 mg, zinc 10 mg, L-carnitine fumarate 1725 mg, acetyl-L-carnitine 500 mg, coenzyme Q10 20 mg, folic acid 0.2 mg, selenium 0.05 mg, and vitamin B12 0.015 mg (Proxeed Plus, Sigma-Tau) orally twice daily for 6 months improves sperm count, sperm concentration, and sperm motility when compared with baseline. Improvement in semen parameters were greatest in subjects with more severe varicoceles. The validity of this study is limited by the lack of a comparator group (111296).
• Mastalgia. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in patients with mastalgia shows that taking a combination of vitamin C 100 mg, vitamin B12, and gamma-linolenic acid daily for 12 weeks does not improve the proportion of patients with minimal or no pain when compared with placebo (111059).
• Melasma. It is unclear if topical vitamin C is beneficial in patients with melasma. Details: A small clinical study in patients with bilateral symmetrically distributed facial melasma shows that applying 0.5 mL of vitamin C (Cosmotech, Alpha Medical Cosmotech) following dermapen microneedling every 2 weeks for 6 weeks is similarly effective to tranexamic acid for improving melasma severity and pigmented, but not vascular, findings on dermoscopic examination (106939). Additionally, a small clinical study in adults with melasma shows that applying 1 to 2 mL of 20% vitamin C solution following dermapen microneedling every 2 weeks for 8 weeks does not improve the degree of pigmentation when compared with topical metformin but does improve the degree of pigmentation when compared to baseline (115610).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral vitamin C is beneficial in patients with NAFLD. Details: A clinical study in patients with NAFLD shows that taking vitamin C 250 mg, 1000 mg, or 2000 mg daily for 12 weeks improves some biochemical markers of liver health and glucose metabolism when compared with baseline. However, the improvement from baseline was similar between groups (106942).
• Nonalcoholic steatohepatitis (NASH). Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research suggests vitamin C in combination with vitamin E might improve hepatic fibrosis in patients with NASH. However, it does not seem to decrease liver inflammation (14005).
• Non-Hodgkin lymphoma. It is unclear if oral vitamin C reduces the risk of developing diffuse large B-cell lymphoma. Details: In one population study, higher dietary or supplemental intake of vitamin C was associated with a reduced risk of diffuse large B-cell lymphoma, a type of non-Hodgkin lymphoma, when compared with lower intake in postmenopausal adults (90945).
• Oral cancer. It is unclear if oral vitamin C reduces the risk of developing oral cancer. Details: Population research has found that higher dietary intake of vitamin C is associated with a reduced risk of oral cancer (10821). However, clinical research has not shown benefit with oral vitamin C supplements. A small clinical trial in Japanese adults with oral leukoplakia shows that taking vitamin C 500 mg and beta-carotene 10 mg daily for 12 months does not reduce the development of oral cancer over 5 years when compared with vitamin C 50 mg daily (91384).
• Oral leukoplakia. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in Japanese adults with oral leukoplakia shows that taking vitamin C 500 mg and beta-carotene 10 mg daily for 12 months does not improve leukoplakia symptoms or reduce the development of oral cancer over 5 years when compared with vitamin C 50 mg daily (91384).
• Osteoarthritis. It is unclear if dietary vitamin C reduces the risk of developing osteoarthritis. Details: Observational research has found that increased vitamin C from dietary sources is associated with a reduced risk of cartilage loss and disease progression in people with osteoarthritis (5881).
• Osteoporosis. It is unclear if dietary vitamin C improves bone density or reduces fracture risk in patients at risk for osteoporosis. Details: Some cross-sectional observational research in postmenopausal patients without a history of smoking or estrogen use has found that higher serum vitamin C levels are associated with lower bone mineral density (9828). However, other observational research in a larger population of adults at risk for osteoporosis has found that higher dietary vitamin C intake is not associated with fracture risk (104415).
• Ovarian cancer. Dietary vitamin C might not affect the risk of ovarian cancer. Details: Epidemiological research has found that dietary vitamin C intake is not linked with ovarian cancer risk (9193,102977).
• Pancreatitis. It is unclear if intravenous vitamin C is beneficial in patients with acute pancreatitis. Details: A small meta-analysis of clinical studies in patients with acute pancreatitis shows that intravenous vitamin C does not improve the odds of developing organ failure when compared with placebo or no intervention. Intravenous vitamin C seems to reduce hospital stay, but not in-hospital mortality (106941).
• Parkinson disease. Dietary vitamin C might not affect the risk of developing this condition. Details: Observational research has found that moderate or high dietary intake of vitamin C is not associated with a reduced risk of Parkinson disease (83316).
• Periodontitis. Oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. It is also unclear if dietary vitamin C reduces the risk of periodontitis. Details: A small clinical study in patients with moderate or advanced periodontitis shows that taking a supplement containing vitamin C 100 mg, alpha-lipoic acid, coenzyme Q10, cranberry extract, grapeseed extract, selenium, vitamin E, and zinc twice daily for 8 weeks in addition to standard nonsurgical therapy does not improve periodontal indices including bleeding on probing, gingival recession, plaque index, or inflammation, among others, when compared with placebo (111708). It is unclear if these effects are due to vitamin C, other ingredients, or the combination. There is also interest in whether dietary vitamin C intake impacts the risk of periodontitis. Observational research in US adults has found that individuals with dietary intake of vitamin C in the third quartile, but not the second or fourth quartiles, have lower odds of periodontitis when compared with vitamin C intake in the lowest quartile. Furthermore, the investigators identified a non-linear relationship between vitamin C intake and periodontitis risk, suggesting that individuals with intakes either much lower or much higher than 158 mg daily are at increased risk of developing periodontitis (109958).
• Peripheral arterial disease (PAD). It is unclear if dietary vitamin C helps to reduce the risk of developing PAD. Details: In females, epidemiological evidence has found that dietary intake of vitamin C of 142 mg daily or greater is associated with a 36% reduced risk of PAD when compared with lower intake levels of less than 80 mg daily (10130).
• Physical performance. It is unclear if oral vitamin C helps to improve physical performance and muscle strength in older people. Details: Population research has found that higher intake of dietary vitamin C is associated with improved physical performance and muscle strength in elderly people (14006). In contrast, a small clinical study in elderly men undergoing strength training shows that taking vitamin C 1000 mg and vitamin E 258IU daily for 12 weeks does not increase strength, and might even attenuate increases in muscle mass, when compared with strength training alone (96701).
• Pneumonia. It is unclear if oral or intravenous vitamin C helps to prevent or treat pneumonia. Details: A meta-analysis of 6 clinical studies in adults with community-acquired pneumonia shows that oral or intravenous vitamin C does not reduce overall mortality, hospital or intensive care unit length of stay, or the risk of mechanical ventilation when compared with control (114490). The interpretation of these results is limited by significant heterogeneity of the included studies. An earlier meta-analysis of two small, low-quality clinical studies in children shows that vitamin C does not seem to reduce the risk of pneumonia when compared with a control (104033).
• Postoperative recovery. It is unclear if oral or intravenous vitamin C improves postoperative recovery. Details: Meta-analyses of clinical research show that oral or intravenous vitamin C can shorten the duration of hospitalization after cardiac surgery when compared with control (91233,96703). However, other research shows no decrease in intensive care unit (ICU) or hospital stay with vitamin C supplementation (96705), while another clinical study in patients undergoing cardiac surgery with extracorporeal circulation shows that intravenous vitamin C administered during surgery and 48 hours after surgery reduces ICU stay and re-admission rates, wound infection, and hospital mortality, but not length of hospital stay, when compared with control (114492). A meta-analysis of 37 clinical trials in adults undergoing low- to high-risk noncardiac surgery (i.e., orthopedic, abdominal, gynecologic, or kidney transplantation), shows that receiving perioperative vitamin C, either orally or intravenously, does not improve duration of hospitalization or overall mortality when compared with control (108087).
• Postoperative pulmonary complications. It is unclear if intravenous vitamin C improves postoperative pulmonary complications. Details: A large, single-blind clinical study in patients with recent cardiac surgery with extracorporeal circulation shows that parenteral administration of vitamin C 50 mg/kg intraoperatively and 50 mg/kg every 6 hours for the next 48 hours, followed by oral vitamin C 2000 mg daily until 1-week post-discharge, reduces the incidence of postoperative pulmonary complications (PPC) by 22% and improves PPC severity scores when compared with control. Specifically, vitamin C reduces the incidence of pneumothorax, pleural effusion, pneumonia, and re-intubation and may ameliorate lung damage as suggested by higher Horowitz index when compared with control (114492). A small clinical trial in patients undergoing low-risk cardiac surgery shows that receiving intravenous vitamin C 1 gram 10 minutes after anesthesia might slightly reduce the rate of postoperative pulmonary complications when compared with receiving a saline injection (104034).
• Postoperative swelling. It is unclear if vitamin C reduces postoperative swelling after dental surgery. Details: A small observational study in adults undergoing surgery for wisdom tooth extraction shows that taking vitamin C 500 mg three times daily for 7 days in addition to standard treatment reduces swelling 7 days after surgery when compared with control. However, vitamin C does not seem to reduce swelling 3 days after surgery when compared with control, suggesting that longer durations are needed for anti-inflammatory effects (113664).
• Premature rupture of membranes (PROM). Oral vitamin C seems to reduce the risk of PROM in some patients; however, the addition of oral vitamin E seems to negate any benefit. Details: A meta-analysis of clinical research shows that taking vitamin C alone decreases the risk of both term and preterm PROM by 45% and 34%, respectively, when compared with placebo or control (96707). Another meta-analysis of clinical research shows that taking vitamin C during pregnancy decreases the risk of PROM by 43% and preterm PROM by 33%, but does not decrease the risk of term PROM, when compared with a control. While vitamin C was studied in doses of 100, 500, and 1000 mg daily, the decreased risk of PROM was only observed in studies of 100 mg daily (114493). A moderate-sized clinical study in patients with a history of PROM shows that taking vitamin C 100 mg daily, starting at 14 weeks' gestation, increases the gestational age at recurrent PROM by around 1 week and increases the gestational age at birth by around 1.3 weeks when compared with placebo (109960). Additionally, a meta-analysis of observational studies suggests that vitamin C levels in the blood tend to be lower in patients with PROM, particularly preterm PROM (114493). Taking vitamin C in combination with vitamin E, however, does not seem to reduce the risk of term or preterm PROM; some research suggests that it might even increase the risk of non-preterm PROM (83472,96707). However, other research shows that taking vitamin C 1000 mg plus vitamin E 400 IU daily, beginning at 24 to 34 weeks gestation and continuing until delivery, may help increase the latency period until delivery by 5 days and increase gestational age at delivery by almost 1 week when compared with placebo in patients with preterm PROM (90078).
• Pressure ulcers. It is unclear if oral vitamin C, when used alone or in combination with other ingredients, can improve the healing of pressure ulcers. Details: A small clinical study in institutionalized patients with pressure ulcers shows that taking vitamin C 500 mg twice daily for 12 weeks does not improve wound closure or increase healing rates when compared with vitamin C 10 mg twice daily (83617). Oral vitamin C has also been evaluated in combination with other ingredients for the treatment of grade II-IV pressure ulcers. Two small clinical studies in hospitalized patients with pressure ulcers shows that administering an oral nutritional supplement enriched with vitamin C, L-arginine, and zinc improves ulcer healing when compared with a standard diet (31953,87173). Also, clinical research in patients living in long-term care facilities shows that taking an oral nutritional supplement enriched in protein, vitamin C, L-arginine, and zinc daily for 9 weeks reduces ulcer area and decreases oozing when compared to baseline (32045). The validity of this finding is limited by the lack of a comparator group.
• Radiation proctopathy. Oral vitamin C has only been evaluated in combination with vitamin E; its effect when used alone is unclear. Details: A small clinical study in patients with chronic radiation proctitis shows that vitamin C 500 mg plus vitamin E 400 IU three times daily might improve symptoms when compared with baseline (9825). The validity of these findings is limited by the lack of a comparator group.
• Renal cell carcinoma. It is unclear if increased dietary intake of vitamin C helps to reduce the risk of renal cell carcinoma. Details: Population research has found that increased dietary intake of vitamin C is associated with a 12% reduced risk of renal cell carcinoma (98779).
• Respiratory tract infections. It is unclear if oral vitamin C is beneficial for preventing respiratory tract infections or reducing the duration of these infections. Details: A meta-analysis of clinical research in children and adults shows that, when compared with placebo, oral vitamin C supplementation reduces the average number of symptomatic days per individual, but does not reduce the average symptom days per respiratory episode. Also, vitamin C intake does not reduce the incidence or severity of respiratory disease or improve recovery in hospitalized patients with respiratory tract infections (108077). The validity of this trial is limited by the high heterogeneity of included studies, which evaluated various vitamin C regimens, ranging from 100 mg to 8 grams daily, as preventive therapy or as an adjuvant to active treatment. A clinical study in children aged 3-10 years shows that taking vitamin C 50 mg in combination with a specific product (Lab4) containing Lactobacillus acidophilus, Bifidobacterium bifidum, and Bifidobacterium animalis subsp. lactis daily for 6 months reduces the incidence of cough and sore throat by 16% and 20%, respectively, when compared with placebo. However, it did not improve total symptoms, nasal congestion, nasal discharge, or sneezing. Also, aside from a 33% reduction in the average number of days with a sore throat, daily supplementation does not reduce the duration of individual symptoms or total symptoms (106943). It is unclear if these effects are due to vitamin C, the probiotics, or the combination.
• Restless legs syndrome (RLS). It is unclear if oral vitamin C helps to reduce symptoms of stress. Details: A small clinical study in hemodialysis patients with RLS shows that taking vitamin C 200 mg daily, alone or in combination with vitamin E 400 mg, for 8 weeks reduces the severity of RLS when compared with placebo (90093). More research is needed to determine if vitamin C is beneficial in treating RLS that is not associated with hemodialysis.
• Sunburn. Topical and oral vitamin C has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking vitamin C orally in combination with vitamin E seems to prevent ultraviolet (UV) radiation-induced erythema (sunburn) (4715,4716). Vitamin C in combination with high dose oral RRR-alpha-tocopherol (natural vitamin E) seems to protect against skin inflammation after exposure to UV radiation (4715). Also, applying topical vitamin C in combination with topical vitamin E and melatonin seems to provide modest photoprotective effects when used prior to UV exposure. However, it has no effect when used during or after UV exposure (4713,4714).
• Stress. It is unclear if oral vitamin C helps to reduce symptoms of stress. Details: A small clinical study in healthy adults shows that taking vitamin C 3000 mg daily for 14 days modestly reduces blood pressure and subjective stress response to psychological stress when compared with placebo (10353).
• Stroke. Observational research has found that although taking vitamin C supplements does not seem to be beneficial, eating more vitamin C-rich food is linked with reduced risk of stroke. Details: Lower plasma levels of vitamin C have been associated with increased stroke risk (90408). Additionally, population research has found that higher dietary intake of vitamin C is associated with a 8% to 19% reduction in stroke risk when compared to lower intake (90408,109779). This reduction appears to be dose-dependent, with each 100 mg/day increase in dietary vitamin C intake associated with about a 17% reduction (90408). However, taking vitamin C supplements has not been found to be associated with reduced stroke risk (1449,90408).
• Tetanus. It is unclear if intravenous vitamin C helps to reduce symptoms of tetanus. Details: A low quality clinical trial in children and young adults with tetanus shows that intravenous vitamin C 1 gram daily along with conventional treatment reduces fatality when compared to control (21539).
• Tooth extraction. It is unclear if oral vitamin C is beneficial for reducing pain or improving healing after tooth extraction. Details: A small clinical study in healthy patients aged 14-41 years who are undergoing bilateral premolar extraction shows that taking vitamin C 200 mg three times daily, beginning immediately after extraction and continued for 10 days, improves pain on days 1-3, and may reduce mesio-distal wound size between days 1 and 7, when compared with placebo, but not when compared with vitamin C 500 mg three times daily. A dose of 500 mg three times daily did not improve pain scores or extraction wound healing when compared with placebo (108084). The validity of this trial is limited by the short duration of treatment; additionally, this study did not report baseline vitamin C levels.
• Urinary tract infections (UTIs). Although there is interest in using oral vitamin C for UTIs, there is insufficient reliable information about the clinical effects of vitamin C for this condition.
• Vascular dementia. It is unclear if oral vitamin C reduces the risk of vascular dementia. Details: Population research has found that supplemental intake of vitamin C and vitamin E is associated with a reduced risk of vascular dementia in Japanese-American men (4636). However, when cases in which dementia was diagnosed prior to the study are excluded from data analysis, intake of vitamin C and vitamin E is not associated with a reduced risk of vascular dementia in these patients (9824).
• Wound healing. It is unclear if oral vitamin C improves the healing of chronic foot ulcers. It is also unclear if intravenous vitamin C improves healing of surgical wounds after total abdominal hysterectomy. Details: A very small clinical study in adults with chronic foot ulcers shows that taking slow-release vitamin C 500 mg daily for 8 weeks seems to result in a median of 100% ulcer healing, compared with a median of 14% ulcer healing in patients taking glucosamine 1000 mg daily (105456). This finding is limited due to the small and heterogeneous patient population, which included patients with diabetes, vascular disease, and/or vitamin C deficiency. Another small clinical study in patients undergoing total abdominal hysterectomy shows that administration of intravenous vitamin C 1 gram the night before surgery and 1 gram during surgery does not reduce the rate of surgical site infection or wound dehiscence when compared with placebo (109465). However, this study may not have been adequately powered to detect differences between groups. More evidence is needed to rate vitamin C for these uses.

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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.

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LIKELY SAFE ...when used orally, parenterally, or rectally and appropriately. Caffeine has Generally Recognized As Safe (GRAS) status in the US (4912,98806). Caffeine is also an FDA-approved product and a component of several over-the-counter and prescription products (4912,11832). According to a review by Health Canada, and a subsequent large meta-analysis conducted in the US, doses of caffeine up to 400 mg daily are not associated with significant adverse cardiovascular, bone, behavioral, or reproductive effects in healthy adults (11733,98806). The US Dietary Guidelines Advisory Committee states that there is strong and consistent evidence that consumption of caffeine 400 mg daily is not associated with increased risk of major chronic diseases, such as cardiovascular disease or cancer, in healthy adults (98806). This amount of caffeine is similar to the amount of caffeine found in approximately 4 cups of coffee. Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine from caffeine-containing natural ingredients such as coffee or green tea does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product.

POSSIBLY UNSAFE ...when used orally, long-term or in high doses (91063). Chronic use, especially in large amounts, can produce tolerance, habituation, psychological dependence, and other adverse effects (3719). Acute use of high doses, typically above 400 mg daily, has been associated with significant adverse effects such as tachyarrhythmia and sleep disturbances (11832). Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine from caffeine-containing natural ingredients such as coffee or green tea does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product.

LIKELY UNSAFE ...when used orally in very high doses. The fatal acute oral dose of caffeine is estimated to be 10-14 grams (150-200 mg/kg). Serious toxicity can occur at lower doses depending on variables in caffeine sensitivity such as smoking, age, or prior caffeine use (11832,95700,97454,104573). Caffeine products sold to consumers in highly concentrated or pure formulations are considered to a serious health concern because these products have a risk of being used in very high doses. Concentrated liquid caffeine can contain about 2 grams of caffeine in a half cup. Powdered pure caffeine can contain about 3.2 grams of caffeine in one teaspoon. Powdered pure caffeine can be fatal in adults when used in doses of 2 tablespoons or less. As of 2018, these products are considered by the FDA to be unlawful when sold to consumers in bulk quantities (95700).

CHILDREN: POSSIBLY SAFE
when used orally or intravenously and appropriately in neonates under the guidance of a healthcare professional (6371,38340,38344,91084,91087,97452). ...when used orally in amounts commonly found in foods and beverages in children and adolescents (4912,11833,36555). Daily intake of caffeine in doses of less than 2.5 mg/kg daily are not associated with significant adverse effects in children and adolescents (11733,98806). Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine from caffeine-containing natural ingredients such as coffee or green tea does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product.

PREGNANCY: POSSIBLY SAFE
when used orally in amounts commonly found in foods. Intakes of caffeine should be monitored during pregnancy. Caffeine crosses the human placenta, but is not considered a teratogen (38048,38252,91032). Fetal blood and tissue levels are similar to maternal concentrations (4260). The use of caffeine during pregnancy is controversial; however, moderate consumption has not been associated with clinically important adverse fetal effects (2708,2709,2710,2711,9606,16014,16015,98806,108814). In some studies consuming amounts over 200 mg daily is associated with a significantly increased risk of miscarriage (16014,37960). This increased risk seems to occur in those with genotypes that confer a slow rate of caffeine metabolism (98806). According to a review by Health Canada, and a subsequent large meta-analysis conducted in the US, up to 300 mg daily can be consumed during pregnancy without an increased risk of spontaneous abortion, stillbirth, preterm birth, fetal growth retardation, or congenital malformations (11733,98806). However, observational research in a Norwegian cohort found that caffeine consumption is associated with a 16% increased odds of the baby being born small for gestational age when compared with no consumption (100369,103707). The same Norwegian cohort found that low to moderate caffeine consumption during pregnancy is not associated with changes in neurodevelopment in children up to 8 years of age (103699). Advise patients to keep caffeine consumption below 300 mg daily during pregnancy. This is similar to the amount of caffeine in about 3 cups of coffee or tea.

PREGNANCY: POSSIBLY UNSAFE
when used orally in amounts over 300 mg daily. Caffeine crosses the placenta, producing fetal blood concentrations similar to maternal levels (4260,98806). Consumption of caffeine in amounts over 300 mg daily is associated with a significantly increased risk of miscarriage in some studies (16014,98806). Advise patients to keep caffeine consumption below 300 mg daily during pregnancy. This is similar to the amount of caffeine in about 3 cups of coffee or tea. Additionally, high doses of caffeine throughout pregnancy have resulted in symptoms of caffeine withdrawal in newborn infants (9891). High doses of caffeine have also been associated with spontaneous abortion, premature delivery, and low birth weight (2709,2711,91033,91048,95949). In a cohort of mother/infant pairs with a median maternal plasma caffeine level of 168.5 ng/mL (range 29.5-650.5 ng/mL) during pregnancy, birth weights and lengths were lower in the 4th quartile of caffeine intake compared with the 1st. By age 7, heights and weights were lower by 1.5 cm and 1.1 kg respectively. In another cohort of mother/infant pairs with higher maternal pregnancy plasma caffeine levels, median 625.5 ng/mL (range 86.2 to 1994.7 ng/mL), heights at age 8 were 2.2 cm lower, but there was no difference in weights (109846).

LACTATION: POSSIBLY SAFE
when used orally in amounts commonly found in foods. Caffeine intake should be closely monitored while breast-feeding. During lactation, breast milk concentrations of caffeine are thought to be approximately 50% of serum concentrations and caffeine peaks in breastmilk approximately 1-2 hours after consumption (23590).

LACTATION: POSSIBLY UNSAFE
when used orally in large amounts. Caffeine is excreted slowly in infants and may accumulate. Caffeine can cause sleep disturbances, irritability, and increased bowel activity in breast-fed infants exposed to caffeine (2708,6026).

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

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

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

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

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

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

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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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LIKELY SAFE ...when used orally and appropriately. Ginger has been safely used in multiple clinical trials (721,722,723,5343,7048,7084,7085,7400,7623,11346)(12472,13080,13237,13244,17369,17928,17929,89889,89890,89894)(89895,89898,89899,90102,96252,96253,96259,96260,96669) (101760,101761,101762,103359,107903).

POSSIBLY SAFE ...when used topically and appropriately, short-term (89893,89897).

CHILDREN: LIKELY SAFE
when consumed in the amounts typically found in foods.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. Ginger powder has been used with apparent safety at a dose of up to 750 mg daily for 4 days in girls aged 14-18 years (96255).

PREGNANCY: LIKELY SAFE
when consumed in the amounts typically found in foods. Ginger is considered a first-line nonpharmacological treatment option for nausea in pregnancy by the American College of Obstetrics and Gynecology (ACOG) (111601). However, it should not be used long-term or without medical supervision and close monitoring.

PREGNANCY: POSSIBLY SAFE
when used for medicinal purposes. Despite some early reports of adverse effects (721,7083) and one observational study suggesting that taking dried ginger and other herbal supplements during the first 20 weeks of pregnancy marginally increased the chance of stillbirth (96254), most research shows that ginger is unlikely to cause harm to the baby. The risk for major malformations in infants of parents who took ginger when pregnant does not appear to be higher than the baseline rate of 1% to 3% (721,1922,5343,11346,13071,13080,96254). Also, other research suggests that ginger intake during various trimesters does not significantly affect the risk of spontaneous abortion, congenital malformations, stillbirth, perinatal death, preterm birth, low birth weight, or low Apgar scores (18211,90103). Ginger use has been associated with an increase in non-severe vaginal bleeding, including spotting, after week 17 of pregnancy (18211).

LACTATION: LIKELY SAFE
when consumed in the amounts typically found in foods. There is insufficient reliable information available about the safety of ginger when used for medicinal purposes; avoid amounts greater than those found in foods.

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LIKELY SAFE ...when used orally in food amounts. The average diet provides glucuronolactone 1-2 mg daily, which has not been associated with any safety concerns (102620,102621). There is insufficient reliable information available about the safety of glucuronolactone when used orally in medicinal amounts. While some countries consider glucuronolactone to be safe when used in amounts found in "energy" drinks (102620,102621), conclusive evidence regarding the safety of glucuronolactone supplements is lacking.

CHILDREN:
Insufficient reliable information available; avoid using in amounts greater than those commonly found in foods.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using in amounts greater than those commonly found in foods.

(Read more about GLUCURONOLACTONE)

LIKELY SAFE ...when green tea is consumed as a beverage in moderate amounts (733,6031,9222,9223,9225,9226,9227,9228,14136,90156)(90159,90168,90174,90184,95696). Green tea contains caffeine. According to a review by Health Canada, and a subsequent large meta-analysis conducted in the US, drinking up to 8 cups of green tea daily, or approximately 400 mg of caffeine, is not associated with significant adverse cardiovascular, bone, behavioral, or reproductive effects in healthy adults (11733,98806). The US Dietary Guidelines Advisory Committee states that there is strong and consistent evidence that consumption of caffeine 400 mg daily is not associated with increased risk of major chronic diseases, such as cardiovascular disease or cancer, in healthy adults (98806). ...when green tea extract cream or ointment is used topically and appropriately, short-term. A green tea extract 3% cream, applied twice daily, has been used with apparent safety for up to 8 weeks, and a specific green tea extract ointment (Veregen, Bradley Pharmaceuticals) providing 15% kunecatechins has been safely used for up to 16 weeks (15067). The safety of treatment for longer durations or multiple treatment courses is not known.

POSSIBLY SAFE ...when green tea extract is used orally. Green tea extract containing 7% to 12% caffeine has been used safely for up to 2 years (8117,37725). Also decaffeinated green tea extract up to 1.3 grams daily enriched in EGCG has been used safely for up to 12 months (90158,97131). In addition, green tea extract has been safely used as part of an herbal mixture also containing garcinia, coffee, and banaba extracts for 12 weeks (90137). ...when used topically and appropriately as a cream or mouthwash (6065,11310,90141,90150,90151).

POSSIBLY UNSAFE ...when consumed as a beverage in large quantities. Green tea contains a significant amount of caffeine. Chronic use, especially in large amounts, can produce tolerance, habituation, psychological dependence, and other significant adverse effects. Doses of caffeine greater than 600 mg per day, or approximately 12 cups of green tea, have been associated with significant adverse effects such as tachyarrhythmias and sleep disturbances (11832). These effects would not be expected to occur with the consumption of decaffeinated green tea. Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine found in ingredients such as green tea, which naturally contains caffeine, does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product. There is also some speculation that green tea products containing higher amounts of the catechin epigallocatechin gallate (EGCG) might have increased risk of adverse events. Some research has found that taking green tea products containing EGCG levels greater than 200 mg is associated with increased risk of mild adverse effects such as constipation, increased blood pressure, and rash (90161). Other research has found that doses of EGCG equal to or above 800 mg daily may be associated with increased risk of liver injury in humans (95440,95696,97131).

LIKELY UNSAFE ...when used orally in very high doses. The fatal acute oral dose of caffeine is estimated to be 10-14 grams (150-200 mg per kilogram). Serious toxicity can occur at lower doses depending on variables in caffeine sensitivity such as smoking, age, and prior caffeine use (11832).

CHILDREN: POSSIBLY SAFE
when used orally by children and adolescents in amounts commonly found in foods and beverages (4912,11833). Intake of caffeine in doses of less than 2.5 mg/kg daily is not associated with significant adverse effects in children and adolescents (11733,98806). ...when used for gargling three times daily for up to 90 days (90150). There is insufficient reliable information available about the safety of green tea extract when used orally in children. However, taking green tea extract orally has been associated with potentially serious, albeit uncommon and unpredictable cases, of hepatotoxicity in adults. Therefore, some experts recommend that children under the age of 18 years of age do not use products containing green tea extract (94897).

PREGNANCY: POSSIBLY SAFE
when used orally in moderate amounts. Due to the caffeine content of green tea, pregnant patients should closely monitor their intake to ensure moderate consumption. Fetal blood concentrations of caffeine approximate maternal concentrations (4260). The use of caffeine during pregnancy is controversial; however, moderate consumption has not been associated with clinically important adverse fetal effects (2708,2709,2710,2711,9606,11733,16014,16015,98806). In some studies consuming amounts over 200 mg daily is associated with a significantly increased risk of miscarriage (16014). This increased risk may be most likely to occur in those with genotypes that confer a slow rate of caffeine metabolism (98806). According to a review by Health Canada, and a subsequent large meta-analysis conducted in the US, most healthy pregnant patients can safely consume doses up to 300 mg daily without an increased risk of spontaneous abortion, stillbirth, preterm birth, fetal growth retardation, or congenital malformations (11733,98806). Advise keeping caffeine consumption below 300 mg daily. This is similar to the amount of caffeine in about 6 cups of green tea. Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine found in ingredients such as green tea, which naturally contains caffeine, does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product. Based on animal models, green tea extract catechins are also transferred to the fetus, but in amounts 50-100 times less than maternal concentrations (15010). The potential impact of these catechins on the human fetus is not known, but animal models suggest that the catechins are not teratogenic (15011).

PREGNANCY: POSSIBLY UNSAFE
when used orally in amounts providing more than 300 mg caffeine daily. Caffeine from green tea crosses the placenta, producing fetal blood concentrations similar to maternal levels (4260). Consumption of caffeine in amounts over 300 mg daily is associated with a significantly increased risk of miscarriage in some studies (16014,98806). Advise keeping caffeine consumption from all sources below 300 mg daily. This is similar to the amount of caffeine in about 6 cups of green tea. High maternal doses of caffeine throughout pregnancy have also resulted in symptoms of caffeine withdrawal in newborn infants (9891). High doses of caffeine have also been associated with spontaneous abortion, premature delivery, and low birth weight (2709,2711). However, some research has also found that intrauterine exposure to even modest amounts of caffeine, based on maternal blood levels during the first trimester, is associated with a shorter stature in children ages 4-8 years (109846). Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine found in ingredients such as green tea, which naturally contains caffeine, does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product. There is also concern that consuming large amounts of green tea might have antifolate activity and potentially increase the risk of folic acid deficiency-related birth defects. Catechins in green tea inhibit the enzyme dihydrofolate reductase in vitro (15012). This enzyme is responsible for converting folic acid to its active form. Preliminary evidence suggests that increasing maternal green tea consumption is associated with increased risk of spina bifida (15068). Also, evidence from epidemiological research suggests that serum folate levels in pregnant patients with high green tea intake (57.3 mL per 1000 kcal) are decreased compared to participants who consume moderate or low amounts of green tea (90171). More evidence is needed to determine the safety of using green tea during pregnancy. For now, advise pregnant patients to avoid consuming large quantities of green tea.

LACTATION: POSSIBLY SAFE
when used orally in moderate amounts. Due to the caffeine content of green tea, nursing parents should closely monitor caffeine intake. Breast milk concentrations of caffeine are thought to be approximately 50% of maternal serum concentrations (9892).

LACTATION: POSSIBLY UNSAFE
when used orally in large amounts. Consumption of green tea might cause irritability and increased bowel activity in nursing infants (6026). There is insufficient reliable information available about the safety of green tea extracts when applied topically during breast-feeding.

(Read more about GREEN TEA)

LIKELY SAFE ...when consumed in amounts typically found in foods. Guarana has Generally Recognized as Safe (GRAS) status for use in foods in the US (4912).

POSSIBLY SAFE ...when used orally and appropriately, short-term (12). Guarana contains caffeine. According to a review by Health Canada, and a subsequent large meta-analysis conducted in the US, doses of caffeine up to 400 mg daily are not associated with significant adverse cardiovascular, bone, behavioral, or reproductive effects in healthy adults (11733,98806). The US Dietary Guidelines Advisory Committee states that there is strong and consistent evidence that consumption of caffeine 400 mg daily is not associated with increased risk of major chronic diseases, such as cardiovascular disease or cancer, in healthy adults (98806).

POSSIBLY UNSAFE ...when used orally long-term or in high doses. Guarana contains a significant amount of caffeine. Chronic use, especially in large amounts, can produce tolerance, habituation, psychological dependence, and other significant adverse effects. Acute use of high doses, typically above 400 mg per day, has been associated with significant adverse effects such as tachyarrhythmias and sleep disturbances (11832,95503,98806). These effects would not be expected to occur with the consumption of decaffeinated guarana.

LIKELY UNSAFE ...when used orally in very high doses. The fatal acute oral dose of caffeine is estimated to be 10-14 grams (150-200 mg per kilogram). Serious toxicity can occur at lower doses depending on variables in caffeine sensitivity such as smoking, age, or prior caffeine use (11832,54425).

PREGNANCY: POSSIBLY SAFE
when consumed in amounts commonly found in foods. Due to the caffeine content of guarana, intake should be closely monitored during pregnancy to ensure moderate consumption. Although it is not considered a teratogen, caffeine crosses the placenta and causes dose-dependent increases in fetal blood concentrations (4260). The use of caffeine during pregnancy is controversial; however, moderate consumption has not been associated with clinically important adverse fetal effects (2708,2709,2710,2711,9606,11733,16014,16015,98806). In some studies, consuming amounts over 200 mg daily is associated with a significantly increased risk of miscarriage (16014). This increased risk may be most likely to occur in individuals with genotypes that confer a slow rate of caffeine metabolism (98806). According to a review by Health Canada, and a subsequent large meta-analysis conducted in the US, caffeine can be safely consumed in doses up to 300 mg daily without an increased risk of spontaneous abortion, stillbirth, preterm birth, fetal growth retardation, or congenital malformations (11733,98806). However, some research has also found that intrauterine exposure to even modest amounts of caffeine, based on maternal blood levels during the first trimester, is associated with a shorter stature in children ages 4-8 years (109846). Advise individuals to keep caffeine consumption below 300 mg daily during pregnancy.

PREGNANCY: POSSIBLY UNSAFE
when used orally in amounts over 300 mg daily. Although it is not considered a teratogen, caffeine crosses the placenta and causes dose-dependent increases in fetal blood concentrations (4260,98806). Consumption of caffeine in amounts over 300 mg daily is associated with a significantly increased risk of miscarriage in some studies (16014,98806). Advise keeping caffeine consumption from all sources below 300 mg daily. High maternal doses of caffeine throughout pregnancy have resulted in symptoms of caffeine withdrawal in newborn infants (9891). High doses of caffeine have also been associated with spontaneous abortion, premature delivery, and low birth weight (2709,2711).

LACTATION: POSSIBLY SAFE
when used orally in amounts commonly found in foods. Due to the caffeine content of guarana, intake should be closely monitored when breast-feeding. Breast milk concentrations of caffeine are thought to be approximately 50% of serum concentrations (9892).

LACTATION: POSSIBLY UNSAFE
when used orally in large amounts. Consumption of guarana might cause irritability and increased bowel activity in nursing infants (6026). Large doses or excessive intake of guarana should be avoided when breast-feeding.

(Read more about GUARANA)

LIKELY SAFE ...when prescription products are used orally and appropriately (12033). ...when niacinamide supplements are taken orally in doses below the tolerable upper intake level (UL) set by the Institute of Medicine (IOM). The UL of niacinamide is 30 mg daily for adults 18 years of age and 35 mg daily for adults 19 years and older (6243).

POSSIBLY SAFE ...when used orally in doses greater than 30 mg but less than 900 mg daily. The European Food Safety Authority has set the tolerable upper intake level (UL) of niacinamide at 900 mg daily (104937). However, oral niacinamide has been safely used in doses up to 1500 mg daily for 12 weeks in some clinical trials (25561,94188,98940,107709,110502) and up to 1000 mg daily for 12 months in other trials (93362,113559,113560). ...when used topically and appropriately for up to 16 weeks (5940,93360,110497,110498,110501,113681,113683,113684).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Niacinamide has been safely used in children for up to 7 years in doses below the tolerable upper intake level (UL) (4874,9957). The UL of niacinamide for children by age is: 1-3 years, 10 mg daily; 4-8 years, 15 mg daily; 9-13 years, 20 mg daily; 14-18 years, 30 mg daily (6243).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the tolerable upper intake level (UL) for niacinamide. The UL of niacinamide during pregnancy and lactation is 30 mg daily for those 14-18 years of age and 35 mg daily for those 19 years and older (6243). There is insufficient reliable information available about the safety of larger oral doses of niacinamide or topical niacinamide; avoid using.

(Read more about NIACINAMIDE)

LIKELY SAFE ...when used orally and appropriately. The pantothenic acid derivative calcium pantothenate has a generally recognized as safe (GRAS) status for use in food products (111258). While a tolerable upper intake level (UL) has not been established, pantothenic has been used in doses of 10-20 grams daily with apparent safety (15,6243,111258) ...when applied topically and appropriately, short-term. The Cosmetic Ingredient Review Expert Panel has concluded that pantothenic acid and its derivatives are safe for use in cosmetic products in concentrations up to 5.3% (111258). Gels or ointments containing a derivative of pantothenic acid, dexpanthenol, at concentrations of up to 5%, have been used safely for up to 30 days (67802,67806,67817).

POSSIBLY SAFE ...when applied intranasally and appropriately, short-term. A dexpanthenol nasal spray has been used with apparent safety up to four times daily for 4 weeks (67826). ...when applied in the eyes appropriately, short-term. Dexpanthenol 5% eyedrops have been used with apparent safety for up to 28 days (67783). ...when injected intramuscularly and appropriately, short-term. Intramuscular injections of dexpanthenol 500 mg daily for up to 5 days or 250 mg weekly for up to 6 weeks have been used with apparent safety (67822,111366).

CHILDREN: LIKELY SAFE
when used orally and appropriately (15,6243). Calcium pantothenate is generally recognized as safe (GRAS) when used as a food additive and in infant formula (111258). However, a tolerable upper intake level (UL) has not been established (15,6243). ...when applied topically and appropriately (67795,105190,111262). Infant products containing pantothenic acid and its derivatives have been used safely in concentrations of up to 5% for infant shampoos and 2.5% for infant lotions and oils. The Cosmetic Ingredient Review Expert Panel has concluded that pantothenic acid and derivatives are safe for use in topical infant products. (111258).

PREGNANCY: LIKELY SAFE
when used orally and appropriately. The daily adequate intake (AI) during pregnancy is 6 mg (3094).

LACTATION: LIKELY SAFE
when used orally and appropriately. The daily adequate intake (AI) during lactation is 7 mg (3094).

(Read more about PANTOTHENIC ACID)

LIKELY SAFE ...when used orally and appropriately. Riboflavin 400 mg daily has been taken for up to 3 months, and 10 mg daily has been taken safely for up to 6 months (4912,91752,105480). A tolerable upper intake level (UL) has not been established (3094,91752,94089).

CHILDREN: LIKELY SAFE
when used orally and appropriately in dietary amounts. A tolerable upper intake level (UL) has not been established (3094,94089). ...when used orally in higher doses for up to 1 year. Doses of 100-200 mg daily have been used safely for 4-12 months in children ages 9-13 years (71483,105484).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately in dietary amounts. A tolerable upper intake level (UL) has not been established (3094,94089).

(Read more about RIBOFLAVIN)

LIKELY SAFE ...when used in amounts found in foods. Typical daily intakes for adults range from 40-400 mg (101471).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts. Taurine 2-4 grams daily in two or three divided doses has been used safely in studies lasting up to 3 months (5248,5271,8217,8221,10454,77147,95612,98337,104165,104167). Higher doses of taurine 6 grams daily have been used safely in studies lasting up to 4 weeks (98336,98337). A risk assessment of orally administered taurine has identified an Observed Safe Level (OSL) of up to 3 grams daily for healthy adults (31996).

CHILDREN: LIKELY SAFE
when used in amounts found in foods.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately in medicinal amounts. Taurine 2.4-4.8 grams daily in three divided doses has been safely used in children 6-16 years of age for up to 12 weeks (103210).

PREGNANCY AND LACTATION: LIKELY SAFE
when used in amounts found in foods. There is insufficient reliable information available about the safety of taurine when used in medicinal amounts during pregnancy and lactation; avoid using.

(Read more about TAURINE)

LIKELY SAFE ...when used orally, topically, intravenously, intramuscularly, or intranasally and appropriately. Vitamin B12 is generally considered safe, even in large doses (15,1344,1345,1346,1347,1348,2909,6243,7289,7881)(9414,9416,10126,14392,15765,82832,82949,82860,82864,90386)(111334,111551).

PREGNANCY: LIKELY SAFE
when used orally in amounts that do not exceed the recommended dietary allowance (RDA). The RDA for vitamin B12 during pregnancy is 2.6 mcg daily (6243). There is insufficient reliable information available about the safety of larger amounts of vitamin B12 during pregnancy.

LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the recommended dietary allowance (RDA). The RDA of vitamin B12 during lactation is 2.8 mcg daily (6243). There is insufficient reliable information available about the safety of larger amounts of vitamin B12 while breastfeeding.

(Read more about VITAMIN B12)

LIKELY SAFE ...when used orally and appropriately in doses that do not exceed the tolerable upper intake level (UL) of 100 mg daily in the form of pyridoxine for adults (15,6243). ...when used parenterally and appropriately. Injectable vitamin B6 (pyridoxine) is an FDA-approved prescription product (15).

POSSIBLY SAFE ...when used orally and appropriately in doses of 101-200 mg daily (6243,8558).

POSSIBLY UNSAFE ...when used orally in doses at or above 500 mg daily. High doses, especially those exceeding 1000 mg daily or total doses of 1000 grams or more, pose the most risk. However, neuropathy can occur with lower daily or total doses (6243,8195). ...when used intramuscularly in high doses and frequency due to potential for rhabdomyolysis (90795).

CHILDREN: LIKELY SAFE
when used orally and appropriately in doses that do not exceed the tolerable upper intake level (UL) of vitamin B6 in the form of pyridoxine 30 mg daily for children aged 1-3 years, 40 mg daily for 4-8 years, 60 mg daily for 9-13 years, and 80 mg daily for 14-18 years (6243).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately in amounts exceeding the recommended dietary allowance (5049,8579,107124,107125,107135).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses, long-term (6243).

PREGNANCY: LIKELY SAFE
when used orally and appropriately. A special sustained-release product providing vitamin B6 (pyridoxine) 75 mg daily is FDA-approved for use in pregnancy. Vitamin B6 (pyridoxine) is also considered a first-line treatment for nausea and vomiting in pregnancy by the American College of Obstetrics and Gynecology (111601). However, it should not be used long-term or without medical supervision and close monitoring. The tolerable upper intake level (UL) refers to vitamin B6 in the form of pyridoxine and is 80 mg daily for those aged 14-18 years and 100 mg daily for 19 years and older (6243).

PREGNANCY: POSSIBLY UNSAFE
when used orally in excessive doses. There is some concern that high-dose maternal vitamin B6 (pyridoxine) can cause neonatal seizures (4609,6397,8197).

LACTATION: LIKELY SAFE
when used orally in doses not exceeding the tolerable upper intake level (UL) of vitamin B6 in the form of pyridoxine 80 mg daily for those aged 14-18 years and 100 mg daily for those 19 years and older. The recommended dietary allowance (RDA) in lactating women is 2 mg daily (6243). There is insufficient reliable information available about the safety of vitamin B6 when used in higher doses in breast-feeding women.

(Read more about VITAMIN B6)

LIKELY SAFE ...when used orally, topically, intramuscularly, or intravenously and appropriately. Vitamin C is safe when taken orally in doses below the tolerable upper intake level (UL). Tell patients not to exceed the UL of 2000 mg daily (1959,4713,4714,4844). ...when used intravenously or intramuscularly and appropriately. Injectable vitamin C is an FDA-approved prescription product (15) and has been used with apparent safety in clinical trials up to 150 mg/kg daily for up to 4 days (114489) and up to 200 mg/kg daily for up to 2 days (114492).

POSSIBLY UNSAFE ...when used orally in excessive doses. Doses greater than the tolerable upper intake level (UL) of 2000 mg daily can significantly increase the risk of adverse effects such as osmotic diarrhea and gastrointestinal upset (4844).

CHILDREN: LIKELY SAFE
when used orally and appropriately (4844,10352,14443).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive amounts. Tell patients not to use doses above the tolerable upper intake level (UL) of 400 mg daily for children ages 1 to 3 years, 650 mg daily for children 4 to 8 years, 1200 mg daily for children 9 to 13 years, and 1800 mg daily for adolescents 14 to 18 years. Higher doses can cause osmotic diarrhea and gastrointestinal upset (4844).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately (4844).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses. Tell patients over age 19 not to use doses exceeding the UL of 2000 mg daily when pregnant or breast-feeding and for those 14-18 years of age not to use doses exceeding 1800 mg daily when pregnant or breast-feeding. Higher doses can cause osmotic diarrhea and gastrointestinal upset. Large doses of vitamin C during pregnancy can also cause newborn scurvy (4844); avoid using.

(Read more about VITAMIN C)

(Read more about BIOTIN)