Kicks Sour Apple by Dixie Botanicals

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). 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). Doses above 10 mg/kg daily reduce the risk of apnea, bronchopulmonary dysplasia, and problematic extubation compared with doses below 10 mg/kg/day (98807,100364). 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). 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

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).

Athletic performance. Oral caffeine taken 30-150 minutes prior to physical activity seems to modestly improve muscle strength and physical endurance, although the magnitude of effect is variable and may be dependent on a number of patient- and activity-specific factors. Caffeine in excess of 800 mg daily can result in 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, muscle strength, physical endurance, and athletic performance (10203,11832,37648,37894,38054,38063,95955,100362,100365,100371)(103701,103703,108798,111250). Meta-analyses of studies using caffeine 3-9 mg/kg as a single dose prior to endurance time trials reports 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). Another meta-analysis of small clinical trials shows that the benefit of caffeine on athletic performance seems to increase with increased duration of the 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). 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. 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. 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). 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 very small study in healthy males shows that taking caffeine alone, 6 mg/kg prior to bench press exercises, has a greater ergogenic benefit than a multi-ingredient supplement containing the same dose of caffeine in combination with L-tyrosine, beta-alanine, L-citrulline maleate, arginine alpha-ketoglutarate, and L-taurine (111250). 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). 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), 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 further research is needed to clarify how these polymorphisms may impact the athletic performance benefits of caffeine. 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 however these studies have not demonstrated clear benefits in athletic performance over taking caffeine alone (112740).
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).
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).

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.

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.
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 resection. Details: A small clinical study in adults undergoing elective laparoscopic colon or rectal resection with primary anastomosis shows that caffeine citrate 100 mg three times daily, starting on the morning of postoperative day 1, reduces the time to self-reported first bowel movement by about 18 hours when compared with placebo. There was no difference between groups in time to self-reported first flatus (108808). Another small study in adults undergoing elective laparoscopic colectomy shows that taking caffeine 100 mg or 200 mg three times daily does not reduce the mean time to first bowel movement, colonic transit time, or length of hospital stay when compared with placebo (111484). However, a meta-analysis of these two clinical trials shows that taking caffeine does not decrease the time to the first stool or length of hospital stay when compared with control (112732).
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.

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

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).

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.

Thiamine deficiency. Oral thiamine prevents and treats thiamine deficiency syndromes. Details: Thiamine deficiency is treated with oral thiamine 5-30 mg daily as a single dose or in divided daily doses for one month. For severe deficiency, thiamine up to 300 mg daily can be used (15).Thiamine deficiency can occur in people with malabsorption conditions such as alcohol use disorder, cirrhosis, and gastrointestinal diseases; in those with inadequate intake due to anorexia, nausea, and vomiting; and in those with increased requirements, including pregnancy, increased carbohydrate intake, increased physical activity, hyperthyroidism, infection, and liver disease. However, deficiency is rare with these conditions (15). The elderly might also be at increased risk for subclinical thiamine deficiency (11076).
Wernicke-Korsakoff syndrome (WKS). Parenteral thiamine is effective for treating symptoms of WKS. Details: Parenteral administration of thiamine 5-200 mg daily for 2 days decreases the risk of developing WKS and decreases symptoms of WKS in acute alcohol withdrawal. Between 30% and 80% of alcoholics are suspected to have thiamine deficiency (11075). An optimal dose for treating WKS has not been established; however, early research suggests that a 200 mg intramuscular dose may be more effective than lower doses (11075). In contrast, a moderate-sized clinical trial in adults with a history of heavy alcohol use who were asymptomatic or symptomatic for WKS shows that there is no benefit to administering high doses (300 mg 3 times daily) compared with medium (100 mg 3 times daily) or low (100 mg daily) doses of parenteral thiamine on cognitive or neurological functioning (111690). The study may have been inadequately powered to detect a difference between groups.

Dysmenorrhea. Oral thiamine might reduce pain in some patients with dysmenorrhea. Details: A clinical study in adolescent Iranian females with dysmenorrhea shows that taking thiamine 100 mg alone or along with fish oil 500 mg daily for 2 months moderately reduces pain intensity and duration when compared with placebo (89341). Another preliminary clinical study in Indian females 12-21 years of age with moderate to severe primary dysmenorrhea shows that taking thiamine 100 mg daily for 90 days eliminates pain in 87% of participants when compared to baseline (77820). The validity of this finding is limited by the lack of a placebo group. Furthermore, available research was conducted in India and Iran, so it is unclear if these findings are generalizable to other geographic locations.

Coronary artery bypass graft (CABG) surgery. Intravenous thiamine does not seem to improve outcomes after CABG surgery. Details: A small clinical study in adults undergoing CABG surgery with cardiopulmonary bypass shows that giving intravenous thiamine 200 mg immediately prior to surgery and immediately after surgery does not improve clinical outcomes or lactate levels when compared with placebo (97010). Larger doses of thiamine also don't seem to be beneficial. Another small clinical study in patients receiving CABG with cardiopulmonary bypass shows that giving thiamine 600 mg intravenously on the day of surgery, and 400 mg daily for three postoperative days, does not improve postoperative outcomes when compared with placebo (103000).
Heart failure. Most research suggests that oral or intravenous thiamine does not improve outcomes in patients with heart failure. Details: Observational research suggests that having heart failure is associated with 2.5-fold increased odds of having thiamine deficiency, possibly because of diuretic use, intestinal malabsorption, and metabolism changes. However, it is unclear if thiamine supplementation is beneficial. A meta-analysis of 2 small clinical trials in adults with systolic heart failure and unclear thiamine status shows that thiamine 200-300 mg given orally or by IV for 7-28 days improves left ventricular ejection fraction (LVEF) by 3% when compared with control (97012). However, other meta-analyses and clinical studies in adults with heart failure with or without thiamine deficiency show that taking intravenous, intramuscular, or oral thiamine 100-500 mg daily does not improve LVEF fraction, left ventricular end-diastolic volume, dyspnea, mortality, hospitalization, or exercise tolerance when compared with placebo or control (103002,111682,111686,111688).
Mosquito repellent. Oral thiamine does not seem to repel mosquitos. Details: Clinical research in healthy volunteers shows that taking thiamine does not improve mosquito repellency when compared with taking vitamin C as a control (18016).
Sepsis. Intravenous or oral thiamine, alone or in combination with vitamin C and hydrocortisone, does not seem to reduce mortality or prevent organ failure in sepsis or septic shock. Details: Multiple meta-analyses of small clinical studies in patients with septic shock show that intravenous or oral thiamine 100-500 mg 2-3 times daily for 3-7 days is no better than placebo for improving mortality, end-organ damage, number of ventilator-free days, and duration of intensive care unit (ICU) stay (105443,107717,107727,111689). One meta-analysis suggests that administration of thiamine alone increases the risk of mortality in these patients (111689). Subgroup analyses including only higher quality studies also fail to show a benefit of thiamine (107717). Another recent small clinical trial in patients with septic shock shows that receiving the same dose of intravenous thiamine does not increase vasopressor-free days when compared with placebo (105441). Intravenous thiamine 200 mg every 12 hours has also been evaluated in combination with intravenous vitamin C 1.5-2 grams and hydrocortisone 50-200 mg every 6-12 hours for 4-10 days (HAT therapy). While some retrospective research found HAT therapy to be beneficial (100315,102980,111689), high-quality, prospective clinical research has shown no benefit (105447,109956,111689). Meta-analyses in patients with sepsis and septic shock shows that receiving HAT therapy does not improve mortality, kidney injury, number of ventilator-free days, or ICU length of stay when compared with control (102129,104027,104028,104032,102998,105447,109956,111642,111689). Additionally, the meta-analyses suggest that HAT therapy does not reverse shock or improve sequential organ failure assessment (SOFA) scores (109556,111642). However, one meta-analysis found that HAT therapy shortened the duration of vasopressor use when compared with placebo (111642). 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 immediate memory scores and development of posttraumatic stress disorder, HAT therapy was less beneficial when compared with placebo (111299).

Acute kidney injury (AKI). It is unclear if oral or intravenous thiamine is beneficial for treating or preventing AKI. Details: Observational research in adults admitted to the intensive care unit (ICU) with AKI has found that treatment with thiamine (dose unspecified) within the first 48 hours of admission is associated with 39% lower odds of in-hospital mortality and 28% higher odds of kidney function recovery when compared with patients that did not receive thiamine. Receiving thiamine was also associated with a 0.5-day reduction in ICU length of stay (107719).
Anxiety. Although there is interest in using oral thiamine for anxiety, there is insufficient reliable information about the clinical effects of thiamine for this purpose.
Cardiac arrest. It is unclear if intravenous thiamine reduces the risk of death after resuscitation from cardiac arrest. Details: A small clinical study in adults resuscitated from cardiac arrest shows that receiving intravenous thiamine 100 mg every 8 hours for 7 days does not reduce 28-day mortality when compare with a normal saline placebo (105442).
Cardiovascular disease (CVD). It is unclear if oral thiamine is beneficial for treating or preventing CVD. Details: Population research in Korea has found that insufficient dietary thiamine intake (daily intake of less than 1.22 mg in males or 1.03 mg in females) is associated with a 16% increased odds of developing angina or myocardial infarction when compared with sufficient dietary thiamine. However, the effects of thiamine supplementation on CVD have not been studied (107725).
Cataracts. Small studies suggest that increased dietary thiamine might help prevent cataracts. Details: Observational research has found that a high dietary intake of thiamine 10 mg daily is associated with 40% lower odds of nuclear cataracts (6378). Other population research has found that higher dietary intake of thiamine is associated with a modestly reduced risk of age-related lens opacification (14301).
Cervical cancer. It is unclear if oral thiamine reduces the risk of developing cervical cancer. Details: Epidemiological research has found that increasing intake of thiamine from dietary and supplemental sources, along with folic acid, riboflavin, and vitamin B12, is associated with a lower odds of precancerous cervical lesions (11074).
Child development. It is unclear if supplementing breastfeeding females with oral thiamine improves infant neurocognitive development. Details: Preliminary clinical research shows that supplementing breastfeeding females with oral thiamine, 1.2-10 mg daily for 22 weeks, starting at 2 weeks postpartum, does not improve most cognitive or neurodevelopmental scores in the child when compared with placebo. However, one subgroup analysis suggests that thiamine supplementation may improve language scores (107726).
Cognitive function. Oral thiamine has only been studied 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 thiamine hydrochloride 50 mg, other group B vitamins, bacopa, and ginkgo daily for 12 weeks does not improve measures of memory, attention, cognition, mood, or stress reactivity when compared with placebo. Subgroup analysis shows a possible benefit of the combination supplementation on measures of attention in those with an optimal diet at baseline (111334). It is unclear if these findings are due to thiamine, other ingredients, or the combination.
Coronavirus disease 2019 (COVID-19). It is unclear if intravenous or oral thiamine improves clinical outcomes in patients hospitalized with COVID-19. Details: A small observational study of adults admitted to the intensive care unit with COVID-19 has found that treatment with intravenous or oral thiamine 100 mg daily for an average of 7 days is associated with a 63% reduction in the odds of death within 30 days when compared with control. However, there was no associated reduction in duration of hospitalization or mechanical ventilation (107721). In addition, a small observational study of adults with encephalopathy that were mechanically ventilated secondary to COVID-19 has found that taking thiamine 500 mg three times daily orally for 5 days improves neurological manifestations, including ophthalmoparesis and ataxia, when compared with baseline. The validity of this study is limited by the lack of a comparator group (107722).
Critical illness (trauma). It is unclear if oral or intravenous thiamine is beneficial in patients with critical illness. Details: A meta-analysis of critically ill patients shows that treatment with oral or intravenous thiamine 100-600 mg daily for up to 7 days does not affect the need for mechanical ventilation, duration of hospital stay, or mortality when compared with control (107727).
Delirium. It is unclear if oral or intravenous thiamine helps to prevent or treat delirium. Details: In critically ill patients, a meta-analysis of clinical research shows that treatment with oral or intravenous thiamine 100-600 mg daily for up to 7 days reduces the odds of developing delirium by 42% when compared with control (107727). However, some 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). In non-critically ill, hospitalized adults with altered mental status, retrospective, observational research has also found that administration of oral or intravenous thiamine is not associated with improved cognitive function or reduced in-hospital mortality when compared with control (107723). Preliminary clinical research in adults undergoing an allogeneic hematopoietic stem cell transplant also shows that administering thiamine 200 mg three times a day intravenously for 7 days does not prevent delirium or shorten duration of delirium when compared with placebo (107718).
Dementia. It is unclear if oral thiamine is beneficial for the prevention of dementia. Details: Observational research in patients with alcohol use disorder has found that taking thiamine is associated with a 24% to 46% lower risk of developing dementia when compared with not taking thiamine (102999).
Depression. It is unclear if oral thiamine is beneficial in patients with depression. Details: Meta-analyses of population research in adults has found that high dietary consumption of thiamine is associated with a 10% to 31% lower risk of having depression when compared with low dietary consumption of thiamine. However, this research did not evaluate the effects of thiamine supplementation on depression (107133,107725). One small clinical study in adults with major depressive disorder shows that taking thiamine 300 mg daily in conjunction with fluoxetine 20 mg daily leads to greater improvements in depressive symptoms at 6 weeks when compared to fluoxetine with placebo. This benefit was no longer present at 12 weeks. This suggests that thiamine may accelerate improvement in symptoms during initiation of fluoxetine therapy (97013).
Diabetes. It is unclear if oral thiamine is beneficial for type 2 diabetes or gestational diabetes. Details: A meta-analysis of 6 clinical studies in adults with type 2 diabetes shows that taking thiamine 100-300 mg or its derivative benfotiamine 120-900 mg daily for 1-3 months does not reduce glycated hemoglobin (HbA1c), fasting blood glucose, or postprandial blood glucose when compared with placebo (111681). A large, prospective cohort study in adults without type 2 diabetes suggests that the risk of new-onset diabetes is minimized in adults consuming thiamine 0.75-1.10 mg daily from the diet, while lower and higher thiamine intake levels are associated with an increased risk of new-onset diabetes (111685). Thiamine has also been studied for preventing gestational diabetes. A large, prospective cohort study in pregnant adults suggests that higher supplementation with thiamine during the first and second trimesters is associated with a lower risk of gestational diabetes when compared with lower levels of total thiamine intake. However, this effect was not found for dietary intake of thiamine, only supplementation. Additionally, the participants were mostly Han Chinese adults, limiting the generalizability of the findings to other populations (111680).
Diabetic nephropathy. It is unclear if oral thiamine is beneficial for diabetic nephropathy. Details: A small clinical study in patients with early-stage diabetic nephropathy and microalbuminuria shows that taking thiamine 100 mg three times daily for 3 months decreases urinary albumin excretion, but does not affect glomerular filtration rate (GFR), when compared with placebo (16556).
Diabetic neuropathy. Although there is interest in using oral thiamine for diabetic neuropathy, there is insufficient reliable information about the clinical effects of thiamine for this condition.
Dry eye. Oral thiamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with dry eye suggests that adding unspecified doses of thiamine and mecobalamin to treatment with daily artificial tears and corticosteroid drops might slightly improve overall symptoms when compared with only artificial tears and corticosteroid drops for 1 month. There were no differences between groups at 2 months (105444). This finding is limited due to incomplete reporting and a lack of adjustment for multiple hypothesis testing.
Dyslipidemia. It is unclear if oral thiamine is beneficial for treating or preventing dyslipidemia. Details: A meta-analysis of 3 clinical studies in adults with type 2 diabetes shows that taking thiamine 100-300 mg or its derivative benfotiamine 120-900 mg daily for 1-3 months does not improve low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides when compared with placebo (111681). Observational research in Korea suggests that insufficient dietary thiamine intake (daily intake of less than 1.22 mg in males or 1.03 mg in females) is associated with 10% higher odds of developing dyslipidemia when compared with sufficient dietary thiamine intake. However, the effects of thiamine supplementation on dyslipidemia have not been studied (107725).
Emergence delirium. It is unclear if intravenous thiamine helps to prevent emergence delirium in patients after surgery. Details: One clinical study in adults in the intensive care unit (ICU) after gastrointestinal surgery shows that receiving intravenous thiamine 200 mg daily for 3 days is associated with up to 84% lower odds of emergence delirium on the first two days, but not on the third day, when compared with a normal saline control (105440).
Fatigue. It is unclear if oral thiamine is beneficial in patients with fatigue. Details: A small clinical crossover study in patients with chronic fatigue and inflammatory bowel disease (IBD) shows that taking thiamine 600-1800 mg daily for 20 days reduces fatigue scores when compared with placebo (105438). Taking oral thiamine 300 mg daily for an additional 12 weeks did not seem to affect fatigue scores when compared with placebo. However, an observational follow-up study found that those who self-continued thiamine for an additional 24 weeks after the study ended reported lower fatigue scores when compared with those who did not self-continue thiamine (107720).
Glaucoma. Although there is interest in using oral thiamine for glaucoma, there is insufficient reliable information about the clinical effects of thiamine for this condition.
Herpes zoster (shingles). It is unclear if subcutaneous thiamine is beneficial in patients with shingles. Details: A small clinical trial shows that receiving subcutaneous thiamine 100 mg injections six times weekly for 4 weeks reduces itching by at least 30% in 67% of patients with herpes zoster. However, thiamine does not appear to significantly reduce pain in most patients (90396).
Hypertension. It is unclear if oral thiamine is beneficial in treating or preventing hypertension. Details: Population research in Korea has found that insufficient dietary thiamine intake (daily intake of less than 1.22 mg in males or 1.03 mg in females) is associated with a 5% increased odds of developing hypertension when compared with sufficient dietary thiamine. However, the effects of thiamine supplementation on hypertension have not been studied (107725).
Impaired glucose tolerance (prediabetes). It is unclear if oral thiamine is beneficial in patients with prediabetes. Details: A very small clinical trial in patients with prediabetes shows that taking thiamine 100 mg by mouth three times daily for 6 weeks modestly decreases 2-hour postprandial plasma glucose levels when compared to baseline and decreases fasting blood glucose levels when compared with placebo (91168).
Kidney failure. Oral thiamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary, low-quality, clinical research in adults with kidney failure undergoing regular hemodialysis shows that taking oral thiamine 90 mg daily with folic acid 30 mg daily for 96 weeks reduces overall mortality by 67% and improves cognitive scores by 31% when compared with no intervention (107724). It is unclear if this effect is due to thiamine, folic acid, or the combination.
Migraine headache. It is unclear if dietary thiamine is beneficial for the prevention or treatment of migraine headache. Details: A large, retrospective, cross-sectional study suggests that higher dietary intake of thiamine is associated with lower odds of severe headache or migraine, especially in females (111684). The validity of these effects is limited by the subjective outcome measures and retrospective study design.
Pneumonia. It is unclear if thiamine is beneficial for patients with pneumonia. Details: A large retrospective cohort study in adults hospitalized with pneumonia and active alcohol use disorder suggests that parenteral administration of thiamine is associated with reduced 14-day mortality and more frequent discharges home, but not a shorter length of stay or fewer ICU transfers, when compared with no thiamine use. Furthermore, parenteral thiamine doses above 200 mg do not appear to improve mortality but may be associated with longer length of stay and less frequent discharges home when compared with low oral doses of thiamine or parenteral thiamine at doses under 200 mg (111679). The validity of these effects is limited by the retrospective study design.
Ventilator-associated pneumonia (VAP). It is unclear if oral or parenteral thiamine is beneficial for patients with VAP. Details: A retrospective study in adults with VAP in the intensive care unit (ICU) suggests that supplementation with intravenous or oral thiamine may be associated with reduced ICU and in-hospital mortality (111683). The validity of these effects is limited by the retrospective study design. More evidence is needed to rate thiamine for these uses.

VITAMIN B12

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).

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).

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).

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.

VITAMIN B6

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).

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).

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).
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).

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).
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 using oral contraceptives. Details: 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).
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.

Safety view details

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

CAFFEINE

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).

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).

LIKELY SAFE ...when used orally and appropriately. A tolerable upper intake level (UL) has not been established for thiamine, and doses up to 50 mg daily have been used without adverse effects (15,6243). ...when used intravenously or intramuscularly and appropriately. Injectable thiamine is an FDA-approved prescription product (15,105445).

CHILDREN: LIKELY SAFE
when used orally and appropriately in dietary amounts. A tolerable upper intake level (UL) has not been established for healthy individuals (6243).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in dietary amounts of 1. 4 mg daily. A tolerable upper intake level (UL) has not been established for healthy individuals (3094,6243).

VITAMIN B12

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.

VITAMIN B6

LIKELY SAFE ...when used orally and appropriately in doses that do not exceed the tolerable upper intake level (UL) of 100 mg daily for adults (15). ...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 (3094).

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 (3094).

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.

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 recommended dietary allowance (RDA) (3094). The RDA in lactating women is 2 mg daily. There is insufficient reliable information available about the safety of vitamin B6 when used in higher doses in breast-feeding women.

Interactions with Drugs view details

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

CAFFEINE

ADENOSINE (Adenocard)

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, caffeine might decrease the vasodilatory effects of adenosine and interfere with its use prior to stress testing.

Details

Some evidence shows that caffeine is a competitive inhibitor of adenosine and can reduce the vasodilatory effects of adenosine in humans (38172). However, other research shows that caffeine does not seem to affect supplemental adenosine because high interstitial levels of adenosine overcome the antagonistic effects of caffeine (11771). It is recommended that methylxanthines and methylxanthine-containing products be stopped 24 hours prior to pharmacological stress tests (11770). However, methylxanthines appear more likely to interfere with dipyridamole (Persantine) than adenosine-induced stress testing (11771).

ALCOHOL (Ethanol)

Interaction Rating = Minor Be watchful with this combination.

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

Theoretically, concomitant use might increase levels and adverse effects of caffeine.

Details

Alcohol reduces caffeine metabolism. Concomitant use of alcohol can increase caffeine serum concentrations and the risk of caffeine adverse effects (6370).

ANTICOAGULANT/ANTIPLATELET DRUGS

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, caffeine may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.

Details

Caffeine is reported to have antiplatelet activity. Theoretically, it might increase the risk of bleeding when used concomitantly with these agents (8028,8029); however, this interaction has not been reported in humans.

ANTIDIABETES DRUGS

Interaction Rating = Minor Be watchful with this combination.

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

Theoretically, taking caffeine with antidiabetes drugs might interfere with blood glucose control.

Details

Data are conflicting. Reports claim that caffeine might increase or decrease blood sugar (6024,8646).

BETA-ADRENERGIC AGONISTS

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, large amounts of caffeine might increase the cardiac inotropic effects of beta-agonists (15).

CARBAMAZEPINE (Tegretol)

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, caffeine might reduce the effects of carbamazepine and increase the risk for convulsions.

Details

Animal research suggests that taking caffeine can lower the anticonvulsant effects of carbamazepine and can induce seizures when taken in doses above 400 mg/kg (23559,23561). Human research has shown that taking caffeine 300 mg in three divided doses along with carbamazepine 200 mg reduces the bioavailability of carbamazepine by 32% and prolongs the plasma half-life of carbamazepine 2-fold in healthy individuals (23562).

CIMETIDINE (Tagamet)

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, cimetidine might increase the levels and adverse effects of caffeine.

Details

Cimetidine decreases the rate of caffeine clearance by 31% to 42% (11736).

CLOZAPINE (Clozaril)

Interaction Rating = Moderate Be cautious with this combination.

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

Caffeine might increase the levels and adverse effects of clozapine and acutely exacerbate psychotic symptoms.

Details

Caffeine might increase the effects and toxicity of clozapine. Caffeine doses of 400-1000 mg per day inhibit clozapine metabolism (5051). Clozapine is metabolized by cytochrome P450 1A2 (CYP1A2). Although researchers speculate that caffeine might inhibit CYP1A2, there is no reliable evidence that caffeine affects CYP1A2. There is also speculation that genetic factors might make some patients more sensitive to an interaction between clozapine and caffeine (13741). In one case report, severe, life-threatening clozapine toxicity and multiorgan system failure occurred in a patient with schizophrenia stabilized on clozapine who consumed caffeine 600 mg daily (108817).

CONTRACEPTIVE DRUGS

Interaction Rating = Minor Be watchful with this combination.

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

Theoretically, contraceptive drugs might increase the levels and adverse effects of caffeine.

Details

Oral contraceptives decrease the rate of caffeine clearance by 40-65% (2714,11737).

CYTOCHROME P450 1A2 (CYP1A2) INHIBITORS

Interaction Rating = Minor Be watchful with this combination.

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

Theoretically, concomitant use might increase the levels and adverse effects of caffeine.

Details

Caffeine is metabolized by CYP1A2. Theoretically, drugs that inhibit CYP1A2 may decrease the rate of caffeine clearance and increase caffeine levels (5051,11741).

DIPYRIDAMOLE (Persantine)

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, caffeine might decrease the vasodilatory effects of dipyridamole and interfere with its use prior to stress testing.

Details

Caffeine inhibits dipyridamole-induced vasodilation (11770,11772). It is recommended that methylxanthines and methylxanthine-containing products be stopped 24 hours prior to pharmacological stress tests (11770). Methylxanthines appear more likely to interfere with dipyridamole (Persantine) than adenosine-induced stress testing (11771).

DISULFIRAM (Antabuse)

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, disulfiram use might increase the levels and adverse effects of caffeine.

Details

Disulfiram decreases the rate of caffeine clearance (11840).

DIURETIC DRUGS

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, using caffeine with diuretic drugs might increase the risk of hypokalemia.

Details

Caffeine, especially in excessive amounts, can reduce potassium levels due to stimulation of the sodium-potassium pump (23579,37905,37953,38003,38034). Diuretics can also cause lower potassium levels.

EPHEDRINE

Interaction Rating = Major Do not take this combination.

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

Theoretically, concomitant use might increase the risk for stimulant adverse effects.

Details

Use of ephedrine with caffeine can increase the risk of stimulatory adverse effects. There is evidence that using ephedrine with caffeine might increase the risk of serious life-threatening or debilitating adverse effects such as hypertension, myocardial infarction, stroke, seizures, and death (1275,6486,10307).

ESTROGENS

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, estrogens might increase the levels and adverse effects of caffeine.

Details

Estrogen inhibits caffeine metabolism (2714,23570).

ETHOSUXIMIDE (Zarontin)

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, caffeine might reduce the effects of ethosuximide and increase the risk for convulsions.

Details

Animal research suggests that caffeine 92.4 mg/kg can decrease the anticonvulsant activity of ethosuximide (23560). However, this effect has not been reported in humans.

FELBAMATE (Felbatol)

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, caffeine might reduce the effects of felbamate and increase the risk for convulsions.

Details

Animal research suggests that a high dose of caffeine 161.7 mg/kg can decreases the anticonvulsant activity of felbamate (23563). However, this effect has not been reported in humans.

FLUCONAZOLE (Diflucan)

Interaction Rating = Minor Be watchful with this combination.

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

Theoretically, fluconazole might increase the levels and adverse effects of caffeine.

Details

Fluconazole decreases caffeine clearance by approximately 25% (11022).

FLUTAMIDE (Eulexin)

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, caffeine might increase the levels and adverse effects of flutamide.

Details

In vitro evidence suggests that caffeine can inhibit the metabolism of flutamide (23553). However, this effect has not been reported in humans.

FLUVOXAMINE (Luvox)

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, fluvoxamine might increase the levels and adverse effects of caffeine.

Details

Fluvoxamine reduces caffeine metabolism (6370).

LITHIUM

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, abrupt caffeine withdrawal might increase the levels and adverse effects of lithium.

Details

Caffeine has diuretic activity. When abruptly discontinued, it might alter the clearance of lithium (609). There are two case reports of lithium tremor that worsened upon abrupt coffee withdrawal (610).

METFORMIN (Glucophage)

Interaction Rating = Minor Be watchful with this combination.

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

Theoretically, metformin might increase the levels and adverse effects of caffeine.

Details

Animal research suggests that metformin can reduce caffeine metabolism (23571). However, this effect has not been reported in humans.

METHOXSALEN (Oxsoralen)

Interaction Rating = Minor Be watchful with this combination.

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

Theoretically, methoxsalen might increase the levels and adverse effects of caffeine.

Details

Methoxsalen reduces caffeine metabolism (23572).

MEXILETINE (Mexitil)

Interaction Rating = Minor Be watchful with this combination.

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

Theoretically, mexiletine might increase the levels and adverse effects of caffeine.

Details

Mexiletine reduces caffeine metabolism (1260,11741).

MONOAMINE OXIDASE INHIBITORS (MAOIs)

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, concomitant use might increase the risk of a hypertensive crisis.

Details

Caffeine has been shown to inhibit monoamine oxidase (MAO) A and B in laboratory studies (37724,37877,37912,38108). Concomitant intake of large amounts of caffeine with MAOIs might precipitate a hypertensive crisis (15). In a case report, a patient that consumed 10-12 cups of caffeinated coffee and took the MAOI tranylcypromine presented with severe hypertension (91086). Hypertension was resolved after the patient switched to drinking decaffeinated coffee.

NICOTINE

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, concomitant use might increase the risk of hypertension.

Details

Concomitant use of caffeine and nicotine has been shown to have additive cardiovascular effects, including increased heart rate and blood pressure. Blood pressure was increased by 10.8/12.4 mmHg when the agents were used concomitantly (36549).

PENTOBARBITAL (Nembutal)

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, caffeine might decrease the effects of pentobarbital.

Details

Caffeine might negate the hypnotic effects of pentobarbital (13742).

PHENOBARBITAL (Luminal)

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, caffeine might reduce the effects of phenobarbital and increase the risk for convulsions.

Details

Animal research suggests that caffeine can decrease the anticonvulsant activity of phenobarbital (23558,23559,23561). However, the exact mechanism of this interaction is unclear.

PHENOTHIAZINES

Interaction Rating = Minor Be watchful with this combination.

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

Theoretically, phenothiazines might increase the levels and adverse effects of caffeine.

Details

Phenothiazines, including perazine, chlorpromazine, levomepromazine, and thioridazine, can reduce the metabolism of caffeine by inhibiting cytochrome P450 1A2 (CYP1A2) (23573,23574).

PHENYLPROPANOLAMINE

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, phenylpropanolamine might increase the risk of hypertension, as well as the levels and adverse effects of caffeine.

Details

Concomitant use of phenylpropanolamine and caffeine might cause an additive increase in blood pressure (11738). Phenylpropanolamine also seems to increase caffeine serum levels (13743).

PHENYTOIN (Dilantin)

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, caffeine might reduce the effects of phenytoin and increase the risk for convulsions.

Details

Animal research suggests that caffeine can decrease the anticonvulsant activity of phenytoin (23559,23561). The effect does not seem to be related to the seizure threshold-lowering effects of caffeine. However, the exact mechanism of this interaction is unclear.

PIOGLITAZONE (Actos)

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, caffeine might increase the levels and clinical effects of pioglitazone.

Details

Animal research suggests that caffeine can modestly increase the maximum concentration, area under the curve, and half-life of pioglitazone, and also reduce its clearance. This increased the antidiabetic effects of pioglitazone (108812). However, the exact mechanism of this interaction is unclear.

QUINOLONE ANTIBIOTICS

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, quinolone antibiotics might increase the levels and adverse effects of caffeine.

Details

Quinolones (also called fluoroquinolones) can decrease caffeine clearance by inhibiting cytochrome P450 1A2 (CYP1A2) enzyme (606,607,608,23554,23555,23556).

RILUZOLE (Rilutek)

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, concomitant use might increase the levels and adverse effects of both caffeine and riluzole.

Details

Caffeine and riluzole are both metabolized by cytochrome P450 1A2 (CYP1A2), and concomitant use might reduce the metabolism of one or both agents (11739).

STIMULANT DRUGS

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, concomitant use might increase stimulant adverse effects.

Details

Due to the central nervous system (CNS) stimulant effects of caffeine, concomitant use with stimulant drugs can increase the risk of adverse effects (11832).

TERBINAFINE (Lamisil)

Interaction Rating = Minor Be watchful with this combination.

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

Theoretically, terbinafine might increase the levels and adverse effects of caffeine.

Details

Terbinafine decreases the clearance of intravenous caffeine by 19% (11740).

THEOPHYLLINE

Interaction Rating = Moderate Be cautious with this combination.

Severity = Mild • Occurrence = Probable • Level of Evidence = C

Theoretically, caffeine might increase the levels and adverse effects of theophylline.

Details

Large amounts of caffeine might inhibit theophylline metabolism (11741).

TIAGABINE (Gabitril)

Interaction Rating = Minor Be watchful with this combination.

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

Theoretically, caffeine might increase the levels and adverse effects of tiagabine.

Details

Animal research suggests that chronic caffeine administration can increase the serum concentrations of tiagabine. However, concomitant use does not seem to reduce the antiepileptic effects of tiagabine (23561).

TICLOPIDINE (Ticlid)

Interaction Rating = Minor Be watchful with this combination.

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

Theoretically, ticlopidine might increase the levels and adverse effects of caffeine.

Details

In vitro evidence suggests that ticlopidine can inhibit caffeine metabolism (23557). However, this effect has not been reported in humans.

VALPROATE

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, caffeine might reduce the effects of valproate and increase the risk for convulsions.

Details

Animal research suggests that caffeine can decrease the anticonvulsant activity of valproate (23558,23559,23561,37882). However, the exact mechanism of this interaction is unclear.

VERAPAMIL (Calan, others)

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, verapamil might increase the levels and adverse effects of caffeine.

Details

Verapamil increases plasma caffeine concentrations by 25% (11741).

None known.

TRIMETHOPRIM (Proloprim)

Interaction Rating = Minor Be watchful with this combination.

Severity = Insignificant • Occurrence = Probable • Level of Evidence = B

Trimethoprim might increase blood levels of thiamine.

Details

In vitro, animal, and clinical research suggest that trimethoprim inhibits intestinal thiamine transporter ThTR-2, hepatic transporter OCT1, and renal transporters OCT2, MATE1, and MATE2, resulting in paradoxically increased thiamine plasma concentrations (111678).

VITAMIN B12

None known.

VITAMIN B6

AMIODARONE (Cordarone)

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, vitamin B6 might increase the photosensitivity caused by amiodarone.

Details

Despite initial case reports suggesting that pyridoxine may have a protective effect against amiodarone-induced photosensitivity, preliminary clinical research suggests that pyridoxine may actually exacerbate this adverse effect (8892,8893).

ANTIHYPERTENSIVE DRUGS

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, vitamin B6 may have additive effects when used with antihypertensive drugs.

Details

Research in hypertensive rats shows that vitamin B6 can decrease systolic blood pressure (30859,82959,83093). Similarly, clinical research in patients with hypertension shows that taking high doses of vitamin B6 may reduce systolic and diastolic blood pressure, possibly by reducing plasma levels of epinephrine and norepinephrine (83091).

LEVODOPA

Interaction Rating = Minor Be watchful with this combination.

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

Vitamin B6 may increase the metabolism of levodopa when taken alone, but not when taken in conjunction with carbidopa.

Details

Vitamin B6 (pyridoxine) enhances the metabolism of levodopa, reducing its clinical effects. However, this interaction does not occur when carbidopa is used concurrently with levodopa (Sinemet). Therefore, it is not likely to be a problem in most people (3046).

PHENOBARBITAL (Luminal)

Interaction Rating = Moderate Be cautious with this combination.

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

High doses of vitamin B6 may reduce the levels and clinical effects of phenobarbital.

Details

Preliminary clinical evidence suggests that vitamin B6 200 mg daily can reduce plasma levels of phenobarbital, possibly by increasing metabolism. It is not known whether lower doses have any effect. Advise people taking phenobarbital to avoid high doses of vitamin B6 (3046,10801).

PHENYTOIN (Dilantin)

Interaction Rating = Moderate Be cautious with this combination.

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

High doses of vitamin B6 may reduce the levels and clinical effects of phenytoin.

Details

Preliminary clinical evidence suggests that vitamin B6 200 mg daily can reduce plasma levels of phenytoin, possibly by increasing metabolism. It is not known whether lower doses have any effect. Advise people taking phenytoin to avoid high doses of vitamin B6 (3046,10801).

Report an Adverse Reaction to Kicks Sour Apple

Adverse Effects view details

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

CAFFEINE

General ...Caffeine in moderate doses is typically well tolerated.
Most Common Adverse Effects:
Orally: Anxiety, dependence with chronic use, diarrhea, diuresis, gastric irritation, headache, insomnia, muscular tremors, nausea, and restlessness.
Serious Adverse Effects (Rare):
Orally: Stroke has been reported rarely.

Cardiovascular ...Caffeine can temporarily increase blood pressure. Usually, blood pressure increases 30 minutes after ingestion, peaks in 1-2 hours, and remains elevated for over 4 hours (36539,37732,37989,38000,38300).
Although acute administration of caffeine can cause increased blood pressure, regular consumption does not seem to increase either blood pressure or pulse, even in mildly hypertensive patients (1451,1452,2722,38335). However, the form of caffeine may play a role in blood pressure increase after a more sustained caffeine use. In a pooled analysis of clinical trials, coffee intake was not associated with an increase in blood pressure, while ingesting caffeine 410 mg daily for at least 7 days modestly increased blood pressure by an average of 4.16/2.41 mmHg (37657). Another meta-analysis of clinical research shows that taking caffeine increases systolic and diastolic blood pressure by approximately 2 mmHg when compared with control. Preliminary subgroup analyses suggest that caffeine may increase blood pressure more in males or at doses over 400 mg (112738).
When used prior to intensive exercise, caffeine can increase systolic blood pressure by 7-8 mmHg (38308). The blood pressure-raising effects of caffeine are greater during stress (36479,38334) and after caffeine-abstinence of at least 24 hours (38241).
Epidemiological research suggests there is no association of caffeine consumption with incidence of hypertension (38190). Habitual coffee consumption also doesn't seem to be related to hypertension, but habitual consumption of sugared or diet cola is associated with development of hypertension (13739).
Epidemiological research has found that regular caffeine intake of up to 400 mg daily is not associated with increased incidence of atrial fibrillation (38018,38076,91028,91034,97451,97453,103708), atherosclerosis (38033), cardiac ectopy (91127), stroke (37804), ventricular arrhythmia (95948,97453), and cardiovascular disease in general (37805,98806). One clinical trial shows that in adults with diagnosed heart failure, consumption of 500 mg of coffee does not result in an increased risk for arrhythmia during exercise (95950). However, caffeine intake may pose a greater cardiovascular risk to subjects that are not regular users of caffeine. For example, in one population study, caffeinated coffee consumption was associated with an increased risk of ischemic stroke in subjects that don't regularly drink coffee (38102). In a population study in Japanese subjects, caffeine-containing medication use was modestly associated with hemorrhagic stroke in adults that do not consume caffeine regularly (91059).
The most common side effect of caffeine in neonates receiving caffeine for apnea is tachycardia (98807).

Dermatologic ...There are several case reports of urticaria after caffeine ingestion (36546,36448,36475).

Endocrine ...Some evidence shows caffeine is associated with fibrocystic breast disease or breast cancer in females; however, this is controversial since findings are conflicting (8043,108806). Restricting caffeine in females with fibrocystic breast conditions doesn't seem to affect breast nodularity, swelling, or pain (8996). A population analysis of the Women's Health Initiative observational study has found no association between consumption of caffeine-containing beverages and the incidence of invasive breast cancer in models adjusted for demographic, lifestyle, and reproductive factors (108806). Also, a dose-response analysis of 2 low-quality observational studies has found that high consumption of caffeine is not associated with an increased risk of breast cancer (108807).
Clinical research in healthy adults shows that an increase consumption of caffeine results in increased insulin resistance (91023).

Gastrointestinal ...Gastrointestinal upset, nausea, diarrhea, abdominal pain, and fecal incontinence may occur with caffeine intake (36466,37755,37806,37789,37830,38138,38136,38223,95956,95963). Also, caffeine may cause feeding intolerance and gastrointestinal irritation in infants (6023). Perioperative caffeine during cardiopulmonary bypass surgery seems to increase the rate of postoperative nausea and vomiting (97451). Caffeine and coffee consumption have been associated with an increase in the incidence of heartburn (37545,37575,38251,38259,38267) and gastrointestinal esophageal reflux disease (GERD) (38329,37633,37631,37603).

Genitourinary ...Caffeine, a known diuretic, may increase voiding, give a sense of urgency, and irritate the bladder (37874,37961,104580). In men with lower urinary tract symptoms, caffeine intake increased the risk of interstitial cystitis/painful bladder syndrome (38115). Excessive caffeine consumption may worsen premenstrual syndrome. Consumption of up to 10 cups of caffeinated drinks daily was associated with increased severity of premenstrual syndrome (38177). Finally, population research shows that exposure to caffeine was not associated with an increased risk of endometriosis (91035).

Immunologic ...Caffeine can cause anaphylaxis in sensitive individuals, although true IgE-mediated caffeine allergy seems to be relatively rare (11315).

Musculoskeletal ...Caffeine can induce or exacerbate muscular tremors (38136,37673,38161). There has also been a report of severe rhabdomyolysis in a healthy 40-year-old patient who consumed an energy drink containing 400 mg of caffeine (4 mg/kg) and then participated in strenuous weightlifting exercise (108818).
Epidemiological evidence regarding the relationship between caffeine use and the risk for osteoporosis is contradictory. Caffeine can release calcium from storage sites and increase its urinary excretion (2669,10202,11317,111489). Females with a genetic variant of the vitamin D receptor appear to be at an increased risk for the detrimental effect of caffeine on bone mass (2669). However, moderate caffeine intake, less than 300 mg daily, does not seem to significantly increase osteoporosis risk in most postmenopausal adults with normal calcium intake (2669,6025,10202,11317). Premature infants treated with intravenous caffeine for apnea of prematurity, have a lower bone mineral content compared with infants who are not treated with caffeine, especially when treatment extends beyond 14 days (111489).

Neurologic/CNS ...Caffeine can cause headaches, anxiety, jitteriness, restlessness, and nervousness (36466,37694,37755,37806,37865,37830,37889,38223,95952). In adolescents, there is an inverse correlation between the consumption of caffeine and various measurements of cognitive function (104579). Insomnia is a frequent adverse effect in children (10755). Caffeine may result in insomnia and sleep disturbances in adults as well (36445,36483,36512,36531,37598,37795,37819,37862,37864,37890)(37968,37971,38091,38242,91022,92952). Additionally, caffeine may exacerbate sleep disturbances in patients with acquired immunodeficiency syndrome (AIDS) (10204). Combining ephedra with caffeine can increase the risk of adverse effects. Jitteriness, hypertension, seizures, temporary loss of consciousness, and hospitalization requiring life support has been associated with the combined use of ephedra and caffeine (2729). Finally, epidemiological research suggests that consuming more than 190 mg of caffeine daily is associated with an earlier onset of Huntington disease by 3.6 years (91078).

Ocular/Otic ...In individuals with glaucoma, coffee consumption and caffeine intake has been found to increase intraocular pressure (8540,36464,36465,37670). The magnitude of this effect seems to depend on individual tolerance to caffeine. Some research in healthy young adults shows that caffeine increases intraocular pressure to a greater degree in low-consumers of caffeine (i.e., 1 cup of coffee or less daily) when compared to high-consumers (i.e., those consuming 2 cups of coffee or more daily) (100371). The peak increase of intraocular pressure seems to occur at about 1.5 hours after caffeine ingestion, and there is no notable effect 4 hours after ingestion (36462,100371).

Oncologic ...Most human studies which have examined caffeine or methylxanthine intake have found that they do not play a role in the development of various cancers, including breast, ovarian, brain, colon, rectal, or bladder cancer (37641,37737,37775,37900,38050,38169,38220,91054,91076,108806).

Psychiatric ...Caffeine may lead to habituation and physical dependence (36355,36453,36512,36599), with amounts as low as 100 mg daily (36355,36453). An estimated 9% to 30% of caffeine consumers could be considered addicted to caffeine (36355). Higher doses of caffeine have caused nervousness, agitation, anxiety, irritability, delirium, depression, sleep disturbances, impaired attention, manic behavior, psychosis and panic attacks (36505,37717,37818,37839,37857,37982,38004,38017,38028,38072)(38079,38138,38306,38325,38331,38332,97464). Similar symptoms have been reported in a caffeine-naïve individual experiencing fatigue and dehydration after a dose of only 200 mg, with resolution of symptoms occurring within 2 hours (95952).
Withdrawal: The existence or clinical importance of caffeine withdrawal is controversial. Some researchers think that if it exists, it appears to be of little clinical significance (11839). Headache is the most common symptom, due to cerebral vasodilation and increased blood flow (37769,37991,37998). Other researchers suggest symptoms such as tiredness and fatigue, decreased energy, alertness and attentiveness, drowsiness, decreased contentedness, depressed mood, difficulty concentration, irritability, and lack of clear-headedness are typical of caffeine withdrawal (13738). Withdrawal symptoms typically occur 12-24 hours after the last dose of caffeine and peak around 48 hours (37769,36600). Symptoms may persist for 2-9 days. Withdrawal symptoms such as delirium, nausea, vomiting, rhinorrhea, nervousness, restlessness, anxiety, muscle tension, muscle pains, and flushed face have been described. However, these symptoms may be from nonpharmacological factors related to knowledge and expectation of effects. Clinically significant symptoms caused by caffeine withdrawal may be uncommon (2723,11839). In a case report, caffeine consumption of 560 mg daily was associated with increased suicidality (91082).

Renal ...Data on the relationship between caffeine intake and kidney stones are conflicting. Some clinical research shows that caffeine consumption may increase the risk of stone formation (37634,111498), while other research shows a reduced risk with increasing caffeine intakes (111498). A meta-analysis of 7 studies found that overall, there is an inverse relationship, with a 32% decrease in the risk of kidney stones between the lowest and highest daily intakes of caffeine (111498).

Other ...People with voice disorders, singers, and other voice professionals are often advised against the use of caffeine; however, this recommendation has been based on anecdotal evidence. One small exploratory study suggests that caffeine ingestion may adversely affect subjective voice quality, although there appears to be significant intra-individual variability. Further study is necessary to confirm these preliminary findings (2724).

General ...Orally, pantothenic acid is generally well tolerated. Topically and intramuscularly, dexpanthenol, a synthetic form of pantothenic acid, seems to be well tolerated.
Most Common Adverse Effects:
Topically: Burning, contact dermatitis, eczema, irritation, and itching related to dexpanthenol.

Cardiovascular ...There is one case of eosinophilic pleuropericardial effusion in a patient taking pantothenic acid 300 mg per day in combination with biotin 10 mg per day for 2 months (3914).

Dermatologic ...Topically, dexpanthenol has been associated with itching, burning, skin irritation, contact dermatitis, and eczema (67779,67781,67788,111258,111262). Three cases of allergic contact dermatitis have been reported (111260,111261).

Gastrointestinal ...Orally, pantothenic acid has been associated with diarrhea (67822,111258).

General ...Orally and parenterally, thiamine is generally well tolerated.
Serious Adverse Effects (Rare):
Parenterally: Hypersensitivity reactions including angioedema and anaphylaxis.

Immunologic ...Orally, thiamine might rarely cause dermatitis and other allergic reactions. Parenterally, thiamine can cause anaphylactoid and hypersensitivity reactions, but this is also rare (<0.1%). Reported symptoms and events include feelings of warmth, tingling, pruritus, urticaria, tightness of the throat, cyanosis, respiratory distress, gastrointestinal bleeding, pulmonary edema, angioedema, hypotension, and death (15,35585,105445).
In one case report, a 46-year-old female presented with systemic allergic dermatitis after applying a specific product (Inzitan, containing lidocaine, dexamethasone, cyanocobalamin and thiamine) topically by iontophoresis; the allergic reaction was attributed to thiamine (91170).

VITAMIN B12

General ...Orally, intramuscularly, and topically, vitamin B12 is generally well-tolerated.
Most Common Adverse Effects:
Intramuscular: Injection site reactions.
Serious Adverse Effects (Rare):
Intramuscularly: Severe hypokalemia has been rarely linked with correction of megaloblastic anemia with vitamin B12.

Cardiovascular ...In human clinical research, an intravenous loading dose of folic acid, vitamin B6, and vitamin B12, followed by daily oral administration after coronary stenting, increased restenosis rates (12150). Hypertension following intravenous administration of hydroxocobalamin has been reported in human research (82870,82864).

Dermatologic ...Orally or intramuscularly, vitamin B12 can cause allergic reactions such as rash, pruritus, erythema, and urticaria. Theoretically, allergic reactions might be caused by the cobalt within the vitamin B12 molecule (82864,90373,90381,103974). In one case report, oral methylcobalamin resulted in contact dermatitis in a 59-year-old Japanese female with a cobalt allergy (103974). In another case report, a 69-year-old female developed a symmetrical erythematous-squamous rash for 5 years after oral vitamin B12 supplementation for 10 years. A patch test confirmed that the systemic allergic dermatitis was due to vitamin B12 supplementation, which resolved 3 months after discontinuation (114578).
Vitamin B12 (intramuscular or oral) has also been associated with at least 19 cases of acneiform eruptions which resolved upon discontinuation of vitamin B12 (90365,90369,90388). High-dose vitamin B12 (20 mcg daily) and vitamin B6 (80 mg daily) have been associated with cases of rosacea fulminans characterized by intense erythema with nodules, papules, and pustules. Symptoms may last up to four months after the supplement is stopped and can be treated with systemic corticosteroids and topical therapy (10998,82870,82871).

Gastrointestinal ...Intravenously, vitamin B12 (hydroxocobalamin) 2. 5-10 grams can cause nausea and dysphagia (82864).

Genitourinary ...Intravenously, vitamin B12 (hydroxocobalamin) 5-15 grams has been associated with chromaturia in clinical research (82870,82871,112282,112264).

Hematologic ...According to case report data, the correction of megaloblastic anemia with vitamin B12 may result in fatal hypokalemia (82914).

Musculoskeletal ...According to case report data, correction of megaloblastic anemia with vitamin B12 has precipitated gout in susceptible individuals (82879).

Neurologic/CNS ...Treatment with vitamin B12 has been rarely associated with involuntary movements in infants with vitamin B12 deficiency (90370,90385,90397). In some cases these adverse reactions were misdiagnosed as seizures or infantile tremor syndrome (90370,90385). These adverse reactions presented 2-5 days after treatment with vitamin B12 and resolved once vitamin B12 was discontinued (90370,90385,90397).

Oncologic ...Although some epidemiological research disagrees (9454), most research has found that elevated plasma levels of vitamin B12 are associated with an increased risk of various types of cancer, including lung and prostate cancers and solid tumors (50411,102383,107743). One study found, when compared with blood levels of vitamin B12 less than 1000 ng/mL, plasma vitamin B12 levels of at least 1000 ng/mL was strongly associated with the occurrence of solid cancer (107743). It is unclear if increased intake of vitamin B12, either through the diet or supplementation, directly affects the risk of cancer. It is possible that having cancer increases the risk of vitamin B12 elevation. However, one observational study has found that the highest quintile of dietary intake of vitamin B12 is associated with a 75% increased incidence of developing esophageal cancer when compared with the lowest quintile in never drinkers, but not drinkers (107147).

Renal ...There is a case report of oxalate nephropathy in a 54-year-old male which was determined to be related to the use of intravenous hydroxocobalamin as treatment for cyanide poisoning. Intermittent hemodialysis was started 5 days after admission, along with a low-oxalate diet, oral calcium acetate, and pyridoxine 5 mg/kg daily (107148). A review of the use of intravenous hydroxocobalamin for suspected cyanide poisoning in 21 intensive care units in France between 2011 and 2017 resulted in a 60% increased odds of acute kidney injury and a 77% increased odds of severe acute kidney injury in the first week. However, biopsies were not conducted and a direct link with use of hydroxocobalamin could not be made (107139).

Other ...Several studies have found that higher vitamin B12 levels may be associated with increased mortality or decreased survival rates in hospitalized elderly patients (82889,82812,82857,82895). Human research has also found a positive correlation between vitamin B12 status and all-cause mortality in Pima Indians with diabetes (82863).

VITAMIN B6

General ...Orally or by injection, vitamin B6 is well tolerated in doses less than 100 mg daily.
Most Common Adverse Effects:
Orally or by injection: Abdominal pain, allergic reactions, headache, heartburn, loss of appetite, nausea, somnolence, vomiting.
Serious Adverse Effects (Rare):
Orally or by injection: Sensory neuropathy (high doses).

Dermatologic ...Orally, vitamin B6 (pyridoxine) has been linked to reports of skin and other allergic reactions and photosensitivity (8195,9479,90375). High-dose vitamin B6 (80 mg daily as pyridoxine) and vitamin B12 (20 mcg daily) have been associated with cases of rosacea fulminans characterized by intense erythema with nodules, papules, and pustules. Symptoms may persist for up to 4 months after the supplement is stopped, and may require treatment with systemic corticosteroids and topical therapy (10998).

Gastrointestinal ...Orally or by injection, vitamin B6 (pyridoxine) can cause nausea, vomiting, heartburn, abdominal pain, mild diarrhea, and loss of appetite (8195,9479,16306,83064,83103,107124,107127,107135). In a clinical trial, one patient experienced infectious gastroenteritis that was deemed possibly related to taking vitamin B6 (pyridoxine) orally up to 20 mg/kg daily (90796). One small case-control study has raised concern that long-term dietary vitamin B6 intake in amounts ranging from 3.56-6.59 mg daily can increase the risk of ulcerative colitis (3350).

Hematologic ...Orally or by injection, vitamin B6 (pyridoxine) can cause decreased serum folic acid concentrations (8195,9479). One case of persistent bleeding of unknown origin has been reported in a clinical trial for a patient who used vitamin B6 (pyridoxine) 100 mg twice daily on days 16 to 35 of the menstrual cycle (83103). It is unclear if this effect was due to vitamin B6 intake.

Musculoskeletal ...Orally or by injection, vitamin B6 (pyridoxine) can cause breast soreness or enlargement (8195).

Neurologic/CNS ...Orally or by injection, vitamin B6 (pyridoxine) can cause headache, paresthesia, and somnolence (8195,9479,16306). Vitamin B6 (pyridoxine) can also cause sensory neuropathy, which is related to daily dose and duration of intake. Doses exceeding 1000 mg daily or total doses of 1000 grams or more pose the most risk, although neuropathy can occur with lower daily or total doses as well (8195). The mechanism of the neurotoxicity is unknown, but is thought to occur when the liver's capacity to phosphorylate pyridoxine via the active coenzyme pyridoxal phosphate is exceeded (8204). Some researchers recommend taking vitamin B6 as pyridoxal phosphate to avoid pyridoxine neuropathy, but its safety is unknown (8204). Vitamin B6 (pyridoxine) neuropathy is characterized by numbness and impairment of the sense of position and vibration of the distal limbs, and a gradual progressive sensory ataxia (8196,10439). The syndrome is usually reversible with discontinuation of pyridoxine at the first appearance of neurologic symptoms. Residual symptoms have been reported in patients taking more than 2 grams daily for extended periods (8195,8196). Tell patients daily doses of 100 mg or less are unlikely to cause problems (3094).

Oncologic ...In females, population research has found that a median intake of vitamin B6 1. 63 mg daily is associated with a 3.6-fold increased risk of rectal cancer when compared with a median intake of 1.05 mg daily (83024). A post-hoc subgroup analysis of results from clinical research in adults with a history of recent stroke or ischemic attack suggests that taking folic acid, vitamin B12, and vitamin B6 does not increase cancer risk overall, although it was associated with an increased risk of cancer in patients who also had diabetes (90378). Also, in patients with nasopharyngeal carcinoma, population research has found that consuming at least 8.6 mg daily of supplemental vitamin B6 during treatment was associated with a lower overall survival rate over 5 years, as well as a reduced progression-free survival, when compared with non-users and those with intakes of up to 8.6 mg daily (107134).

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