Arson [Discontinued] by M.A.P. Muscle Asylum Project

EFFECTIVE

• Migraine headache. Oral caffeine in combination with acetaminophen, aspirin, and/or sumatriptan is approved by the US Food and Drug Administration (FDA) for treating migraine headache. Details: Taking caffeine 100-260 mg orally in combination with acetaminophen 500-2000 mg, aspirin 500 mg, and/or sumatriptan 50-100 mg is effective for treating migraine headache (2715,2716,2717,37614,37626,37816,91068). Some evidence shows that caffeine in combination with aspirin and acetaminophen may be more effective than sumatriptan in treating a migraine attack (37666). However, taking caffeine 200 mg plus ergotamine seems to be less effective than sumatriptan or calcium carbasalate plus metoclopramide (37685,38312). Caffeine is an FDA-approved product for use with analgesics for the treatment of migraine.
• Neonatal apnea. Oral or intravenous caffeine citrate is approved by the US Food and Drug Administration (FDA) for the short-term treatment of neonatal apnea in very preterm infants. Details: Using caffeine orally or intravenously improves apnea of prematurity in very preterm infants and reduces the risk of bronchopulmonary dysplasia, invasive mechanical ventilation, and neurodevelopmental impairment (6023,6371,37857,37906,38124,38344,98807,100364). 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).

POSSIBLY EFFECTIVE

• 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).

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral caffeine prevents cognitive decline with aging. Details: Population research from a small cohort of elderly females shows that caffeine intake of more than 371 mg daily is associated with an attenuation in cognitive decline when compared to less than 30 mg daily. This is equivalent to the difference seen over a 7 year span of age. Caffeinated coffee consumption, but not caffeinated chocolate, tea, or cola, was associated with this attenuation in cognitive decline (91088).
• Alzheimer disease. It is unclear if oral caffeine is beneficial for preventing dementia; the available research is conflicting. Details: Population research from the UK Biobank has found that caffeine intake up to 400 mg daily is associated with a 24% to 34% reduced risk of developing Alzheimer disease when compared with lower intake. Conversely, population research from the Rush Memory and Aging Project in the US has found that caffeine intake of more than 100 mg daily is associated with a 41% increased risk of developing Alzheimer disease when compared with lower intake. However, when those with mild cognitive impairment at baseline or cases diagnosed within 2 years of follow-up are excluded, these findings become insignificant (108810).
• Asthma. Oral caffeine seems to modestly improve airway function for up to 4 hours in patients with mild to moderate asthma. However, it is unclear if oral caffeine has a clinically significant effect on asthma symptoms or quality of life. Details: Taking caffeine 9 mg/kg orally appears to modestly improve airway function for up to 4 hours in people with mild to moderate asthma (37907,37915). However, more research is needed to determine the appropriate dose, whether any benefit is clinically significant, or whether tolerance occurs with chronic dosing.
• Cancer pain. It is unclear if intravenous caffeine is beneficial for cancer pain. Details: Clinical research shows that receiving caffeine 200 mg intravenously once daily for 2 days results in a significant reduction in pain intensity by 0.833 points on the NRS scale when compared with control in patients receiving opioids for pain from advanced cancer (91081).
• Cognitive function. It is unclear if oral caffeine improves cognitive performance in trained athletes. Details: A meta-analysis of small studies in trained adult athletes shows that consumption of a low to moderate amount of caffeine 15-60 minutes prior to exercise and during exercise improves attention performance, but not reaction time or inhibitory control, when compared with placebo (108797). The validity of these findings is limited by unclear reporting.
• Dementia. It is unclear if oral caffeine is beneficial for preventing dementia or improving behavior in patients with dementia. Details: Population research from the Women's Health Initiative has found that caffeine intake of more than 175 mg daily is associated with a 26% reduced risk of developing probable dementia or global cognitive impairment when compared to less than 175 mg daily in postmenopausal adults 65-80 years of age (97458). Population research from the UK Biobank has found that caffeine intake up to 400 mg daily is associated with a 17% to 26% reduced risk for developing all-cause dementia when compared with lower intake. Conversely, population research from the Rush Memory and Aging Project in the US has found that caffeine intake of more than 100 mg daily is associated with a 35% increased risk of developing all-cause dementia when compared with lower intake. However, when those with mild cognitive impairment at baseline or cases diagnosed within 2 years of follow-up are excluded, these findings become insignificant (108810). Caffeine consumption has also been evaluated in patients with dementia. A cross-sectional study in patients with dementia in a care home has found that intake of 'normal' to 'high' amounts of caffeine are associated with reduced agitation and other behavioral symptoms when compared to 'low' intakes of caffeine (104574).
• Depression. It is unclear if oral caffeine is beneficial for depression prevention. Details: Some population research found that caffeine intake is associated with an increased incidence of depressive symptoms in pediatric patients (37839,38162). However, other population research found that caffeinated beverage intake is associated with a decreased incidence of depression in adults (37969,38165,91067,100366).
• Electroconvulsive therapy (ECT) augmentation. Although there has been interest in using intravenous caffeine sodium benzoate to augment electroconvulsive therapy, there is insufficient reliable information about the clinical effects of caffeine for this condition.
• Exercise-induced hypoxemia. It is unclear if oral caffeine is beneficial for hypoxemia associated with exercise. Details: Preliminary clinical research in athletes experiencing exercise-induced hypoxemia shows that taking caffeine 8 mg/kg can improve exercise ventilation, but not ventilatory response or oxygen saturation, when compared with placebo (37750).
• Exercise-induced muscle soreness. It is unclear if oral caffeine is beneficial for reducing muscle soreness during exercise. Details: There is conflicting clinical evidence as to whether caffeine can reduce exercise-induced muscle pain. Some evidence shows that taking caffeine 100 mg or 10 mg/kg can reduce muscle pain during exercise when compared with placebo (37622,38146). However, the effect of lower doses is unclear. Some evidence shows that taking caffeine 5 mg/kg may reduce exercise-induced muscle pain when compared with placebo (37747,91050), while other evidence suggests that taking caffeine 2-5 mg/kg does not affect muscle pain during exercise (38141).
• Gallbladder disease. It is unclear if increased dietary caffeine intake reduces the risk of developing gallstones. Details: Consumption of caffeinated beverages that provide 400 mg or greater of caffeine per day is associated with a significantly reduced risk of developing symptomatic gallstone disease (3345,8032). The effect seems to be dose-dependent; consumption of 800 mg caffeine per day has the greatest reduction in risk (3345).
• Hepatitis C. It is unclear if increased dietary caffeine reduces the risk for hepatitis C-associated severe liver inflammation, although it may reduce the risk of developing advanced fibrosis. Details: A meta-analysis of population research has found that regular consumption of caffeine at doses of at least 123 mg daily is associated with a 48% reduced risk of advanced liver fibrosis when compared to lower caffeine intake in patients with hepatitis C virus (95947). An individual population study also found that higher intake of caffeine from coffee is associated with reduced severity of liver fibrosis in patients with chronic hepatitis C virus. For these patients, the risk of advanced fibrosis is reduced by 14% for each 67 mg of caffeine (37896). However, caffeine intake does not appear to be associated with a reduced risk of moderate to severe liver inflammation in patients with hepatitis C (95947).
• Hypnic headache. It is unclear if oral caffeine reduces the pain associated with this rare condition. Details: Anecdotal evidence suggests that drinking a cup of coffee containing caffeine before bed or upon waking up may help alleviate pain associated with hypnic headaches (38078).
• Hypotension. It is unclear if oral caffeine is beneficial in people with low blood pressure. Details: Preliminary clinical research shows that consuming caffeinated beverages increase blood pressure in elderly people with postprandial hypotension (11834,11835).
• Intermittent claudication. It is unclear if oral caffeine is beneficial for intermittent claudication. Details: Taking a single dose of caffeine 6 mg/kg orally seems to improve walking distance, muscular strength, and endurance in patients with intermittent claudication; however, balance seems to be reduced (38038).
• Liver disease. It is unclear if oral caffeine is beneficial for liver disease prevention. Details: Population research found that there is an inverse association between intake of coffee and the incidence of liver cirrhosis (37576,37608). However, it is unclear if this effect of coffee is attributable to caffeine, since other caffeinated beverages do not show this effect.
• 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.

(Read more about CAFFEINE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging. Although there has been interest in using oral dimethylglycine for aging, there is insufficient reliable information about the clinical effects of dimethylglycine for this purpose.
• Attention deficit-hyperactivity disorder (ADHD). Although there has been interest in using oral dimethylglycine for ADHD, there is insufficient reliable information about the clinical effects of dimethylglycine for this purpose.
• Athletic performance. Although there has been interest in using oral dimethylglycine to improve athletic performance, there is insufficient reliable information about the clinical effects of dimethylglycine for this purpose.
• Autism spectrum disorder. It is unclear if oral dimethylglycine is beneficial in males with autism spectrum disorder. Details: A very small clinical crossover study in males aged 4-30 years shows that taking low doses of dimethylglycine daily for 1 month does not improve symptoms of autism when compared with placebo (5819).
• Cardiovascular disease (CVD). Although there has been interest in using oral dimethylglycine for CVD, including hyperlipidemia, there is insufficient reliable information about the clinical effects of dimethylglycine for these conditions.
• Cognitive function. Although there has been interest in using oral dimethylglycine for cognitive function, there is insufficient reliable information about the clinical effects of dimethylglycine for this purpose.
• Epilepsy. It is unclear if oral dimethylglycine is beneficial in patients with frequent generalized or myoclonic seizures. Details: A small clinical study in patients institutionalized with frequent generalized-onset, myoclonic, or atonic seizures shows that taking dimethylglycine 300 mg daily for 2 weeks followed by 600 mg daily for 2 weeks does not reduce seizure frequency when compared with placebo (5823).
• Multiple sclerosis (MS). It is unclear if oral dimethylglycine is beneficial in patients with progressive MS. Details: A small clinical study in patients with primary or secondary progressive MS shows that taking dimethylglycine 125 mg daily for 12 months does not improve cognition, fatigue, or motor performance when compared with placebo (108050).
• Stress. Although there has been interest in using oral dimethylglycine for stress, there is insufficient reliable information about the clinical effects of dimethylglycine for this purpose. More evidence is needed to rate dimethylglycine for these uses.

(Read more about DIMETHYLGLYCINE (DMG))

POSSIBLY EFFECTIVE

• Dyslipidemia. Small studies show that oral gamma-oryzanol might decrease total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels in patients with dyslipidemia. Details: Most clinical research in patients with dyslipidemia, comprised of small clinical studies, shows that gamma-oryzanol 100-300 mg daily for up to 2-6 months decreases total cholesterol, LDL cholesterol, and triglyceride levels, although effects on high-density lipoprotein (HDL) cholesterol levels are mixed (752,757,51108,51109). Other preliminary clinical evidence in patients with dyslipidemia shows that taking gamma-oryzanol 40.2 mg with vitamin E 4 mg, omega-3 fatty acids 1100 mg, and niacin 18 mg daily for 4 months reduces LDL cholesterol by an additional 23 mg/dL when compared with vitamin E and omega-3 fatty acids (51073). Gamma-oryzanol as a component of rice brain oil has also been evaluated. While rice bran oil has been shown to lower lipid levels, it is unclear if gamma-oryzanol content alters outcomes (51066,100481). One small clinical study in males with mild hypercholesterolemia shows that consuming rice bran oil containing a high amount of gamma-oryzanol (0.8 grams daily) as part of the diet for 4 weeks lowers LDL and total cholesterol to the same degree as rice bran oil low in gamma-oryzanol (0.05 grams daily) (51066). However, another small clinical study in patients with hyperlipidemia shows that taking rice brain oil 30 mL containing 8000 or 11000 ppm gamma-oryzanol daily for 4 weeks decreases LDL-C levels to a greater extent than oil containing 4000 ppm gamma-oryzanol (100481).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Athletic performance. Although there is interest in using oral gamma-oryzanol to improve athletic performance, there is insufficient reliable information about the clinical effects of gamma-oryzanol for this purpose.
• Atopic dermatitis (eczema). It is unclear if topical gamma-oryzanol is beneficial for eczema in children. Details: A small clinical study in children shows that bathing in bathwater containing 20 mL of a solution containing gamma-oryzanol 0.5% daily for up to 6 months appears to improve symptoms of atopic dermatitis when compared with baseline (51112). The validity of this finding is limited by the lack of a comparator group.
• Hypertension. Oral gamma-oryzanol has only been evaluated in combination with sesame oil; its benefits when used alone are unclear. Details: Preliminary clinical research in patients with hypertension shows that using a 20:80 blend of sesame oil and gamma-oryzanol-rich rice bran oil (Vivo, Adani Wilmar) as cooking oil for 8 weeks improves blood pressure and lipid profile. In patients using a low dose of nifedipine, 20 mg daily, adding the oil blend seems to further reduce blood pressure when compared with nifedipine alone (96180).
• Menopausal symptoms. Although there is interest in using oral gamma-oryzanol for symptoms of menopause, there is insufficient reliable information about the clinical effects of gamma-oryzanol for this purpose.
• Muscle strength. It is unclear if oral gamma-oryzanol is beneficial for improving muscle strength. Details: Preliminary clinical research in well-trained male athletes over 40 years old shows that taking gamma-oryzanol 500 mg daily for 9 weeks while participating in a resistance exercise program does not improve muscle strength or vertical jump power when compared with placebo (751). Conversely, a small clinical study in young healthy males shows that taking gamma-oryzanol 600 mg daily for 9 weeks during resistance training modestly increases muscular strength when compared with placebo (100482). More evidence is needed to rate gamma-oryzanol for these uses.

(Read more about GAMMA-ORYZANOL)

EFFECTIVE

• Sickle cell disease. A specific oral glutamine powder (Endari, Emmaus Medical, Inc) is approved by the US Food and Drug Administration (FDA) to reduce acute complications of sickle cell disease. Details: Clinical research in adults and children 5 years of age and older shows that taking glutamine 5-15 grams (0.3 grams/kg body weight) orally twice daily for 48 weeks, either with or without hydroxyurea, delays the median time to first crisis by 30 days, and reduces the incidence of acute chest syndrome by 15%, number of hospitalizations by 33%, and the number of hospitalized days by 40%, when compared with placebo (96519,99414).

POSSIBLY EFFECTIVE

• Burns. Oral glutamine seems to improve healing in patients with severe burns and may also reduce the risk for burn wound infections; however, it is unclear if glutamine improves hospitalization length or mortality. Details: Some clinical research shows that administering enteral nutrition supplemented with glutamine 0.35-0.5 grams/kg daily for 12-14 days, beginning within 24-48 hours of hospitalization for severe burn injury (excluding inhalation injury), decreases the length of hospital stay by 6-9 days and may shorten wound healing when compared to control enteral nutrition (52307,52337). A clinical study in adults with moderate to severe burns (including inhalation injury) shows that administering enteral nutrition supplemented with intravenous alanyl glutamine 0.5 grams/kg daily, beginning within 24 hours of burn injury and continued for 14 days, may improve burn-induced organ damage, particularly intestinal mucosal injury, but does not improve mortality or length of hospitalization, when compared with standard nutritional support (108027). Another study in the same population shows that administering enteral nutrition supplemented with glutamine 4.3 grams every 4 hours, beginning within 24 hours of burn injury, decreases the risk of mortality by 83% and the risk of Pseudomonas wound infections; however, it does not decrease the duration of hospitalization (52311). A meta-analysis of these trials and one additional trial shows that administering glutamine enterally reduces the risk of Gram-negative bacterial wound infections by 73% and reduces the risk of mortality by 87% when compared to a control group. However, there was no difference in length of stay or overall wound infection rate (97363). Results were based on a small number of patients within each outcome evaluation. Intravenous glutamine has also been evaluated. One small clinical study shows that intravenous glutamine 0.57 grams/kg daily decreases the incidence of Gram-negative bacteremia by 35% when compared with control in patients with severe burns. However, it does not appear to decrease the incidence of Gram-positive bacteremia, the need to use antibiotics, or risk of mortality (52272).
• Critical illness (trauma). Oral and intravenous glutamine seem to reduce infectious complications in critically ill adults. However, glutamine does not seem to reduce mortality in this population. Details: Some studies show that glutamine reduces the risk of infectious complications in critically ill, multiple-trauma, or postoperative adult patients (5449,5450,7309,7731,8184,52288,52359). However, other studies show no benefit (52308,52360,97362). Meta-analyses of these and other clinical trials suggest that glutamine supplementation reduces the risk of nosocomial infections in critically ill patients by 15% to 18% and the risk of nosocomial infections in surgical patients by 30% to 41%. This benefit was seen only with parenteral glutamine; enteral glutamine does not appear to reduce the risk for nosocomial infection (91355,91358). The role of glutamine for reducing mortality in critically ill adults is conflicting. Some clinical trials suggest that glutamine-enriched enteral and parenteral nutrition reduces mortality in critically ill patients (52283,52289,52408). However, other studies show no benefit (52288,52308,52354,52359,97362). Meta-analyses of results from these and other clinical trials show that, overall, taking glutamine does not reduce the risk of mortality in critically ill patients (91355,91358). However, the dose and dosage form may affect outcomes. One meta-analysis shows that glutamine does not affect the risk of mortality when administered at doses up to 0.5 grams/kg daily, although doses greater than 0.5 grams/kg daily may INCREASE mortality by 18% (91355). Another meta-analysis shows that glutamine decreases short-term mortality in critically ill patients by 25% when administered parenterally, but not enterally (91358). Neither parenteral nor enteral glutamine appears to decrease the risk of long-term mortality in critically ill patients (91358). Research evaluating glutamine in critically ill children is limited. One clinical study in children ages 1-17 admitted to an intensive care unit (ICU) shows that enteral administration of glutamine along with zinc, selenium, and intravenous metoclopramide does not reduce nosocomial infections when compared with whey supplementation (86095).
• HIV/AIDS-related wasting. Oral glutamine seems to attenuate weight loss related to HIV/AIDS. Details: Very small clinical studies show that taking glutamine orally seems to enhance intestinal absorption of nutrients, decrease intestinal permeability, and increase weight gain in adults with HIV/AIDS when compared with placebo. Doses of 40 grams daily seem to produce the greatest effect (2337,2702). Lower doses of 14 grams daily might also be effective when used in combination with arginine and hydroxymethylbutyrate (a leucine metabolite) (7310).
• Postoperative recovery. Oral or intravenous glutamine seems to reduce the duration of hospitalization and improve postoperative nutritional status in adults. However, it does not seem to reduce postoperative mortality. Details: Although some conflicting evidence exists (52316), most clinical research shows that receiving free glutamine or glutamine-containing dipeptide intravenously decreases the duration of hospitalization after surgery, particularly after major abdominal surgery (2363,5448,7300,7732,52275,52341). A meta-analysis of this research and other studies shows that IV supplementation with glutamine-containing dipeptides reduces the length of hospital stay by 3 days when compared with no supplementation (96507). Other meta-analyses of clinical research also show that glutamine supplementation, as free glutamine or glutamine-containing dipeptides, reduces the risk of hospital-acquired infections by 30% in surgical intensive care unit (ICU) patients and by 41% in elective surgical patients (91355,91358). In cancer patients undergoing abdominal surgery, glutamine-supplemented parenteral nutrition seems to improve nutritional status and gastrointestinal function (100943). Glutamine-containing dipeptides also appear to help to preserve intestinal integrity (7299,7300,7732,52306). One small study has evaluated oral glutamine 10 grams, in combination with arginine 4.5 grams, in patients undergoing surgery for enterocutaneous fistulas. This study shows that taking this combination daily for 7 days prior to surgery reduces recurrence of fistulas by 35%, and also reduces postoperative infections (103837). Although glutamine seems to decrease length of stay and reduce infection rate, it does not appear to reduce the risk of mortality in either surgical ICU or elective surgical patients (91355,91358,96509,103834), including those receiving major abdominal surgery (5448,52316,91355,96507). Additionally, most research shows that glutamine supplementation does not reduce the incidence of infectious complications following abdominal surgery (52306,52316,52341,5448,7300,96507). The effects of glutamine on reducing infection rate might be related to patient population, modes of nutrition, or dose of glutamine. Taking a combination of glutamine 7 grams, arginine 7 grams, and hydroxymethylbutyrate 1.2 grams (Abound, Abbott) orally daily for 3 days before and 7 days after abdominal surgery does not reduce the incidence of wound infections or other complications (99413). Most of the research evaluating glutamine in surgical patients has been conducted in adults. Information in children is limited. Existing clinical research shows that glutamine-fortified parenteral nutrition does not improve intestinal permeability, nitrogen balance, duration of hospitalization, incidence of infectious complications, or risk of mortality in newborns and infants undergoing digestive-tract surgery (52338,96508).

POSSIBLY INEFFECTIVE

• Athletic performance. Oral glutamine does not seem to improve athletic performance. Details: Small studies in trained athletes or healthy adults show that taking glutamine orally does not seem to enhance performance or immune response during intense acute or prolonged exercise when compared with placebo (2341,2342,5455,5456).
• Crohn disease. Oral glutamine does not seem to improve symptoms of this condition. Details: Small clinical studies in adults and children with Crohn disease show that taking glutamine 7 grams three times daily or following a glutamine-enriched diet for 4 weeks does not seem to improve intestinal permeability or disease activity, and might even worsen disease activity, when compared with placebo or a low-glutamine diet (2338,6256).
• Cystinuria. Oral glutamine does not seem to improve cystinuria. Details: According to case reports, taking glutamine orally does not seem to reduce the excretion of cysteine in the urine in patients with homozygous cystinuria (2339).
• Low birth weight. Oral glutamine does not seem to reduce adverse consequences of low birth weight in infants. Details: Most clinical studies show that glutamine supplementation does not improve the time to full enteral feeding, infant growth rate, or length of hospital stay in low birth weight infants (52305,52312,52325,52342,52362,52410). One follow-up study also shows that neonatal glutamine supplementation is not associated with improvements in cognitive function, motor skills, or behavior outcomes by school age when corrected for neonatal infection rate (52342,97365).
• Muscular dystrophy. Oral glutamine does not seem to improve symptoms of Duchenne muscular dystrophy. Details: Clinical studies show that taking glutamine 0.5-0.6 grams/kg orally does not significantly improve muscle strength or whole body protein degradation in children with Duchenne muscular dystrophy when compared with placebo or a nonspecific amino acid mixture (46657,52363).
• Prematurity. Oral glutamine does not seem to reduce morbidity or mortality associated with prematurity. Details: A meta-analysis of clinical trials in preterm infants, including infants with low to very low birth weight, shows that use of enteral or parenteral glutamine does not reduce the risk of mortality or morbidities, such as necrotizing enterocolitis, when compared with control. However, limited evidence from a sub-group analysis suggests that enteral glutamine might modestly reduce the risk of invasive infection when compared with control (105015). These findings are limited by the selection bias and heterogeneity of the included trials.
• Radiation-induced diarrhea. Oral glutamine does not seem to improve diarrhea due to radiation therapy. Details: One meta-analysis of five randomized, controlled trials shows that taking oral glutamine during radiotherapy for pelvic cancers does not prevent or reduce the severity of diarrhea when compared with placebo (97367).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Antiretroviral-associated diarrhea. It is unclear if oral glutamine improves diarrhea caused by antiretroviral agents. Details: A small crossover clinical study in HIV patients shows that oral glutamine 30 grams daily for 10 days seems to reduce the severity of nelfinavir-associated diarrhea when compared with placebo (52313).
• Alcohol use disorder. Although there is interest in using oral glutamine for alcohol use disorder, there is insufficient reliable information about the clinical effects of glutamine for this condition.
• Attention deficit-hyperactivity disorder (ADHD). Although there is interest in using oral glutamine for ADHD, there is insufficient reliable information about the clinical effects of glutamine for this condition.
• Chemotherapy-induced diarrhea. It is unclear if oral glutamine improves diarrhea caused by chemotherapy. Details: Although preliminary clinical studies show that glutamine might reduce the occurrence of chemotherapy-induced diarrhea (7235,7285), a meta-analysis of this research and others shows no difference in the severity of diarrhea (7233,7295,96516). Despite results showing a significant 1-day reduction in the duration of diarrhea, this might not be considered clinically significant (96516).
• Chemotherapy-induced lymphocytopenia. It is unclear if oral glutamine reduces lymphocytopenia caused by chemotherapy. Details: One small clinical study in patients with esophageal cancer receiving chemo-radiotherapy shows that taking glutamine 30 grams daily for 28 days seems to prevent a reduction in lymphocytes when compared with placebo (2705). However, another small clinical trial in patients with leukemia or lymphoma receiving intensive chemotherapy shows that adding glutamine 26 grams to total parenteral nutrition (TPN), in place of other amino acids, does not affect duration of neutropenia when compared with receiving an isonitrogenous standard TPN (7295).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral glutamine is beneficial in patients hospitalized with COVID-19 pneumonia. Details: A very small, nonblinded, non-randomized evaluation of otherwise healthy patients over 50 years of age who were hospitalized with mild COVID-19 pneumonia shows that taking glutamine 10 grams three times daily orally with meals is associated with a 1-day decrease in hospital stay (from 10 days to 9) when compared with patients not taking glutamine. In the latter group, 4 patients required transfer to the ICU, compared with no patients in the glutamine group (103839). A similar, non-randomized evaluation of adults hospitalized with COVID-19 pneumonia shows that adding the same dose of glutamine to other therapies for 5 days is associated with a 3-day decrease in hospital stay (from 14 days to 11) when compared with patients not taking glutamine. At the end of treatment, 0% of patients in the glutamine group required ICU services, compared with 54% of patients who did not receive glutamine. This study also shows that taking glutamine may increase appetite (108035). The validity of these findings is limited by short duration of treatment and use of non-standardized treatments.
• Cystic fibrosis. It is unclear if oral glutamine improves growth and development in children with cystic fibrosis. Details: A small clinical study in undernourished or stunted children with cystic fibrosis shows that taking glutamine 0.7 grams/kg daily orally for 4 weeks with or without recombinant human growth hormone (rhGH) does not promote protein gain when compared with rhGH alone (52321).
• Diabetic foot ulcers. Oral glutamine 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 nutritional supplement drink containing glutamine 7 grams, arginine 7 grams, and hydroxymethylbutyrate 1.5 grams (Abound, Abbott) twice daily for 16 weeks does not improve total wound closure or reduce the time to complete healing when compared with a control drink in patients with diabetic foot ulcers (96637). It is unclear if this effect is due to glutamine, other ingredients, or the combination.
• Diarrhea. It is unclear if oral glutamine improves diarrhea in children and infants. Details: One preliminary clinical study in 6-24 month-old otherwise healthy children with acute diarrhea shows that taking capsules prepared with a specific glutamine powder (Power Glutamine, Champion Nutrition) 0.3 grams/kg daily for 7 days reduces the duration of diarrhea by about one day when compared with placebo (52323). However, other clinical research in male infants 1-12 months old with acute diarrhea and dehydration shows that adding glutamine 90 mmol/L along with the standard World Health Organization oral rehydration salts (ORS) does not decrease the duration of diarrhea, stool output, or the volume of oral rehydration solution required to achieve and maintain hydration when compared with standard ORS alone (7298).
• Hematopoietic stem cell transplant (HSCT). It is unclear whether oral glutamine or glutamine added to parenteral nutrition improves morbidity and mortality in patients undergoing HSCT. Some research has suggested that intravenous glutamine may actually worsen outcomes. Details: Some research suggests that patients receiving glutamine-supplemented parenteral nutrition (PN) after HSCT primarily to treat hematologic malignancies have a diminished incidence of clinical infections, lower rates of microbial colonization, and decreased length of hospital stay when compared to control (2366,52381). However, not all patients seem to benefit. Some research shows that oral glutamine or PN with glutamine does not reduce the risk of mortality or infections in patients with hematologic malignancies and/or solid tumors (5451,52385). Also, a small clinical study in patients undergoing HSCT shows that PN with glutamine dipeptide may increase the duration of hospital stay (52292). Furthermore, one small study has found that receiving PN with glutamine was associated with lower disease-free survival and event-free survival over 3 years when compared with standard PN in patients receiving HSCT for hematologic malignancies (52355).
• Irritable bowel syndrome (IBS). There is limited evidence on the oral use of glutamine in patients with IBS. Details: A clinical trial in adults with IBS (diarrhea-predominant, constipation-predominant, mixed, or alternating bowel habits) shows that following a low FODMAP diet supplemented with oral glutamine 15 grams three times daily for 6 weeks improves IBS-Severity Scoring System (IBS-SSS) scores, with 88% of patients in the glutamine group reporting a 45% improvement in severity scores, compared with 60% of patients following the low FODMAP diet alone (108037). The validity of this finding is limited by short duration of treatment and lack of follow-up. Preliminary clinical research in patients with postinfectious, diarrhea-predominant IBS shows that taking glutamine 5 grams three times daily for 8 weeks leads to a nearly 14-fold greater likelihood of symptom improvement, defined as a reduction of 50 points or more on the IBS-SSS, and decreases stool frequency by 2.45 stools daily when compared with placebo. Taking glutamine also seems to reduce abdominal pain ratings by 55% and improve quality of life scores by 53% when compared to baseline in these patients (100944). The validity of these findings is limited by the lack of a comparator group.
• Lung cancer. It is unclear if oral glutamine improves survival in patients with advanced lung cancer. Details: One small clinical study in patients with advanced non-small cell lung cancer shows that taking glutamine 10 grams three times daily for 12 months along with palliative chemoradiotherapy prevents weight loss, which is an important predictor of survival, but does not increase the likelihood of progression-free survival when compared with palliative chemoradiotherapy alone (100942). It is unclear if this study was adequately powered to detect a difference in survival between groups.
• Malnutrition. It is unclear if oral alanyl-glutamine improves height and weight in children at risk for malnutrition. Details: Preliminary clinical research in children aged 2 months to 5 years from a low-income area of Brazil and at risk for malnutrition, shows that taking 3-12 grams of alanyl-glutamine orally daily for 10 days improves gut integrity and is associated with a modest, short-term increase in weight when compared with a glycine placebo (103838).
• Exercise-induced muscle damage. It is unclear if oral glutamine is beneficial for exercise-induced muscle damage. Details: A very small clinical crossover trial in professional athletes undergoing rigorous training shows that taking oral glutamine 6 grams daily for 20 days reduces serum levels of creatine kinase and myoglobin when compared with placebo (108031). The validity of these findings is limited due to the small size and short duration of treatment.
• Obesity. It is unclear if oral glutamine is beneficial for weight loss. Details: A preliminary clinical study in 36 overweight or obese adults shows that taking glutamine 30 grams daily for 2 weeks reduces waist circumference by 1.8 cm, but does not improve body weight, body mass index, or glycemic indices, when compared to baseline. None of these outcomes were improved over baseline in an alanine control group (100941). Given the small study size and short duration of therapy, the long-term effects of glutamine on anthropometric measures is unclear.
• Opioid withdrawal. Oral glutamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in Chinese patients undergoing detoxification from heroin shows that taking a combination of tyrosine, lecithin, 5-HTP, and glutamine 50 mg/kg orally daily for 6 days might reduce mood-related withdrawal symptoms when compared with placebo (88178). It is unclear if this effect is due to glutamine, other ingredients, or the combination.
• Oral mucositis. There is contradictory evidence about the effects of glutamine in patients with, or at risk of developing, oral mucositis from chemotherapy or radiotherapy. Details: Small clinical studies suggest that taking glutamine orally or swishing and swallowing a glutamine solution can decrease the incidence, severity, and duration of oral mucositis in some patients undergoing chemotherapy and/or radiation therapy for cancer or hematopoietic stem cell transplant (HSCT) (2336,2368,2704,5029). Additionally, three meta-analyses of highly heterogeneous clinical trials in patients with cancer receiving chemotherapy and/or radiation therapy suggests that glutamine reduces the incidence of severe (grade ≥3) oral mucositis when compared with control (105014,108028,108036). These analyses are limited for several reasons, including reporting bias, lack of sensitivity analysis, and population heterogeneity. Some small clinical studies included in these meta-analyses suggest that supplementation with glutamine may reduce the need for feeding tubes and opioid analgesics (108028,108036). However, not all research has been positive. Some small clinical studies in patients receiving chemotherapy with 5-fluorouracil for cancer or HSCT suggest that oral or intravenous glutamine does not reduce the incidence of oral mucositis when compared with control (2365,5451,5462,7296,52349,52350). Furthermore, a meta-analysis of 5 clinical trials in patients with head or neck cancers shows that oral glutamine does not reduce the overall incidence or the incidence of moderate to severe radiation-induced oral mucositis when compared with control (103836). The Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology (MASCC/ISOO) cautiously recommends the use of oral glutamine to prevent oral mucositis in patients with head and neck cancer receiving chemoradiotherapy. However, due to some evidence suggesting that intravenous glutamine may actually worsen outcomes in HSCT patients, the MASCC/ISOO recommends against its use for the prevention of oral mucositis in patients receiving high-dose chemotherapy, with or without total body irradiation, for HSCT (105004).
• Paclitaxel-induced myalgia and arthralgia. It is unclear if oral glutamine reduces the risk for myalgias and arthralgias due to paclitaxel. Details: One small clinical study shows that taking glutamine 10 grams three times daily for 5 days, starting on the day of chemotherapy and repeated over 2 cycles of chemotherapy, does not reduce the rate or severity of paclitaxel-induced myalgias or arthralgias when compared with placebo (52331).
• Pancreatitis. It is unclear if oral glutamine improves outcomes in patients with acute pancreatitis. Details: Two meta-analyses of the available clinical research in patients with pancreatitis show that enteral or parenteral supplementation with glutamine increases albumin, decreases C-reactive protein, and might reduce mortality, multiple organ dysfunction syndrome, hospital length of stay, and infections. Results are difficult to interpret due to the significant heterogeneity of the included trials and limited generalizability of the results (96513,103835).
• Peptic ulcers. Although there is interest in using oral glutamine for peptic ulcers, there is insufficient reliable information about the clinical effects of glutamine for this condition.
• Postoperative infection. It is unclear if oral or intravenous glutamine is beneficial for the prevention of postoperative infection in patients with colorectal cancer who are recovering from surgery. Details: A meta-analysis of nonblinded clinical research in adults with colorectal or colon cancer who recently underwent radical surgery shows that daily supplementation with glutamine 0.3-1 grams/kg, administered either orally or parenterally, improves the rate of surgical site infections and anastomotic leakage when compared with control (108033). These findings are limited by the high heterogeneity of the included studies and unclear reporting.
• Postoperative recovery. It is unclear if oral or intravenous glutamine is beneficial in patients with colorectal cancer who are recovering from surgery. Details: A meta-analysis of nonblinded clinical research in adults with colorectal or colon cancer who recently underwent radical surgery shows that taking either oral or parenteral glutamine 0.3-1 grams/kg daily may reduce the length of hospital stay when compared with control (108033). These findings are limited by the high heterogeneity of the included studies and unclear reporting.
• Pressure ulcers. Oral glutamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in patients with stages II-IV pressure ulcers shows that taking a specific nutritional supplement drink containing glutamine 7 grams, arginine 7 grams, and hydroxymethylbutyrate 1.5 grams per packet (Abound, Abbott Nutrition) as two packets twice daily by mouth for 2 weeks has no effect on wound area or healing scores by the Pressure Ulcer Scale for Healing (PUSH) measurement when compared with standard nutritional care (96506).
• Radiation dermatitis. It is unclear if oral glutamine reduces the risk of developing dermatitis from radiation therapy. Details: One small clinical study in patients with head and neck cancers receiving cisplatin shows that taking a specific supplement containing glutamine 7 grams, arginine 7 grams, and hydroxymethylbutyrate 1.5 grams (Abound, Abbott) orally twice daily, starting on day 1 of radiation and continuing until 1 week after radiation therapy, does not reduce the incidence of severe radiation-induced dermatitis when compared with no supplementation (96639). However, another small clinical study in patients with breast cancer who have had both chemotherapy and surgery shows that taking oral glutamine 5 grams three times daily, starting 1 week before radiation and continuing until 1 week after radiation, is associated with a reduction in grade 1 and grade 2 radiation dermatitis when compared with placebo (97366).
• Radiation-induced esophagitis. It is unclear if oral glutamine reduces the risk of developing esophagitis from radiation therapy. Details: A small clinical study in patients with advanced non-small cell lung cancer shows that taking glutamine 10 grams three times daily for 12 months along with a palliative dose of chemoradiotherapy (total 30 Gy) results in a 7% incidence of symptomatic (grade 2 or higher) radiation-induced esophagitis, compared with a 53% incidence with palliative chemoradiotherapy alone. The glutamine group also had a 5.8-day delay in the onset of esophagitis (100942). However, a lower dose of glutamine in patients receiving higher doses of radiotherapy might not be beneficial. A small clinical study in patients with advanced thoracic malignancies shows that taking glutamine 4 grams mixed in water twice daily for 4 weeks along with radiotherapy (total dose of at least 45 Gy) to the esophagus, with or without chemotherapy, does not slow the onset of radiation-induced esophagitis or reduce its severity when compared with a glycine placebo (105011).
• Short bowel syndrome. It is unclear if oral glutamine improves symptoms of short bowel syndrome. Details: Although small clinical studies suggest that glutamine plus growth hormone can decrease dependence on parenteral nutrition in some patients (2334,2361,2362,2703), it has not shown benefit for improving intestinal absorption of energy in all studies (8185). Additionally, glutamine alone doesn't appear to be beneficial (7730).
• Traumatic Brain injury (TBI). It is unclear if intravenous glutamine is beneficial in patients hospitalized with severe TBI. Details: A clinical trial in patients hospitalized for a severe TBI shows that adherence to a hypocaloric, low-protein diet supplemented with daily intravenous glutamine 0.3 g/kg for 7 days does not improve 28-day mortality when compared with standard nutritional support alone. However, it may reduce the length of ventilator use, hospitalization, and duration of intensive care unit stay (108034).
• Vincristine-induced neuropathy. It is unclear if oral glutamine reduces the risk of developing neuropathy from treatment with vincristine in children. Details: Preliminary clinical research in children ages 1-21 years receiving vincristine for various cancer types shows that taking glutamine 6 grams/m2 twice daily orally for 21 days reduces sensory neuropathy when compared with placebo. There was a significant improvement in self-reported, but not parent-reported, quality of life scores as measured by the PedsQL scale. However, there was no effect on motor neuropathy with the use of glutamine (96517).
• Wound healing. It is unclear if oral glutamine improves wound healing. Details: Preliminary clinical research in trauma patients with wound healing disorders shows that taking glutamine 20 grams orally daily in combination with ascorbic acid 500 mg, vitamin E 166 mg, beta-carotene 3.2 mg, selenium 100 mcg, and zinc 6.6 mg (Glutamine Plus, Fresenius Kabi) for 14 days reduces the time to wound closure by 29 days when compared with placebo. However, there is no difference in length of stay (97364). More evidence is needed to rate glutamine for these uses.

(Read more about GLUTAMINE)

POSSIBLY EFFECTIVE

• Cholera. Oral L-histidine seems to reduce diarrhea in adults with cholera. Details: A clinical study in adults with severe cholera receiving ciprofloxacin shows that drinking a rice-based oral rehydration solution (CeraLyte-90, CERA products) supplemented with L-histidine (Ajinomoto Chemical) 2.5 grams per liter as needed for 72 hours decreases the frequency of stool output at 32 hours, the weight of stool at 72 hours, the amount of intravenous fluid needed during the first 48 hours, and the duration of diarrhea by roughly 5 hours when compared with drinking the oral rehydration solution alone (96312).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Atopic dermatitis (eczema). It is unclear if oral L-histidine is beneficial in adults and children with atopic dermatitis. Details: A small clinical crossover study in adults with atopic dermatitis shows that taking L-histidine 4 grams daily for 8 weeks improves clinician-reported disease severity scores by 32% to 34% when compared with baseline (108621). The lack of washout period prior to crossover and its subsequent carryover effect prevents useful statistical comparison to placebo, limiting the validity of these findings. A small clinical study in children aged 1-7 years with mild to moderate atopic dermatitis shows that taking L-histidine 0.8 grams daily for 12 weeks improves disease severity by 49% when compared with baseline (108652). The lack of statistical comparison to the placebo group limits the validity of these findings.
• Kidney failure. It is unclear if oral L-histidine is beneficial for anemia in patients with kidney failure. Details: A small clinical study in patients with chronic uremia and patients undergoing maintenance hemodialysis shows that taking L-histidine 4 grams daily does not improve anemia when compared with placebo (2352).
• Metabolic syndrome. It is unclear if oral histidine is beneficial in patients with metabolic syndrome. Details: A clinical study in females with obesity and metabolic syndrome shows that taking histidine 2 grams twice daily is associated with reduced insulin resistance, body mass index, waist circumference, and fat mass at 12 weeks when compared with placebo. It is unclear if the improvement from baseline differed between groups. Other lipid parameters were not affected (96311).
• Rheumatoid arthritis (RA). It is unclear if oral L-histidine is beneficial in patients with RA. Details: A small clinical study in patients with RA shows that taking L-histidine 4.5 grams daily for 30 weeks does not improve clinical measurements when compared with placebo (2350). More evidence is needed to rate histidine for these uses.

(Read more about HISTIDINE)

EFFECTIVE

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

POSSIBLY EFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about L-CARNITINE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Erectile dysfunction (ED). Preliminary clinical research in middle-aged men with ED shows that taking two capsules of a specific combination product (Revactin, MD Concepts LLC) containing muira puama, ginger root, guarana, and L-citrulline twice daily for 3 months improves scores related to erectile function and intercourse satisfaction, but does not improve sexual desire or orgasmic function scores, when compared to baseline (103224). This study is limited by the lack of a placebo control, the use of per-protocol analysis, and a high dropout rate. In fact, 44% of patients withdrew in order to resume use of phosphodiesterase type 5 (PDE5) inhibitors. Further, it is unclear if these effects are due to muira puama, other ingredients, or the combination.
• Sexual dysfunction. Preliminary clinical research in women with a low sex drive shows that taking 2-6 tablets of a specific combination product (Herbal vX) containing muira puama extract (HV-430) 350-1050 mg and ginkgo extract 32-96 mg modestly improves sexual desire and the frequency of sexual intercourse when compared with baseline (63920). The lack of control group limits the validity of these findings. Further, it is unclear if these effects are due to muira puama, ginkgo, or the combination. More evidence is needed to rate muira puama for these uses.

(Read more about MUIRA PUAMA)

LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

• Acne. Topical niacinamide seems to improve acne symptoms in some patients. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical study shows that applying niacinamide 4% gel twice daily for 8 weeks is as effective as clindamycin 1% gel for reducing the number and severity of acne lesions. The niacinamide gel appears to be more effective in patients with oily skin than those with non-oily skin (93360). Other preliminary clinical research in adults with mild to moderate acne vulgaris shows that applying niacinamide 5% cream twice daily, 10 minutes after applying benzoyl peroxide 2.5% gel, for 12 weeks reduces the number of acne lesions, but not erythema or inflammation, when compared with benzoyl peroxide alone (107711). Niacinamide has also been studied in combination with other ingredients. In preliminary clinical research, oral niacinamide has been reported to improve acne when used in combination with zinc, copper, and folic acid (Nicomide) (25557), or in combination with azelaic acid, zinc, pyridoxine, copper, and folic acid (NicAzel, Elorac Inc.) (90800). In a small observational study, topical niacinamide 4% combined with gallic acid 1% and lauric acid 1% was associated with some improvement in acne (104931). It is unclear if the effects in these studies are due to niacinamide, other ingredients, or the combinations.
• Diabetes. Oral niacinamide does not seem to prevent the onset of type 1 diabetes, although it might slow its progression. Details: Although some older research has suggested that taking high-dose niacinamide can reduce the risk of type 1 diabetes in high-risk children (4874), results from higher quality, more rigorous clinical trials show that taking niacinamide up to 3 grams daily for 5 years does not prevent the onset of type 1 diabetes in first-degree relatives of patients with type 1 diabetes (4875,25553,25554). However, taking niacinamide 1.2 grams/m2 daily for 5 years may prevent the loss of beta-cell function in these patients (25555). Also, there is evidence showing that niacinamide can preserve residual beta-cell function in patients with newly diagnosed type 1 diabetes (4877,4878,4879,4880,25556). Clinical trials, including one placebo-controlled trial and one vitamin E-comparison study, show niacinamide can prolong the "honeymoon period" in those newly diagnosed with type 1 diabetes, when the pancreas is still capable of producing some insulin (4877,4878,4879,4880,25556). However, some scientists have raised concerns about potential induction of insulin resistance with short-term use of niacinamide 2 grams daily for 2 weeks (4881). Niacinamide has also been evaluated in adults with type 2 diabetes. A small clinical study in lean patients with type 2 diabetes who failed sulfonylurea therapy shows that taking niacinamide 500 mg three times daily for 6 months in addition to continuing insulin or a sulfonylurea increases C-peptide release and improves insulin secretion when compared with insulin alone (4882).
• Hyperphosphatemia. Adding oral niacinamide to standard treatment with phosphate binders further lowers blood levels of phosphorus in patients on hemodialysis. Details: A meta-analysis of nine small clinical trials in patients on hemodialysis with hyperphosphatemia who are using a phosphate binder shows that taking niacinamide 250-1500 mg daily for 2-6 months lowers serum phosphorus and parathyroid hormone levels when compared with placebo (98940) Another meta-analysis of two small clinical trials in the same patient population also shows that taking niacinamide, titrated from 500 mg to 1500 mg daily over 8 weeks, reduces serum phosphorus levels by about 0.9 mg/dL when compared with placebo (94188). Other clinical research in this population shows that taking modified-release niacinamide 250-1500 mg orally daily for 12-24 weeks also lowers serum phosphate and parathyroid levels when compared with placebo. However, these effects were not maintained at 40-52 weeks follow-up (107709,110499). In addition, this product was not compared with immediate-release niacinamide. Niacinamide has also been studied in place of phosphate binders. One small clinical study in patients on hemodialysis with hyperphosphatemia shows that taking niacinamide 500-1750 mg daily for 12 weeks, beginning 2 weeks after discontinuation of phosphate binders, decreases serum phosphorus levels by 1.5 mg/dL and intact parathyroid hormone levels by 50 pg/mL, without affecting calcium levels, when compared to baseline (25561).The validity of these findings is limited due to the lack of a control group.
• Nonmelanoma skin cancer. Oral niacinamide might reduce the rate of nonmelanoma skin cancer development. Details: One clinical study in patients with a history of nonmelanoma skin cancers shows that taking niacinamide 500 mg orally twice daily for 12 months reduces the rate of new nonmelanoma skin cancers at 12 months by 23% and the number of actinic keratoses by 13% when compared with placebo (93362). Other clinical research shows that taking niacinamide (Nature's Own, Virginia) 500 mg orally once or twice daily for 4 months reduces the total number of actinic keratoses by up to 35% and decreases the odds of developing at least one nonmelanoma skin cancer by 86% when compared with placebo in patients with at least four actinic keratoses (93365). However, some conflicting research exists. One small clinical study in adults with actinic keratoses shows that taking niacinamide 500 mg twice daily for 120 days does not reduce the number of actinic keratoses when compared with control. However, the validity of this study is limited by the short study duration (107714). A meta-analysis of many small clinical trials shows that using niacinamide, up to 2000 mg orally or 4% topically, daily for 1 month to 5 years lowers the risk of skin cancer, including basal cell carcinoma and cutaneous squamous cell carcinoma by 50% when compared with control. Using niacinamide did not reduce the risk of actinic keratoses. However, the validity of this study is limited by inclusion of populations with different cancer risks and high heterogeneity (110497).
• Osteoarthritis. Oral high-dose niacinamide might be beneficial for improving osteoarthritis symptoms. Details: Clinical research in patients with osteoarthritis shows that taking niacinamide 3 grams daily in six divided doses for 12 weeks improves joint flexibility, reduces inflammation, and modestly decreases use of nonsteroidal anti-inflammatory drugs (NSAIDs) when compared with placebo (4883).

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. Although there is interest in using oral niacinamide for age-related cognitive decline, there is insufficient reliable information about the clinical effects of niacinamide for this purpose.
• Age-related macular degeneration (AMD). Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients with early-stage age-related maculopathy shows that taking a combination of niacinamide 18 mg, vitamin E 20 mg, and lutein 15 mg daily for nearly a year improves retinal function when compared with no treatment (60134). It is unclear if this effect is due to niacinamide, other ingredients, or the combination.
• Aging skin. It is unclear if topical niacinamide improves symptoms of aging skin. Details: A small study in females with signs of facial photo-aging shows that applying niacinamide 5% cream to half of the face twice daily for 12 weeks improves blotchiness, the appearance of wrinkles, skin elasticity, and skin pigmentation when compared with applying placebo cream to the other half of the face (25551).
• Atopic dermatitis (eczema). It is unclear if topical niacinamide improves eczema symptoms. Details: A small clinical study in patients with atopic dermatitis and dry skin shows that applying niacinamide 2% cream twice daily for 8 weeks decreases skin water loss and improves skin hydration when compared with using a white petrolatum moisturizer (25560).
• Attention deficit-hyperactivity disorder (ADHD). Oral niacinamide has only been evaluated in combination with other vitamins; its effect when used alone is unclear. Details: A small clinical study in children with ADHD shows that taking a maximum of niacinamide 3 grams, ascorbic acid 3 grams, calcium pantothenate 1.2 grams, and pyridoxine 600 mg daily for 3 months seems to improve behavior in 29% of participants when compared with baseline (9957). The validity of this finding is limited by the lack of a comparator group.
• Bladder cancer. Oral niacinamide has only been evaluated in combination with carbogen for improving survival in advanced bladder cancer; its effect when used alone is unclear. Details: A phase II clinical study in patients with locally advanced bladder cancer shows that adding inhaled carbogen and oral niacinamide 40-60 mg/kg about 2 hours before radiotherapy shows a trend to improved survival at 3 years when compared with inhaled carbogen and radiotherapy (25558), and a larger phase III study shows that carbogen and oral niacinamide improves 3-year survival by about 13% when compared with radiotherapy alone (93366). An observational follow-up of the phase III study found a trend to increased survival at 5 years in the carbogen and niacinamide group when compared with radiotherapy alone. And in a subgroup of patients with tumor necrosis, the 5-year survival was significantly greater with carbogen and niacinamide when compared with radiotherapy alone (93356). It is unclear if these effects are due to niacinamide, carbogen, or the combination.
• Child growth. It is unclear if oral niacinamide improves child growth. Details: Preliminary clinical research in children in rural Tanzania shows that supplementing niacinamide orally from birth to 18 months of age does not improve length-for-age, weight-for-age, or head circumference when compared with control. Niacinamide was initially supplemented to breast-feeding mothers, 250 mg daily, until 6 months of age, followed by 100 mg daily taken by the child until 18 months of age (107713).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral niacinamide is beneficial for COVID-19. Details: Observational research in adults with acute kidney injury secondary to coronavirus disease-19 infection has found that taking niacinamide 1000 mg orally daily for 7 days is associated with a 55% lower risk of mortality when compared with control. However, taking niacinamide was not associated with a lower risk of renal replacement therapy (110500).
• Cutaneous lupus erythematosus (CLE). It is unclear if topical niacinamide is beneficial for CLE. Details: Preliminary clinical research in adults with discoid lupus erythematosus, a type of CLE, shows that applying topical niacinamide 2% to 4% twice daily for 12 weeks modestly improves lesion scores, but not quality of life scores, when compared with placebo. However, the study may have been inadequately powered to detect a difference between groups (110498).
• Depression. Although there is interest in using oral niacinamide for depression, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Diabetic neuropathy. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with diabetic polyneuropathy shows that taking a specific combination product (Cytoflavin, Polysan) containing niacinamide, inosine, riboflavin, and succinate daily for 12 weeks improves symptom scores, including paresthesia and numbness scores, when compared with placebo. The therapy was administered intravenously, containing niacinamide 20 mg, inosine 40 mg, riboflavin 4 mg, and succinate 200 mg, for 10 days followed by orally, containing niacinamide 50 mg, inosine 100 mg, riboflavin 10 mg and succinate 600 mg, for the remainder of the study (110503).
• Erythema. Topical niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: There is interest in using niacinamide to reduce the side effects of topical tretinoin, including erythema. A small preliminary clinical study in patients using isotretinoin for acne shows that applying a specific cream (Sebiaclear Hydra, SVr Laboratoire Dermatologique) containing niacinamide 5% and omega-ceramides 8% twice daily for 6 months reduces isotretinoin-induced erythema, dryness, and itching of the skin when compared with a glycerin placebo (98938). It is not clear if this effect is due to niacinamide, omega-ceramides, or the combination.
• Head and neck cancer. Oral niacinamide has only been evaluated in combination with carbogen for improving survival in laryngeal cancer; its effect when used alone is unclear. Details: A phase III clinical trial in patients with laryngeal cancer shows that treatment with accelerated radiotherapy plus carbogen and niacinamide 60 mg/kg taken orally 1-1.5 hours prior to each fraction of radiation improves local tumor control, but does not improve overall survival or 5-year disease-free survival, when compared with accelerated radiotherapy alone. In a subgroup of patients with hypoxic tumors, anemia, or high expression of epidermal growth factor receptor, receiving niacinamide and carbogen seems to improve both survival and tumor control when compared with radiotherapy alone (93358,93359,93363).
• Melasma. It is unclear if topical niacinamide improves uneven skin pigmentation. Details: A small clinical study in Japanese females with uneven facial hyperpigmentation shows that applying niacinamide 5% moisturizer to the face twice daily reduces hyperpigmentation and increases skin lightness after 4 weeks when compared with placebo moisturizer. However, further improvements are not observed after another 4 weeks of treatment (25552). Another small clinical study in Korean females with uneven facial hyperpigmentation shows that applying a moisturizer containing niacinamide 2% plus tranexamic acid 2% (Regederm RX White Project, Aestura) twice daily for 8 weeks reduces skin pigmentation by about 9% when compared with a placebo cream (93361).
• Non-Hodgkin lymphoma. It is unclear if adding oral niacinamide to chemotherapy reduces relapses of refractory lymphoma. Details: One small clinical study in patients with relapsed or refractory lymphoma shows that 24% of patients achieve complete or partial remission and 57% achieve disease stabilization when compared with baseline, following treatment with vorinostat 400 mg daily and niacinamide titrated from 20 mg/kg to 100 mg/kg over the first 14 days of a 21-day cycle for up to 18 cycles (93355). It is unclear how these outcomes compare to using vorinostat alone, or to other control treatments.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral niacinamide is beneficial for NAFLD. Details: Preliminary clinical research in adults with NAFLD and diabetes shows that taking a specific niacinamide product (Nature's Life) 1000 mg orally daily for 12 weeks does not improve liver function tests, liver steatosis, or liver fibrosis when compared with no intervention. However, some quality of life domain scores were moderately improved. However, the study may have been inadequately powered to detect a difference between groups (110502).
• Premenstrual syndrome (PMS). Although there is interest in using oral niacinamide for PMS, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Pruritus. It is unclear if oral niacinamide reduces pruritus in patients with kidney failure. Details: A small clinical study in patients with pruritus due to kidney failure shows that taking niacinamide sodium 500 mg twice daily for 4 weeks does not reduce pruritus severity when compared with placebo (93364). This study is limited due to small size and short study duration.
• Psoriasis. It is unclear if oral niacinamide is beneficial for psoriasis. Details: Preliminary clinical research in adults with mild to moderate psoriasis shows that applying niacinamide 4% cream topically twice daily for 12 weeks improves psoriasis scores by 31% when compared with baseline. The validity of these results is limited by the lack of a comparator group (110501).
• Rosacea. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that 71% of adult and adolescent patients with rosacea who take a combination product (Nicomide) containing niacinamide 750 mg, zinc 25 mg, copper 1.5 mg, and folic acid 500 mcg once or twice daily report improvement in appearance after 4 weeks when compared to baseline (25557). The validity of these findings is limited by the lack of a control group.
• Schizophrenia. Although there is interest in using oral niacinamide for schizophrenia, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Seborrheic dermatitis. It is unclear if topical niacinamide is beneficial for reducing seborrheic dermatitis symptoms. Details: One small clinical study in patients with seborrheic dermatitis shows that applying niacinamide 4% cream once daily for 12 weeks reduces the severity of symptoms such as redness and scaling by 75%, compared with a 35% reduction when using a placebo cream (93357). More evidence is needed to rate niacinamide for these uses.

(Read more about NIACINAMIDE)

POSSIBLY EFFECTIVE

• Athletic performance. Taking ornithine orally, as a single dose or daily for 1 week, may improve some measures of athletic performance, although there is no clear pattern to the effects. Details: A small clinical study in healthy volunteers shows that taking ornithine hydrochloride 1 gram twice daily for 7 days followed by 3 grams with breakfast and lunch immediately before a cycling test seems to reduce fatigue when compared with placebo (67395). Also, small clinical studies show that taking a single dose of ornithine hydrochloride 0.1 gram/kg seems to increase peak cycling speed in active young males, without changing exercise duration, maximal oxygen consumption, or maximal heart rate (67400,67404). A small clinical study in young male weightlifters shows that taking a combination of ornithine 1 gram and arginine 1 gram daily for 30-35 days is associated with increased lean body mass, strength, and peak anaerobic power when compared with placebo (32207,67427).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Dry skin. Oral ornithine 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 low skin moisture shows that ingesting a 30 mL drink containing fish scale-derived collagen peptides 10 grams and ornithine 400 mg (FUJIFILM) daily for 8 weeks does not improve skin moisture. However, it seems to improve skin elasticity and reduce water loss from the skin when compared with placebo (101607). This study was limited by its small size.
• Insomnia. Although there is interest in using oral ornithine for insomnia, there is insufficient reliable information about the clinical effects of ornithine for this condition.
• Periodontitis. It is unclear if oral ornithine is beneficial in patients with periodontitis. Details: Preliminary clinical research in patients with chronic periodontitis shows that using ornithine, 3 grams three times daily orally for 15 days after scaling and root planing, does not improve periodontal pocket depth or bleeding on probing when compared with untreated controls (108926).
• Wound healing. Although there is interest in using oral ornithine for wound healing, there is insufficient reliable information about the clinical effects of ornithine for this purpose. More evidence is needed to rate ornithine for for these uses.

(Read more about ORNITHINE)

LIKELY EFFECTIVE

• Familial hypercholesterolemia. Oral plant sterols are beneficial for reducing levels of low-density lipoprotein (LDL) cholesterol when used in combination with a cholesterol-lowering diet in children and adults with familial hypercholesterolemia (FH). Details: A meta-analysis of results from clinical research in children and adults with FH shows that taking plant sterols while following a cholesterol-lowering diet reduces total cholesterol by an additional 12 mg/dL and LDL cholesterol by an additional 23 mg/dL when compared with following a cholesterol-lowering diet alone (90743). Individual clinical trials in adults and children 5 years and up show that consuming margarine spreads or yogurt enriched with plant sterol 1.6-2.3 grams daily for 4-26 weeks, sometimes in combination with statin therapy, reduces total cholesterol by up to 11% and LDL cholesterol by up to 14% in patients with FH (90726,90731,35037,35106). However, most clinical research shows that plant sterols do not reduce triglyceride levels or increase high-density lipoprotein (HDL) cholesterol levels in patients with FH (35037,35106,90743).
• Hypercholesterolemia. Oral plant sterols in doses of 2-3 grams daily are beneficial for reducing levels of low-density lipoprotein (LDL) cholesterol, but not triglycerides, when used in combination with a cholesterol-lowering diet. Details: Clinical research shows that taking plant sterols, alone or in combination with plant stanols, reduces total and LDL cholesterol levels in patients with hypercholesterolemia. Taking plant sterols daily while following a cholesterol-lowering diet reduces total cholesterol by about 3% to 8% and LDL cholesterol by about 5% to 15% when compared with dieting alone (5336,5437,7105,65749,90686,90720,90722,90723,90724,90734)(90741,90748,90752,106093). Plant sterols seem to have the most significant cholesterol-lowering effect in people who naturally produce a high amount of cholesterol (90742). When taken along with statin therapy, plant sterols can lower total cholesterol by about 12-22 mg/dL and LDL cholesterol by about 11-16 mg/dL when compared with statin therapy alone (90728,96272). Predictive modeling suggests that the cholesterol reduction from plant sterols can reduce the risk of cardiovascular disease over time. In English adults with hypercholesterolemia and no cardiovascular disease, replacing regular spreads with plant sterol -enriched spreads over a 20-year period could potentially prevent 69 cardiovascular events per 10,000 males and 40 events per 10,000 females (98449). Plant sterols, usually as esters, with or without plant stanols, 0.2-9 grams daily for up to one year have been used (5336,5437,5814,7105,14298,90686,90720,35034,90722,90723)(90724,90726,90730,90732,90733,90734,90741,90742,90744,90748)(90752,96272). However, the optimal dosage of plant sterols for reducing LDL cholesterol is about 2-3 grams daily taken with meals (5814,90733,90748). At this dosage, plant sterols seem to work as well as plant stanols but less effectively than taking policosanol 5-40 mg daily (14298,90730). When taken as fortified foods, plant sterols appear to be more effective when taken in dairy products than in breads or cereals (35034). No increased benefit is seen at dosages higher than 2-3 grams daily (90744). In post-menopausal females, a meta-analysis of 6 studies shows that plant sterols are most effective for reducing total and LDL cholesterol in patients with obesity, using a daily dose of plant sterols greater than 2 grams, and duration of treatment greater than 8 weeks (112081). Additionally, some clinical research shows that plant sterols might become less effective after about 2-3 months of treatment (90726). Results from most individual clinical studies show that plant sterols do not reduce triglyceride levels in patients with hypercholesterolemia (65749,90720,90732,96272,106093,112081). However, a meta-analysis of results from 12 clinical studies shows that taking plant sterols 0.8-4 grams daily reduces triglyceride levels by 6% in patients with hypercholesterolemia (90732). This suggests that plant sterols might modestly lower triglyceride levels in some patients, but more research in larger patient populations is needed to confirm this finding. There is also some evidence showing that plant sterols prepared as ester derivatives using fish oil rather than sunflower oil, olive oil, or rapeseed oil can moderately lower triglyceride levels when compared with placebo (90739). However, this benefit is likely due to the triglyceride-lowering activity of fish oil rather than plant sterols. Taking plant sterols does not improve levels of high-density lipoprotein (HDL) cholesterol (65749,90728,90732,96272,112081).

POSSIBLY EFFECTIVE

• Coronary heart disease (CHD). The US Food and Drug Administration (FDA) has approved an authorized health claim for dietary plant sterols, when taken in doses of at least 3.4 grams daily as part of a diet low in saturated fat and cholesterol, for reducing the risk of CHD. Details: In 2010, the US FDA authorized a health claim stating that consuming at least 3.4 grams of plant sterols daily, as part of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease (102365). This health claim is based on evidence showing that plant sterols can lower cholesterol levels. However, there is currently no evidence directly linking dietary intake of plant sterols with a reduced risk for developing CHD.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cancer. It is unclear if dietary plant sterols are beneficial for cancer prevention. Details: A meta-analysis of population research has found that the highest intake of plant sterols is associated with a 37% reduced risk of cancer when compared with the lowest intake (106084).
• Colorectal cancer. It is unclear if dietary plant sterols are beneficial for colorectal cancer prevention. Details: Population research has found that dietary intake of specific plant sterols, including campesterol, stigmasterol, or beta-sitosterol, is not associated with risk of developing colon cancer. Dietary intake of plant sterols also does not affect the risk of rectal cancer in females; however, in males, higher dietary intake of the plant sterols campesterol or stigmasterol is associated with an INCREASED risk of rectal cancer (34993).
• Esophageal cancer. It is unclear if dietary plant sterols influence the outcome of esophageal cancer. Details: In Chinese people with esophageal squamous cell carcinoma, the mortality rate does not seem to differ between those with the lowest versus the highest intake of dietary plant sterols, measured five years before diagnosis (112082).
• Gastric cancer. It is unclear if dietary plant sterols are beneficial for gastric cancer prevention. Details: Population research has found that consuming at least 82.5 mg of plant sterols daily as part of the diet is associated with moderately lower odds of developing gastric cancer when compared to those who consume less than 45.5 mg daily (34984).
• Impaired glucose tolerance (prediabetes). Although there is interest in using oral plant sterols for prediabetes, there is insufficient reliable information about the clinical effects of plant sterols for this condition.
• Metabolic syndrome. It is unclear if oral plant sterols are beneficial for metabolic syndrome; the available research is conflicting. Details: One clinical study shows that taking yogurt mini-drinks providing plant sterols 2 grams twice daily for 8 weeks reduces total cholesterol by about 16%, low-density lipoprotein (LDL) cholesterol by about 20%, and triglyceride levels by about 19% when compared with control yogurt drinks without plant sterols (90749). However, results from a much smaller study in patients with metabolic syndrome shows that taking plant sterols 2 grams daily for 8 weeks in breakfast cereal and margarine does not improve plasma lipids or other cardiovascular markers when compared with placebo foods (90745). Reasons for the discrepancy are not clear but might relate to the dose or formulation of plant sterol, or the lipid levels of the patients at baseline.
• Myocardial infarction (MI). It is unclear if dietary plant sterols are beneficial for MI prevention. Details: Population research has found that consuming approximately 340 mg of plant sterols daily is associated with a 29% lower risk of first myocardial infarction in males when compared with those who consume about 150 mg daily. However, dietary plant sterol intake is not associated with a reduced risk of first myocardial infarction in females (90740).
• Obesity. It is unclear if oral plant sterols are beneficial for obesity. Details: In Chinese adults, higher dietary intakes of beta-sitosterol, stigmasterol, and total plant sterols are inversely related to the risk of being overweight. The risk of central obesity is linked to stigmasterol intake in females, and to beta-sitosterol intake in males (112083). Preliminary clinical research in obese individuals shows that consuming rice bran snack bars fortified with a mixture of plant sterols and stanols 1.8 grams daily for 8 weeks while following a reduced calorie diet does not increase weight loss, reduce low-density lipoprotein (LDL) cholesterol, or improve blood glucose control when compared to dieting and consuming unfortified rice bran snack bars. However, the plant sterol-enriched rice bran snacks appear to decrease total cholesterol by about 10% more than unfortified rice bran snacks (90738). More evidence is needed to rate plant sterols for these uses.

(Read more about PLANT STEROLS)

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).

(Read more about CAFFEINE)

POSSIBLY SAFE ...when used orally, short-term. Dimethylglycine has been used with apparent safety in small clinical trials lasting up to 28 days (5819,5823).

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

(Read more about DIMETHYLGLYCINE (DMG))

POSSIBLY SAFE ...when used orally and appropriately. Gamma-oryzanol 300 mg daily has been used most commonly in clinical research without reports of adverse events (751,752,753,754,755,51111). ...when used topically and appropriately (51112).

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

(Read more about GAMMA-ORYZANOL)

LIKELY SAFE ...when used orally and appropriately. Glutamine has been safely used in clinical research in doses up to 40 grams per day or 1 gram/kg daily (2334,2337,2338,2365,5029,5462,7233,7288,7293), (52288,52307,52308,52311,52313,52337,52349,52350,96516,97366). A specific glutamine product (Endari) is approved by the US Food and Drug Administration (FDA) (96520). ...when used intravenously. Glutamine has been safely incorporated into parenteral nutrition in doses up to 600 mg/kg daily in clinical trials (2363,2366,5448,5452,5453,5454,5458,7293,52272,52275), (52283,52289,52304,52306,52316,52341), (52359,52360,52371,52377,52381,52284,52385,52408,96637,96507,96516).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Glutamine has been shown to be safe in clinical research when used in amounts that do not exceed 0.7 grams/kg daily in children 1-18 years old (11364,46657,52321,52323,52363,86095,96517). A specific glutamine product (Endari) is approved by the US Food and Drug Administration for certain patients 5 years of age and older (96520). ...when used intravenously. Glutamine has been safely incorporated into parenteral nutrition in doses up to 0.4 grams/kg daily in clinical research (52338,96508). There is insufficient reliable information available about the safety of glutamine when used in larger amounts in children.

PREGNANCY AND LACTATION: LIKELY SAFE
when consumed in amounts commonly found in foods. There is insufficient reliable information available about the safety of glutamine when used in larger amounts as medicine during pregnancy or lactation.

(Read more about GLUTAMINE)

LIKELY SAFE ...when used orally in the amounts found in foods.

POSSIBLY SAFE ...when used orally in larger amounts, short-term. L-histidine has been used with apparent safety in doses of up to 4 grams daily for up to 12 weeks (2347,2353,96311,108621), or in doses of up to 8 grams daily for up to 4 weeks (108620).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in the amounts found in foods. There is insufficient reliable information available about the safety of histidine when used in larger amounts during pregnancy or lactation.

(Read more about HISTIDINE)

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

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

PREGNANCY:
Insufficient reliable information available; avoid using.

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

(Read more about L-CARNITINE)

POSSIBLY SAFE ...when used orally and appropriately, short-term. Taking muira puama 500-1050 mg daily, as part of a combination product, has been used with apparent safety for 1 month (63920,103224). There is insufficient reliable information available about the safety of muira puama when used long-term.

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

(Read more about MUIRA PUAMA)

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

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

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

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

(Read more about NIACINAMIDE)

POSSIBLY SAFE ...when used orally and appropriately, short-term. Ornithine hydrochloride has been used with apparent safety at doses up to 500 mg daily for up to 8 weeks and at doses up to 12 grams daily for up to 4 weeks (95226,110717).

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

(Read more about ORNITHINE)

LIKELY SAFE ...when used orally and appropriately. Plant sterols have been safely used in studies lasting up to one year (35022,35037,90724,90726,90730,90732,90733,90734,90739,90742). Due to the unknown safety of plant sterol oxidation products, and the known production of these oxidation products during the heating of foods (106092), there is insufficient reliable information available about the safety of heat-treated foods containing added plant sterols.

CHILDREN: LIKELY SAFE
when used orally and appropriately. Plant sterols have been safely used in children in studies lasting for up to 6 months (35037,90722,90723,90726,90731,35106). PREGNANCY AND LACTATION: Insufficient reliable information available; avoid using.

(Read more about PLANT STEROLS)

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).

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).

(Read more about CAFFEINE)

(Read more about DIMETHYLGLYCINE (DMG))

(Read more about GAMMA-ORYZANOL)

ANTICONVULSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, glutamine might antagonize the effects of anticonvulsant medications.  Details Glutamine is metabolized to the excitatory neurotransmitter glutamate. Glutamate might have antagonistic effects with anticonvulsant drugs (7292,7293,7294). However, this interaction has not yet been reported in humans.

(Read more about GLUTAMINE)

(Read more about HISTIDINE)

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

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

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

(Read more about L-CARNITINE)

(Read more about MUIRA PUAMA)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, niacinamide may have additive effects when used with anticoagulant or antiplatelet drugs, especially in patients on hemodialysis.  Details Several cases of thrombocytopenia have been reported for hemodialysis patients treated with niacinamide 1 gram daily. Hemodialysis patients receiving niacinamide had almost a three-fold higher risk of developing thrombocytopenia when compared with those receiving placebo (25563,98940).

CARBAMAZEPINE (Tegretol) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Niacinamide might increase the levels and adverse effects of carbamazepine.  Details Plasma levels of carbamazepine were increased in two children given high-dose niacinamide, 60-80 mg/kg/day. This might be due to inhibition of the cytochrome P450 enzymes involved in carbamazepine metabolism (14506). There is not enough data to determine the clinical significance of this interaction.

PRIMIDONE (Mysoline) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Niacinamide might increase the levels and adverse effects of primidone.  Details Case reports in children suggest niacinamide 60-100 mg/kg/day reduces hepatic metabolism of primidone to phenobarbital, and reduces the overall clearance rate of primidone (14506); however, there is not enough data to determine the clinical significance of this potential interaction.

(Read more about NIACINAMIDE)

(Read more about ORNITHINE)

(Read more about PLANT STEROLS)

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).

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General ...Orally, no adverse effects have been reported in clinical trials in adults and children using dimethylglycine. However, a thorough evaluation of safety outcomes has not been conducted.

Gastrointestinal ...Theoretically, dimethylglycine might react with nitrites in the gastrointestinal tract to form carcinogenic substances (5827). However, research suggests that dimethylglycine does not react with nitrites and is not carcinogenic (13172).

(Read more about DIMETHYLGLYCINE (DMG))

General ...Gamma-oryzanol is generally well tolerated. No adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.

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General ...Orally and intravenously, glutamine is generally well tolerated.
Most Common Adverse Effects:
Orally: Belching, bloating, constipation, cough, diarrhea, flatulence, gastrointestinal pain, headache, musculoskeletal pain, nausea, and vomiting.

Endocrine ...One case of hot flashes has been reported in a patient taking glutamine 5-15 grams orally twice daily for up to 1 year (96520).

Gastrointestinal ...Orally, glutamine has been associated with belching, bloating, constipation, flatulence, nausea, vomiting, diarrhea, and gastrointestinal (GI) pain. Nausea, vomiting, constipation, diarrhea, and GI pain have been reported in clinical trials using high-dose glutamine 10-30 grams (0.3 grams/kg) in two divided doses daily to treat sickle cell disease (99414). One case of dyspepsia and one case of abdominal pain have been reported in patients taking glutamine 5-15 grams twice daily orally for up to 1 year (96520). In a small trial of healthy males, taking a single dose of about 60 grams (0.9 grams/kg of fat free body mass [FFM]) was associated with a 50% to 79% incidence of GI discomfort, nausea, and belching, compared with a 7% to 28% incidence with a lower dose of about 20 grams (0.3 gram/kg FFM). Flatulence, bloating, lower GI pain, and urge to regurgitate occurred at similar rates regardless of dose, and there were no cases of heartburn, vomiting, or diarrhea/constipation (105013). It is possible that certain GI side effects occur only after multiple doses of glutamine.

Musculoskeletal ...Orally, glutamine 30 grams daily has been associated with cases of musculoskeletal pain and non-cardiac chest pain in clinical trials for patients with sickle cell disease (99414).

Neurologic/CNS ...Orally, glutamine has been associated with dizziness and headache. A single case of dizziness has been reported in a patient treated with oral glutamine 0.5 grams/kg. However, the symptom resolved after reducing the dose to 0.25 grams/kg (91356). Mania and hypomania have been reported in 2 patients with bipolar disorder taking commercially purchased glutamine up to 4 grams daily (7291). Glutamine is metabolized to glutamate and ammonia, both of which might have neurological effects in people with neurological and psychiatric diseases or in people predisposed to hepatic encephalopathy (7293).

Oncologic ...There is some concern that glutamine might be used by rapidly growing tumors and possibly stimulate tumor growth. Although tumors may utilize glutamine and other amino acids, preliminary research shows that glutamine supplementation does not increase tumor growth (5469,7233,7738). In fact, there is preliminary evidence that glutamine might actually reduce tumor growth (5469).

Other ...Orally, glutamine has been associated with cough when a powdered formulation is used. It is unclear if this was due to accidental inhalation. One case of a burning sensation and one case of hypersplenism has been reported in a patient taking glutamine 5-15 grams twice daily orally for up to 1 year (96520).

(Read more about GLUTAMINE)

General ...Orally, histidine has been used with apparent safety in clinical research; however, a thorough evaluation of safety outcomes has not been conducted.

(Read more about HISTIDINE)

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

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

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

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

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

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

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

(Read more about L-CARNITINE)

General ...No adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.

(Read more about MUIRA PUAMA)

General ...Orally, niacinamide is well tolerated in amounts typically found in food. When used topically and orally in higher doses, niacinamide seems to be generally well tolerated.
Most Common Adverse Effects:
Orally: Dizziness, drowsiness, itching, gastrointestinal disturbances, headache, and rash.
Topically: Burning sensation, itching, and mild dermatitis.

Dermatologic ...Orally, large doses of niacinamide are associated with occasional reports of rashes, itching, and acanthosis nigricans (4880,11695,11697,14504,107709). Topically, application of niacinamide in a cream has been reported to cause a burning sensation, itching and pruritus, crusting, and mild dermatitis (93357,93360,110501,110498).

Endocrine ...Orally, niacinamide in high doses, 50 mg/kg daily, has been associated with modestly higher insulin requirements in patients with type 1 diabetes, when compared with taking niacinamide 25 mg/kg daily. Theoretically, high-dose niacinamide might increase insulin resistance, although to a lesser extent than niacin (4881,14512).

Gastrointestinal ...Orally, large doses of niacinamide can cause gastrointestinal disturbances including nausea, vomiting, heartburn, anorexia, epigastric pain, flatulence, and diarrhea (6243,11694,11695,11696,11697,107709).

Hematologic ...Orally, niacinamide supplementation might increase the risk for thrombocytopenia in patients undergoing hemodialysis (98940,107709). A meta-analysis of small clinical studies shows that taking niacinamide during hemodialysis to reduce phosphate levels is associated with a 2.8-fold increased risk for thrombocytopenia when compared with placebo. In one of the included studies, platelet levels returned to normal within 20 days after niacinamide discontinuation (98940).

Hepatic ...Orally, older reports of elevated liver function tests with high doses of niacinamide (3 grams or more daily) have raised concerns about liver toxicity. However, newer studies have not reported this concern; it is possible that some of these cases were due to contamination with niacin (4880,11694,11695,14503).

Neurologic/CNS ...Orally, large doses of niacinamide can cause dizziness, drowsiness, and headaches (11694,11695,11696,11697,107709).

(Read more about NIACINAMIDE)

General ...Orally, ornithine seems to be well-tolerated. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Gastrointestinal symptoms (unspecified)

Gastrointestinal ...Orally, ornithine might cause adverse gastrointestinal effects. In a small, uncontrolled trial, gastrointestinal symptoms were reported in around 22% of individuals taking ornithine 3.2-12 grams daily (110717).

Genitourinary ...Orally, ornithine has been associated with one case of hematuria. In a small, uncontrolled trial, hematuria was reported in one individual taking ornithine, which resolved quickly without treatment when ornithine was discontinued. While the researchers suspected the hematuria was not related to ornithine supplementation, no cause could be determined (110717).

(Read more about ORNITHINE)

General ...Orally, plant sterols are generally well tolerated.

Dermatologic ...Acute dermatitis has been reported in a case report of a 51-year-old female who used a pharmacy-brand plant sterol supplement to lower cholesterol levels. The rash was widespread with lesions on the hands and feet and a red and swollen face. The patient was treated orally with prednisolone and topically with emollients for 2 weeks (90737). It is not entirely clear if this adverse effect was due to the plant sterol supplement or another contributing factor.

Endocrine ...Peripheral precocious puberty has been described in a 20-month-old boy who ingested about 15 grams daily of a chicken essence product containing the plant sterol avenasterol, also known as clerosterol or chondrillasterol. Signs and symptoms included elevated estradiol and testosterone levels, acne, hairiness, increased penis size, hoarse voice, and increased growth rate. These effects were reversed when the product was stopped (112084).

Gastrointestinal ...Abdominal discomfort has occurred in one child in a clinical trial of oral plant sterols (35106). Because plant sterols decrease cholesterol absorption in the gut, there is concern that they might produce some gastrointestinal symptoms like diarrhea and excess amounts of fat in the stool (steatorrhea), although these adverse effects have not been reported in clinical research.

(Read more about PLANT STEROLS)