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Athletic performance. In some adults, taking beta-alanine appears to improve some, but not all, measures of athletic performance. Beta-alanine appears to work better for exercises that lasts at least 1 minute in duration; however, many other factors likely alter efficacy, such as the type of exercise, the subject's training experience, and the dosing regimen. Details: Many small clinical trials have evaluated the effects of beta-alanine supplementation in untrained individuals, recreational athletes, and professional athletes in a variety of sports and activities, including running, cycling, swimming, basketball, football, soccer, rowing, water polo, wrestling, weight lifting, skiing, and others. However, the results of individual trials are conflicting. Furthermore, studies have included multiple endpoints that have been both lab-based, such as time to exhaustion, strength endurance, time trials, and power output, and field-based, such as performance times (18227,94333,94334,94335,94336,94337,94338,94339,94340,94341)(94342,94343,94345,94346,94347,94348,94349,97956,97958,97960)(97962,97969,97970,97971,97972,101027,101028,101029,101030,104144)(104145,106710,106711,106713,106717,106718,112794). Meta-analyses of clinical trials show that taking beta-alanine 2-6.4 grams orally daily for 3-12 weeks provides minor improvements in exercise capacity and performance when compared with control (18227,94357,106717). In one meta-analysis, exercise capacity improved by an average of approximately 3% when compared with placebo (18227). However, meta-analyses suggest that improvements in exercise performance are less than exercise capacity (18227,94357). The majority of this research has only included males. Preliminary clinical research assessing the effect of beta-alanine on exercise capacity in females has not consistently demonstrated a benefit. However, the validity of these studies is limited by small sample sizes (14611,94338,94339,94345,97957,97967,104144,112791). Preliminary clinical research also suggests that beta-alanine is more effective for short exercises, lasting at least 1 minute. Longer exercises, lasting more than 10 minutes, have not been well studied. In addition, the type of athlete and type of exercise most likely to benefit from beta-alanine supplementation is unclear (18227,94357,106717). Pooled analyses have not identified the most effective dose of beta-alanine; however, preliminary subgroup analyses suggest that prolonged supplementation of at least 3-6 weeks may be needed to gain benefits (94357,106717). There does not seem to be a relationship between the daily beta-alanine dose and exercise-related outcomes, although one analysis suggests outcomes may be related to the total cumulative dose; most studies have used a total daily dose of 2.4-6.4 grams (18227,94357,101026,101027,101028,101029,101030,106712,106717). The majority of studies have evaluated various marketed formulations of beta-alanine (Carnosyn, Natural Alternatives International; Sustained Release Beta-Alanine, Musashi; Balance 100% unflavored pure beta-alanine, Vitaco Health; Intra X cell, Athletics Edge Nutrition) (94333,94335,94336,94337,94339,94342,94346,94347,94348,94349)(101028,101029,101030,104144,106710,106711,106718). Beta-alanine has also been studied in combination with 1 additional ingredient, namely sodium bicarbonate or creatine. Preliminary clinical research in physically active or trained males shows that taking beta-alanine 6-6.4 grams orally daily for 4-6 weeks with sodium bicarbonate 300-500 mg/kg orally daily for 1-7 days does not increase exercise capacity or exercise performance while cycling or sprinting when compared with individual supplementation (97959,97964,97966,101028). In contrast, preliminary clinical research in male athletes participating in martial arts or rowing shows that taking beta-alanine with sodium bicarbonate modestly increases exercise performance when compared with either ingredient taken alone (97962,97963). Other preliminary clinical research in healthy, untrained males shows that taking beta-alanine 1.6 grams daily for 28 days with creatine 5 grams twice daily for 22 days, followed by four times daily for 6 days, modestly increases power output during cycling when compared with placebo or taking either supplement alone (97973). In another very small clinical study in trained military males, taking beta-alanine 6.4 grams daily for 28 days with creatine 0.3 grams/kg daily for the last 7 days improves leg muscle power but not anaerobic power or muscle strength when compared with beta-alanine plus placebo (112793). Beta-alanine has also been studied in combination with multiple other ingredients. Preliminary clinical research shows that taking a specific product containing beta-alanine, creatine monohydrate, arginine, alpha-ketoisocaproate, and leucine (NO-Shotgun) or a different product containing beta-alanine, L-histidine, and carnosine (BETAFOR3MAX, Martinez Nieto S.A.) for 28 or 7 days, respectively, also improves strength and power output when compared with placebo (34451,106714). However, another very small crossover clinical study in healthy males shows that taking 6 mg/kg of a multi-ingredient pre-workout supplement containing beta-alanine, L-tyrosine, L-citrulline maleate, arginine alpha-ketoglutarate, L-taurine, and caffeine 30 minutes prior to weight training does not increase bench press strength endurance when compared with an equivalent amount of anhydrous caffeine (111250). It is unclear if these effects are due to beta-alanine, other ingredients, or the combination.
Physical performance. Preliminary clinical research shows that taking beta-alanine improves exercise capacity and fatigue, but not strength or exercise performance, in older adults. Details: Clinical research in older adults shows that taking beta-alanine 2.4-3.2 grams daily for 4-12 weeks increases exercise capacity and delays fatigue during exercise when compared with placebo (16442,97955,97965). In addition, preliminary clinical research in older adults shows that taking an oral nutritional supplement fortified with beta-alanine 0.8-1.2 grams twice daily for 12 weeks increases exercise capacity when compared with taking the oral nutritional supplement alone (97961). Taking beta-alanine 2.4 grams daily also minimizes the reduction of executive functioning after cycling in older adults when compared with placebo (97955). However, 2 clinical studies in older adults show that taking beta-alanine (Natural Alternatives International) 2.4-3.2 grams daily for 10-12 weeks with or without an endurance-based resistance-training program does not improve strength, power, fatigue, or performance when compared with the resistance training program alone or placebo (101031,112792).

Age-related cognitive decline. It is unclear if oral beta-alanine is beneficial for cognitive decline in older adults. Details: A small clinical study in older adults shows that taking beta-alanine 1200 mg twice daily for 10 weeks reduces symptoms of depression and might improve cognitive function in subjects with borderline or low cognitive function at baseline when compared with placebo. However, beta-alanine supplementation does not improve cognitive function in older adults with normal cognitive function at baseline and does not benefit mood, anxiety, or executive function when compared with placebo (112792).
Chronic obstructive pulmonary disease (COPD). It is unclear if oral beta-alanine improves physical function in people with COPD. Details: A small clinical study in adults with COPD shows that taking beta-alanine (SR CarnoSyn, Natural Alternatives International, Inc) 800 mg four times daily for 12 weeks does not improve exercise capacity, muscle function, or physical activity when compared with placebo (112790).
Cognitive function. Oral beta-alanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in trained military males shows that taking beta-alanine 6.4 grams daily for 28 days with creatine 0.3 grams/kg daily for the last 7 days modestly improves mathematical processing when compared to baseline, but not when compared with beta-alanine plus placebo. However, improvement from baseline was not found in the group taking beta-alanine plus placebo (112793).
Exercise-induced muscle breakdown. It is unclear if oral beta-alanine improves muscle recovery after exercise. Details: Preliminary clinical research in untrained adults shows that taking beta-alanine 4.8 grams orally daily for 4 weeks does not improve muscle recovery after resistance exercises when compared with placebo (101026).
Menopausal symptoms. Although there has been interest in using oral beta-alanine for menopausal symptoms, there is insufficient reliable information about the clinical effects of beta-alanine for this purpose.
Obesity. It is unclear if oral beta-alanine improves body composition in adults. Details: A meta-analysis of several small clinical studies in active and sedentary adults shows that supplementing with beta-alanine 1.6-6.4 grams daily for 3-10 weeks does not reduce body mass, fat mass, body fat percentage, or free fat mass when compared with various controls. Subgroup analysis of dose, duration, and type of additional training did not change the results (112789).
Sarcopenia. Although there has been interest in using oral beta-alanine for sarcopenia, there is insufficient reliable information about the clinical effects of beta-alanine for this purpose. More evidence is needed to rate beta-alanine for these uses.

CAFFEINE (Caffeine Anhydrous, ZumXR XR Caffeine)

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).

Athletic performance. Oral caffeine taken 30-150 minutes prior to physical activity seems to modestly improve muscle strength and physical endurance, although the magnitude of effect is variable and may be dependent on a number of patient- and activity-specific factors. Caffeine in excess of 800 mg daily can result in levels greater than those allowed by the National Collegiate Athletic Association. Details: Clinical research and meta-analyses of clinical research show that taking caffeine 2-10 mg/kg modestly improves work produced, muscle strength, physical endurance, and athletic performance (10203,11832,37648,37894,38054,38063,95955,100362,100365,100371)(103701,103703,108798,111250). Meta-analyses of studies using caffeine 3-9 mg/kg as a single dose prior to endurance time trials reports variability in results. Sports studied included running, rowing, cycling, swimming, and Nordic skiing, and included both recreational and trained athletes. Overall there was a small positive effect on time to exhaustion, endurance performance, and mean power output, and a decrease in the time needed to complete the trials when compared with placebo (98808,111497). Another meta-analysis of small clinical trials shows that the benefit of caffeine on athletic performance seems to increase with increased duration of the activity. This suggests that caffeine can improve physical endurance during athletic activities (100371). In these trials, caffeine is typically provided as a single dose 30-150 minutes prior to testing (98808), although one study suggests that taking caffeine 60 minutes prior to peak activity has the most consistent ergogenic benefits (104577). Most research has investigated the acute effects of a single dose of caffeine. The evidence is mixed as to whether chronic intake of caffeine could induce tolerance and reduce any acute ergogenic benefits. One study shows that the consistent consumption of caffeine 3 mg/kg daily for 28 days eliminates the acute benefits of caffeine in work produced when compared with placebo, suggesting the development of tolerance (95955). However, chronic use of caffeine at a dose of 6 mg/kg for 4 days does not seem to induce tolerance to an acute dose of caffeine 6 mg/kg taken 60 minutes prior to a cycling time trial in males who are moderate to high users of caffeine (104576). Similarly, a small clinical study in trained individuals shows that acute supplementation with oral caffeine 6 mg/kg about 1 hour prior to performance improves strength and endurance when compared with placebo or control, regardless of habitual caffeine consumption (108804). Differences may be due to the type of exercise, the acute dose of caffeine, the length of the chronic intake period, and/or the normal caffeine intake of the athlete. Some clinical research also shows that taking caffeine can decrease subjective feelings of exertion and fatigue during exercise such as fencing and cycling (17618,37656,91026,91058,91062). Although some other clinical studies show that caffeine does not affect perceived exertion, caffeine does seem to improve performance and cause small increases in the amount of physical work done when compared with placebo in various athletes, including cyclists, runners, basketball players, and golfers (37702,37860,37872,38031,38119,38320,91037,91077,97457,97459)(104580,108800,108804). These effects do not seem to be dependent upon the dose of caffeine (97459), although some research shows that the timing of caffeine intake and exercise may alter overall benefit, with a greater effect seen in the morning compared to the evening (97457,104580). Caffeine might improve performance in some athletic activities but not others. Some research shows that caffeine does not improve performance during athletic activities requiring a high amount of exertion over a short period of time. Such activities include sprinting and lifting (11832,37564,37758,37837,37841,37890,38319,95963,97459,112740). However, it is possible that the negative lifting studies were underpowered. Ballistic exercise, such as jumping or throwing, requires rapid increases in velocity, force, and muscle activation. A meta-analysis of 10 studies shows that caffeine in a range of doses (mean: 3 mg/kg) has a significant ergogenic effect on throwing performance and velocity (111488). A meta-analysis of small studies shows that caffeine modestly improves bench press repetitions and maximum strength, but not perceived exertion, when compared with placebo. Caffeine also tends to improve these parameters for leg presses, but the improvement does not reach significance when compared with placebo (103701). A very small study in healthy males shows that taking caffeine alone, 6 mg/kg prior to bench press exercises, has a greater ergogenic benefit than a multi-ingredient supplement containing the same dose of caffeine in combination with L-tyrosine, beta-alanine, L-citrulline maleate, arginine alpha-ketoglutarate, and L-taurine (111250). A meta-analysis of small clinical studies in female team-sport athletes shows that caffeine improves specific team-sport skills but has no effect on perceived exertion or agility tests performed after exertion (108799). Conversely, a small individual clinical study shows that taking caffeine 6.5 mg/kg 60 minutes before strength training decreases perceived exertion while increasing the number of repetitions of both upper and lower limb exercises by 17% to 33% over placebo (104581). Most studies suggest that there is significant inter-individual variability in response to caffeine for improvement of athletic performance (100365). These differences might be due, at least in part, to genotype (100370), although research is conflicting. Caffeine is metabolized by the cytochrome P450 1A2 (CYP1A2) enzyme. One small clinical trial in resistance-trained males shows that taking caffeine 6 mg/kg improves resistance exercise performance in those homozygous for the CYP1A2 rs762551 polymorphism (AA) when compared with those without or heterozygous for that polymorphism (CC or A/C, respectively) (100370). However, another clinical study in trained male athletes shows that taking oral caffeine 4 mg/kg about 30 minutes prior to performance decreases handgrip strength by about 13% in individuals with the CC genotype when compared with placebo, but not in those with the AA or A/C genotypes. No groups experienced an improvement in vertical jump performance (108803). Another small clinical study suggests that CYP1A2 genotype does not affect exercise performance in athletes 60 minutes after taking caffeine 3 mg/kg. In addition, the ADORA2A genotype, which plays a role in caffeine sensitivity, does not seem to affect exercise performance benefits from caffeine (104578). However, these studies are small and further research is needed to clarify how these polymorphisms may impact the athletic performance benefits of caffeine. Limited research has also evaluated the use of a caffeine mouth rinse, with mixed findings. Two very small clinical studies in healthy trained males shows that rinsing the mouth with 25 mL of water containing caffeine 85 or 300 mg for 5-10 seconds does not affect athletic performance or time to exhaustion while cycling when compared with placebo (103709,108801). However, another small study in healthy Taekwondo athletes fasting for Ramadan suggests that using a mouth rinse containing caffeine 6 mg/kg, ten seconds prior to exertion, modestly reduces perceived exertion and modestly improves kick performance when compared with using a placebo rinse (103710). Similarly, another small clinical study in healthy, resistance-trained males shows that rinsing the mouth with 25 mL of a solution containing caffeine 3%, but not 1% or 2%, reduces perceived exertion and increases muscular endurance, but not strength, when compared with placebo. The mouth rinse was used for 5 seconds immediately prior to a strength test or once per minute for 2 minutes during a muscular endurance test (108802). Preliminary clinical research has also investigated the use of caffeine in combination with other ingredients, such as sodium bicarbonate however these studies have not demonstrated clear benefits in athletic performance over taking caffeine alone (112740).
Bronchopulmonary dysplasia. Intravenous caffeine may reduce the risk for bronchopulmonary dysplasia in preterm infants. Details: Population research has found that initiating caffeine treatment prior to the third day of life in premature infants is associated with a reduced risk of developing bronchopulmonary dysplasia compared to later initiation of treatment with caffeine. Additionally, a meta-analysis of available clinical research shows that high-dose caffeine (40-80 mg/kg loading dose, 20 mg/kg daily maintenance) lowers the risk of bronchopulmonary dysplasia when compared with standard dosing (20 mg/kg loading dose, followed by 5-10 mg/kg daily maintenance). However, small sample sizes and high heterogeneity limit the validity of these findings (97462,100364).
Diabetes. Dietary caffeine seems to be beneficial for the prevention of type 2 diabetes; it is unclear if it is beneficial for the prevention of gestational diabetes. Also, it is unclear if oral caffeine is beneficial in patients with type 1 or type 2 diabetes. Details: Total caffeine consumption from beverages such as coffee or tea is associated with a lower risk of developing type 2 diabetes. This effect appears to be dose-dependent (11353,14313,37850,37871,91040,100368). For example, an increase of 200 mg daily caffeine intake seems to be associated with a 14% decrease in the incidence of type 2 diabetes (91055). Additionally, in North American males, consuming caffeine 417 mg daily from coffee or tea is associated with a 20% lower risk of developing type 2 diabetes when compared with those consuming less than 37 mg daily. North American females consuming at least 258 mg of caffeine daily from coffee or tea seem to have a 10% to 30% lower risk of developing type 2 diabetes when compared with those consuming less than 140 mg daily (11353). Japanese adults who consume at least 416 mg of caffeine daily from beverages including coffee or green tea seem to have a 33% lower risk of developing type 2 diabetes compared to those who consume no more than 57 mg daily. The risk reduction appears to be more pronounced in Japanese females when compared with males (14313). It is unclear if caffeine is beneficial in adults with diabetes. A few small studies show that caffeine consumption may further reduce insulin sensitivity in patients with type 2 diabetes, gestational diabetes, or those at risk for developing diabetes (13744,37653,37820). Caffeine consumption has also been evaluated during pregnancy. An observational study has found that self-reported consumption of beverages containing up to 100 mg of caffeine at 16-22 weeks' gestation is associated with a 47% lower risk of developing gestational diabetes when compared with no intake (108814). Research regarding the effects of caffeine in patients with type 1 diabetes shows conflicting results. One study shows that taking caffeine 250 mg twice daily for 2 weeks can reduce the incidence of elevated blood sugar at night in patients with type 1 diabetes (37660). However, another study in patients with type 1 diabetes shows that taking caffeine 200 mg daily for 3 months may increase the ability to perceive hypoglycemic symptoms when compared with placebo, although overall glycemic control does not seem to be affected (6024).
Memory. Oral caffeine seems to be beneficial for short-term memory recall in college students and extroverted personalities. It is unclear if oral caffeine is beneficial for introverted personalities or other populations. Details: Taking a single dose of caffeine 65-200 mg orally daily seems to improve memory function in some individuals such as college students and people with extroverted personalities. A small study shows that taking caffeine does not improve memory function in individuals with introverted personalities (37845,38071,91080).
Obesity. Oral caffeine, when taken in combination with ephedrine or as a component of green tea, seems to be beneficial for weight loss, short-term. Details: Taking caffeine orally, in combination with ephedrine or as a component of green tea, seems to help reduce weight, short-term (695,696,1704,8647,16892,37617,37831). Caffeine 192 mg in combination with ephedra 20-90 mg per day for 6 months seems to cause a modest weight reduction (5.3 kg) in people with a body mass index (BMI) between 25-40 kg/m². This combination, along with limiting fat intake to 30% of calories and moderate exercise, also seems to reduce body fat, decrease low-density lipoprotein (LDL) cholesterol, and increase high-density lipoprotein (HDL) cholesterol. However, even in carefully screened and monitored otherwise healthy adults, caffeine/ephedra combinations can cause small changes in blood pressure and heart rate (8647). Preliminary clinical research also shows that taking 1000 mg of a proprietary combination product containing caffeine and multiple other ingredients (Prograde Metabolism) twice daily for 8 weeks in conjunction with dieting reduces body weight, fat mass, waist circumference, and hip circumference by 1.5%, 5%, 1.8%, and 1.3%, respectively, when compared with dieting alone (40802).
Pain (acute). Oral caffeine, when taken in combination with acetaminophen, propyphenazone, ibuprofen, or other pain-relieving agents, seems to be beneficial for acute pain. Details: Clinical research shows that taking caffeine 50-130 mg in combination with acetaminophen, propyphenazone, ibuprofen, or other pain-relieving agents can reduce acute pain when compared with the effects of pain-relieving agents alone (37587,37904,38036,38303,91038). Adding ≥100 mg caffeine to treatment with acetaminophen or ibuprofen results in 5% to 10% more patients that achieve at least 50% of maximum pain relief for over 4 hours when compared to treatment with acetaminophen or ibuprofen alone (91038).
Postdural puncture headache. Oral or intravenous caffeine seem to be beneficial for preventing postdural puncture headache. Details: Using caffeine 300 mg orally or 500 mg in 1,000 mL normal saline intravenously seems to help treat and prevent postdural puncture headache (2727,2728). Using a combination of ergotamine and caffeine seems to be less effective than gabapentin for treating this condition (38147). Lower doses of oral caffeine may not be beneficial. Clinical research shows that oral caffeine, 75-125 mg, does not decrease the risk of postdural headache (91022).

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

Age-related cognitive decline. It is unclear if oral caffeine prevents cognitive decline with aging. Details: Population research from a small cohort of elderly females shows that caffeine intake of more than 371 mg daily is associated with an attenuation in cognitive decline when compared to less than 30 mg daily. This is equivalent to the difference seen over a 7 year span of age. Caffeinated coffee consumption, but not caffeinated chocolate, tea, or cola, was associated with this attenuation in cognitive decline (91088).
Alzheimer disease. It is unclear if oral caffeine is beneficial for preventing dementia; the available research is conflicting. Details: Population research from the UK Biobank has found that caffeine intake up to 400 mg daily is associated with a 24% to 34% reduced risk of developing Alzheimer disease when compared with lower intake. Conversely, population research from the Rush Memory and Aging Project in the US has found that caffeine intake of more than 100 mg daily is associated with a 41% increased risk of developing Alzheimer disease when compared with lower intake. However, when those with mild cognitive impairment at baseline or cases diagnosed within 2 years of follow-up are excluded, these findings become insignificant (108810).
Asthma. Oral caffeine seems to modestly improve airway function for up to 4 hours in patients with mild to moderate asthma. However, it is unclear if oral caffeine has a clinically significant effect on asthma symptoms or quality of life. Details: Taking caffeine 9 mg/kg orally appears to modestly improve airway function for up to 4 hours in people with mild to moderate asthma (37907,37915). However, more research is needed to determine the appropriate dose, whether any benefit is clinically significant, or whether tolerance occurs with chronic dosing.
Cancer pain. It is unclear if intravenous caffeine is beneficial for cancer pain. Details: Clinical research shows that receiving caffeine 200 mg intravenously once daily for 2 days results in a significant reduction in pain intensity by 0.833 points on the NRS scale when compared with control in patients receiving opioids for pain from advanced cancer (91081).
Cognitive function. It is unclear if oral caffeine improves cognitive performance in trained athletes. Details: A meta-analysis of small studies in trained adult athletes shows that consumption of a low to moderate amount of caffeine 15-60 minutes prior to exercise and during exercise improves attention performance, but not reaction time or inhibitory control, when compared with placebo (108797). The validity of these findings is limited by unclear reporting.
Dementia. It is unclear if oral caffeine is beneficial for preventing dementia or improving behavior in patients with dementia. Details: Population research from the Women's Health Initiative has found that caffeine intake of more than 175 mg daily is associated with a 26% reduced risk of developing probable dementia or global cognitive impairment when compared to less than 175 mg daily in postmenopausal adults 65-80 years of age (97458). Population research from the UK Biobank has found that caffeine intake up to 400 mg daily is associated with a 17% to 26% reduced risk for developing all-cause dementia when compared with lower intake. Conversely, population research from the Rush Memory and Aging Project in the US has found that caffeine intake of more than 100 mg daily is associated with a 35% increased risk of developing all-cause dementia when compared with lower intake. However, when those with mild cognitive impairment at baseline or cases diagnosed within 2 years of follow-up are excluded, these findings become insignificant (108810). Caffeine consumption has also been evaluated in patients with dementia. A cross-sectional study in patients with dementia in a care home has found that intake of 'normal' to 'high' amounts of caffeine are associated with reduced agitation and other behavioral symptoms when compared to 'low' intakes of caffeine (104574).
Depression. It is unclear if oral caffeine is beneficial for depression prevention. Details: Some population research found that caffeine intake is associated with an increased incidence of depressive symptoms in pediatric patients (37839,38162). However, other population research found that caffeinated beverage intake is associated with a decreased incidence of depression in adults (37969,38165,91067,100366).
Electroconvulsive therapy (ECT) augmentation. Although there has been interest in using intravenous caffeine sodium benzoate to augment electroconvulsive therapy, there is insufficient reliable information about the clinical effects of caffeine for this condition.
Exercise-induced hypoxemia. It is unclear if oral caffeine is beneficial for hypoxemia associated with exercise. Details: Preliminary clinical research in athletes experiencing exercise-induced hypoxemia shows that taking caffeine 8 mg/kg can improve exercise ventilation, but not ventilatory response or oxygen saturation, when compared with placebo (37750).
Exercise-induced muscle soreness. It is unclear if oral caffeine is beneficial for reducing muscle soreness during exercise. Details: There is conflicting clinical evidence as to whether caffeine can reduce exercise-induced muscle pain. Some evidence shows that taking caffeine 100 mg or 10 mg/kg can reduce muscle pain during exercise when compared with placebo (37622,38146). However, the effect of lower doses is unclear. Some evidence shows that taking caffeine 5 mg/kg may reduce exercise-induced muscle pain when compared with placebo (37747,91050), while other evidence suggests that taking caffeine 2-5 mg/kg does not affect muscle pain during exercise (38141).
Gallbladder disease. It is unclear if increased dietary caffeine intake reduces the risk of developing gallstones. Details: Consumption of caffeinated beverages that provide 400 mg or greater of caffeine per day is associated with a significantly reduced risk of developing symptomatic gallstone disease (3345,8032). The effect seems to be dose-dependent; consumption of 800 mg caffeine per day has the greatest reduction in risk (3345).
Hepatitis C. It is unclear if increased dietary caffeine reduces the risk for hepatitis C-associated severe liver inflammation, although it may reduce the risk of developing advanced fibrosis. Details: A meta-analysis of population research has found that regular consumption of caffeine at doses of at least 123 mg daily is associated with a 48% reduced risk of advanced liver fibrosis when compared to lower caffeine intake in patients with hepatitis C virus (95947). An individual population study also found that higher intake of caffeine from coffee is associated with reduced severity of liver fibrosis in patients with chronic hepatitis C virus. For these patients, the risk of advanced fibrosis is reduced by 14% for each 67 mg of caffeine (37896). However, caffeine intake does not appear to be associated with a reduced risk of moderate to severe liver inflammation in patients with hepatitis C (95947).
Hypnic headache. It is unclear if oral caffeine reduces the pain associated with this rare condition. Details: Anecdotal evidence suggests that drinking a cup of coffee containing caffeine before bed or upon waking up may help alleviate pain associated with hypnic headaches (38078).
Hypotension. It is unclear if oral caffeine is beneficial in people with low blood pressure. Details: Preliminary clinical research shows that consuming caffeinated beverages increase blood pressure in elderly people with postprandial hypotension (11834,11835).
Intermittent claudication. It is unclear if oral caffeine is beneficial for intermittent claudication. Details: Taking a single dose of caffeine 6 mg/kg orally seems to improve walking distance, muscular strength, and endurance in patients with intermittent claudication; however, balance seems to be reduced (38038).
Liver disease. It is unclear if oral caffeine is beneficial for liver disease prevention. Details: Population research found that there is an inverse association between intake of coffee and the incidence of liver cirrhosis (37576,37608). However, it is unclear if this effect of coffee is attributable to caffeine, since other caffeinated beverages do not show this effect.
Narcolepsy. It is unclear if oral caffeine is beneficial for narcolepsy. Details: A small clinical study in patients with narcolepsy shows that taking caffeine 200 mg daily in the morning for 1 week does not affect reaction time, but modestly reduces drowsiness, when compared with baseline (103698). The validity of this finding is limited by the lack of a statistical comparison between the treatment and placebo groups.
Neonatal resuscitation. It is unclear if oral caffeine improves the likelihood for successful extubation in preterm infants. Details: Preliminary clinical research in extremely preterm infants requiring mechanical ventilation within the first 5 days of birth shows that early administration of caffeine, given as a loading dose of caffeine citrate 20 mg/kg followed by a maintenance dose of 5 mg/kg daily until extubation, does not reduce mortality or shorten time to first successful extubation when compared to giving a bolus dose of caffeine citrate 20 mg/kg just prior to extubation (97461).
Nocturnal enuresis. Reducing caffeine intake might reduce the frequency of nocturnal enuresis episodes in children. Details: Preliminary clinical research in children aged 6-15 years with primary nocturnal enuresis shows that limiting caffeine intake to less than 30 mg daily reduces the mean number of bedwetting episodes from 3.5 to 2.4 per week, when compared with no change in the group with intakes of 80-100 mg daily. The probability of bedwetting in the caffeine restricted group was about 14% lower than that in the control group (111495).
Nonmelanoma skin cancer. It is unclear if oral caffeine is beneficial for nonmelanoma skin cancer prevention. Details: A review of available population research shows that increased caffeine intake from any source is associated with a 14% reduction in the risk of developing nonmelanoma skin cancer. Consumption of caffeinated coffee, but not decaffeinated coffee, is associated with an 18% reduced risk (97465).
Parkinson disease. Although consuming caffeinated beverages might reduce the risk of developing Parkinson disease, it is unclear if oral caffeine is beneficial for improving symptoms. Also, oral caffeine does not seem to prevent tardive dyskinesia. Details: It is unclear whether caffeine improves some symptoms of Parkinson disease, as results from clinical research are conflicting (91069,95951,95954,103705). One clinical study in Parkinson disease patients with extreme daytime somnolence shows that taking caffeine 100 mg twice daily for 3 weeks and then 200 mg twice daily for 3 weeks results in modest improvements in rigidity and bradykinesia, but inconsistent improvements in drowsiness, when compared with placebo (91069). Other clinical research shows that caffeine 200 mg twice daily does not lead to improvements in motor severity, cognition, or somnolence after 6, 12, or 18 months when compared with placebo (95954). Furthermore, a large retrospective study has found that caffeine consumption of more than 300 mg daily for 18 months in conjunction with dopaminergic therapy does not slow the rate of Parkinson disease progression. This research also shows that a reported consumption of caffeine greater than 300 mg, in conjunction with creatine 10 grams daily for 18 months, may accelerate the rate of Parkinson disease progression (95951). The retrospective nature of this study limits the validity of these findings. Caffeine does not appear to be helpful for reducing the risk of tardive dyskinesia. A retrospective analysis has found no definitive difference in onset of tardive dyskinesia in Parkinson patients consuming more than 204 mg caffeine daily when compared with those consuming less than 68 mg daily (91090). Despite these mainly negative findings, large-scale epidemiological studies have found that people who consume caffeinated beverages, such as coffee, tea, and cola, have a decreased risk of Parkinson disease (37931,91060,91071,103705). Males consuming 3-4 cups (28 oz) of caffeinated coffee per day, or 421-2716 mg total caffeine, seem to have the lowest risk of developing this condition. However, a lower risk is also associated with consumption of as little as 124-208 mg of caffeine (6022). In females, more moderate caffeinated coffee consumption, such as 1-3 cups per day, seems to be best (1238). Caffeine does not appear to provide additional protection from Parkinson disease in cigarette smokers (9236,91060).
Postoperative ileus. It is unclear if oral caffeine is beneficial for improving bowel recovery following colorectal resection. Details: A small clinical study in adults undergoing elective laparoscopic colon or rectal resection with primary anastomosis shows that caffeine citrate 100 mg three times daily, starting on the morning of postoperative day 1, reduces the time to self-reported first bowel movement by about 18 hours when compared with placebo. There was no difference between groups in time to self-reported first flatus (108808). Another small study in adults undergoing elective laparoscopic colectomy shows that taking caffeine 100 mg or 200 mg three times daily does not reduce the mean time to first bowel movement, colonic transit time, or length of hospital stay when compared with placebo (111484). However, a meta-analysis of these two clinical trials shows that taking caffeine does not decrease the time to the first stool or length of hospital stay when compared with control (112732).
Postoperative pain. It is unclear if intravenous caffeine is beneficial for reducing opioid consumption in adults undergoing surgery. Details: A small clinical study in adults undergoing laparoscopic colorectal and gastrointestinal surgery shows that intravenous caffeine citrate 200 mg at the initiation of surgical closure has no effect on cumulative opioid consumption through postoperative day 3 when compared with placebo. In fact, post-hoc analysis with adjustment for age, sex, comorbidities, history of anxiety or depression, and open surgical conversion suggests an increase in opioid consumption with administration of caffeine when compared with placebo (108809).
Pre-eclampsia. It is unclear if oral caffeine intake affects the risk of gestational hypertension or pre-eclampsia. Details: a meta-analysis of 10 observational studies including about 115,000 pregnant people did not find an association between the level of caffeine intake during pregnancy and the risk of developing gestational hypertension or pre-eclampsia (111485).
Stroke. It is unclear if oral caffeine is beneficial for stroke prevention. Details: Population research has found that increased intake of either caffeinated or decaffeinated coffee is associated with a decreased risk of stroke in females (37804). However, it is not clear if the effect of coffee is attributable to the caffeine component.
Tinnitus. It is unclear if oral caffeine is beneficial in patients with chronic tinnitus. Details: A small clinical study in adults with chronic tinnitus shows that taking a single dose of caffeine 300 mg improves mood and quality of life at 1 hour when compared with baseline. (108805). The lack of statistical comparison to the placebo group limits the validity of these findings. More evidence is needed to rate the effectiveness of caffeine for these uses.

CITICOLINE

Age-related cognitive decline. Clinical research in elderly patients shows that taking oral or intravenous citicoline daily improves some memory scores, short-term. Details: Several small clinical studies in people 50-85 years of age with age-related cognitive decline shows that taking citicoline 500-2000 mg daily, either orally or by intravenous infusion, for up to 12 weeks moderately improves memory scores when compared with placebo (12130,12131,43284,109016). Citicoline consistently improves short-term recall and verbal memory, but the effects on other domains are less clear (12130,12131,43284). In one clinical study, a specific citicoline product (Cognizin, Kyowa Hakko) 500 mg daily for 12 weeks was used (109016).
Glaucoma. Clinical research shows that oral, intramuscular, or ophthalmic citicoline may improve vision or slow the rate of vision loss in patients with glaucoma. However, these different routes of administration have not been directly compared. Details: Preliminary clinical research in adults with open-angle glaucoma shows that taking citicoline 1600 mg orally daily for 60 days improves visual evoked potentials, but not intraocular pressure (IOP), when compared with baseline (43256). Other preliminary clinical research in patients with rapidly progressing glaucoma shows that taking a specific citicoline product (Neukron Ofta, Omikron), 500 mg orally daily for 4 four-month cycles over the course of 2 years, reduces the rate of visual field loss when compared with baseline (98448). The validity of both of these studies is limited by the lack of a comparator group. Small clinical studies in adults with open-angle glaucoma also show that treatment with intramuscular citicoline 1000 mg daily for 60 days improves visual evoked potentials, but not IOP, when compared with placebo or baseline (12173,43219,43256). Also, one clinical study shows that using a specific citicoline 2% eye drop (OMK1, Omicron) three times a day for 3 years reduces the loss of retinal nerve fibers and decreases visual field progression rates in patients with open-angle glaucoma and controlled IOP when compared with placebo (104827). Citicoline has also been used as part of a combination product. Preliminary clinical research in adults with primary open-angle glaucoma and controlled IOP shows that taking citicoline 500 mg, homotaurine 50 mg, and vitamin E 12 mg orally once daily for 4 months improves visual contrast sensitivity scores by less than 10% and self-reported quality of life scores by about 10% when compared with no additional interventions (104786). It is unclear if these effects are clinically relevant or if they are due to citicoline, other ingredients, or the combination.

Stroke. Oral or intravenous citicoline, started within 12-24 hours of onset of ischemic stroke symptoms, does not seem to improve outcomes in most patients. However, it may be modestly beneficial in those who are not candidates for recombinant tissue plasminogen activator (rtPA). Details: A meta-analysis of 10 trials shows that treatment with oral or intravenous citicoline 500-2000 mg daily for up to 6 weeks after ischemic stroke does not improve mortality, ability to complete activities of daily living, or neurologic function when compared with placebo or no intervention (104828). A different meta-analysis of 10 trials shows that treatment with oral or intravenous citicoline 250-2000 mg daily for up to 6 weeks after ischemic stroke increases the odds of recovery to independence by 56% and decreases the mortality rate and long-term disability by 10-12% when compared with placebo. However, this second meta-analysis included older, lower-quality trials in which the standard of care with conventional medicines was lower and ischemic stroke diagnoses were not confirmed via imaging (98228). Higher-quality trials have not confirmed these benefits, especially when patients receive early treatment with rtPA (98228,104828). A third meta-analysis of 7 trials with more limited inclusion criteria also did not demonstrate benefit on mortality or functional independence when compared with control (98447). Also, a large clinical trial of patients with moderate to severe acute ischemic stroke who received standard of care stroke management, including rtPA when indicated, shows that citicoline 1000 mg, administered intravenously over 30-60 minutes every 12 hours for 3 days and started within 24 hours of symptom onset, does not increase the rate of recovery at 90 days when compared with placebo (98444).

Alzheimer disease. It is unclear if oral citicoline is beneficial in patients with Alzheimer disease. Details: Preliminary clinical research in adults with Alzheimer disease shows that taking citicoline 1000 mg orally daily for 12 weeks modestly improves cognitive function scores when compared with placebo (43222). Observational research in adults with Alzheimer disease has also found that taking citicoline 1000 mg orally in conjunction with memantine and rivastigmine for up to 12 months is associated with clinically non-significant improvements in cognitive function scores when compared with memantine and rivastigmine alone. In addition, taking citicoline was not associated with improvement in depression scores or activities of daily living (105730).
Amblyopia. It is unclear if oral or intramuscular citicoline is beneficial in patients with amblyopia. Details: Preliminary clinical research in children with amblyopia shows that taking citicoline orally once daily, in combination with covering the affected eye with a patch, for 12 months moderately improves visual acuity when compared with the patch alone. Children aged less than 5 years took 250 mg daily and children aged 5-13 years took 500 mg daily (98442). Retrospective research in children aged 5-6 years with amblyopia has also found that citicoline treatment for up to 8 months is associated with modest improvements in visual acuity when compared with baseline. However, preliminary subgroup analyses suggest that benefits may not last longer than 3-4 months (109017). Preliminary clinical research in older patients with amblyopia, aged 9-37 years, shows that treatment with intramuscular citicoline 1000 mg daily for 15 days improves visual acuity in both eyes for 92% of patients when compared with baseline (43281). The validity of this study is limited by the lack of a comparator group.
Attention deficit-hyperactivity disorder (ADHD). Although there has been interest in using oral citicoline for ADHD, there is insufficient reliable information about the clinical effects of citicoline for this purpose.
Bipolar disorder. It is unclear if oral citicoline is beneficial in patients with bipolar disorder. Details: Preliminary clinical research in adults with bipolar disorder and cocaine dependence shows that taking citicoline orally for 12 weeks improves verbal learning scores, but not symptoms of depression or mania, when compared with placebo. Citicoline was titrated from 500 mg daily to 2000 mg daily over the first 6 weeks and then continued at 2000 mg daily for 6 weeks (43248).
Cardiac arrest. It is unclear if intravenous citicoline can improve outcomes in children with cardiac arrest. Details: A small clinical study in children 1-12 years of age with successful resuscitation from cardiac arrest shows that using citicoline 10 mg/kg intravenously every 12 hours for 6 weeks improves disability and coma scores at 12 weeks when compared with no intervention. This study also suggests that using citicoline reduces mortality by 80% and duration of hospitalization by 12% when compared with no intervention (105729). However, the small size of this study limits the reliability of these findings.
Cerebrovascular disease. It is unclear if oral, intramuscular, or intravenous citicoline is beneficial in patients with cerebrovascular disease. Details: Several small clinical trials in adults with chronic cerebrovascular disease shows that treatment with citicoline 600-1000 mg orally daily for up to 12 months or 600-1000 mg intramuscularly or intravenously daily for up to 12 weeks moderately improves memory and behavior scores when compared with placebo or no intervention (12131,43240,43288,98443). One of these clinical trials failed to show improvement in activities of daily living, although the study may have been inadequately powered to detect a difference between groups (98443).
Cocaine dependence. It is unclear if oral citicoline is beneficial in patients with cocaine dependence. Details: Preliminary clinical research in adults with cocaine dependence and bipolar disorder shows that taking citicoline orally for 12 weeks reduces the likelihood of positive urine cocaine test results when compared with placebo. Citicoline was titrated from 500 mg daily to 2000 mg daily over the first 6 weeks and then continued at 2000 mg daily for 6 weeks (43248). However, a post-hoc analysis suggests that the effects of citicoline on abstaining from cocaine use decline over time and were no different than placebo in the last weeks of the study (98230). In addition, other clinical research in adults with cocaine dependence that also received weekly counseling shows that taking citicoline 500 mg orally twice daily for 8 weeks does not reduce cocaine craving or consumption levels when compared with placebo (98445).
Delirium. Although there has been interest in using oral citicoline for delirium, there is insufficient reliable information about the clinical effects of citicoline for this purpose.
Depression. It is unclear if oral citicoline is beneficial in patients with depression. Details: Preliminary clinical research in patients with major depressive disorder shows that adding citicoline 100 mg orally twice daily for 6 weeks to citalopram therapy improves symptoms of depression, as measured by the Hamilton Depression Rating Scale, and increases the relative rate of remission by 64% when compared with placebo. These results suggest that for every 4 patients treated with citicoline, remission is expected in one additional patient (98446).
Diabetic retinopathy. Citicoline eye drops have only been evaluated in combination with other ingredients; the effect of citicoline when used alone is unclear. Details: Preliminary clinical research in patients with mild diabetic retinopathy shows that using a specific ophthalmic solution containing citicoline 2% and cyanocobalamin 0.05% (OMK2, Omikron Italia) three times a day for 3 years decreases visual field progression rates and stabilizes retinal nerve fiber thickness when compared with placebo (104825).
Intracranial hemorrhage. It is unclear if intravenous citicoline is beneficial in patients with intracranial hemorrhage. Details: Preliminary clinical research in patients with non-traumatic intracerebral hemorrhage shows that using citicoline 250 mg intravenously twice daily for 14 days improves muscular strength by 25% when compared with placebo (43252).
Ischemic optic neuropathy. It is unclear if oral citicoline is beneficial in patients with ischemic optic neuropathy. Details: Preliminary clinical research in patients with non-arteritic ischemic optic neuropathy shows that taking a specific type of citicoline (Cebrolux-Tubilux) 1600 mg orally daily for 60 days improves visual acuity and visual evoked potentials when compared with no intervention (43250).
Methamphetamine use disorder. It is unclear if oral citicoline is beneficial in patients with methamphetamine use disorder. Details: Preliminary clinical research in adults with methamphetamine dependence shows that taking citicoline 1000 mg orally twice daily for 8 weeks reduces the severity of cravings when compared with baseline, but not when compared with placebo. Taking citicoline also did not reduce the number of methamphetamine positive urine samples when compared with placebo (109015). This study may have been inadequately powered to detect a difference between groups.
Parkinson disease. It is unclear if oral or intramuscular citicoline is beneficial in patients with Parkinson disease. Details: Preliminary clinical research shows that taking citicoline 1200 mg orally daily for one month improves Parkinson disease symptom scores when compared with no intervention (43259). Other preliminary clinical research in adults with Parkinson disease shows that treatment with citicoline 500 mg orally daily or citicoline 500-1000 mg intramuscularly daily for 30 days improves rigidity and bradykinesia scores, but not tremor scores, when compared with baseline (43253,43262). The validity of these studies is limited by the lack of a comparator group.
Schizophrenia. It is unclear if oral citicoline is beneficial in patients with schizophrenia. Details: Preliminary clinical research in patients with chronic, stable schizophrenia shows that taking citicoline 1250 mg twice daily for 8 weeks as an add-on to risperidone therapy modestly reduces negative symptoms, but not positive symptoms, of schizophrenia when compared with placebo plus risperidone (100988). Other preliminary clinical research in patients with chronic, stable schizophrenia shows that taking citicoline 500 mg, 1000 mg, or 2000 mg as a single dose does not improve sensory gating when compared with placebo (100987). However, both studies may have been inadequately powered to detect a difference between groups.
Traumatic brain injury (TBI). It is unclear if oral citicoline is beneficial in patients with TBI; the available research is conflicting. Details: A meta-analysis of 5 low-quality studies in patients with TBI shows that treatment with oral or intravenous citicoline up to 2000 mg daily for up to 9 days does not improve Glasgow outcome scores or cognitive performance. Additionally, one study included in this analysis showed no improvement in survival with citicoline when compared with placebo (98227). However, a very small clinical study not included in this analysis shows that taking citicoline 1000 mg orally daily improves memory, learning, and verbal ability in patients with TBI (43287). Some observational research has found that continuous intravenous infusion of citicoline 3000 mg over 24 hours for up to 21 days is associated with 6.7-fold greater odds of survival while in the intensive care unit (ICU) when compared with matched controls not receiving citicoline. Citicoline therapy was also linked to 2.6-fold greater odds of having a favorable outcome after 6 months, defined as a score of 5-8 on the extended version of the Glasgow Outcome Scale (100989). The discrepant results may be explained by differences in the severity of TBI at baseline and the doses of citicoline used in these studies.
Vascular dementia. It is unclear if oral citicoline is beneficial in patients with vascular dementia. Details: Preliminary clinical research in adults with vascular dementia shows that taking citicoline 500 mg orally twice daily for 12 months does not improve neuropsychological symptom scores when compared with placebo (12135). More evidence is needed to rate citicoline for these uses.

L-CITRULLINE

Athletic performance. Small studies show that taking a single oral dose of L-citrulline before anaerobic resistance exercise might reduce exhaustion and improve some performance measures. It is unclear if L-citrulline improves aerobic exercise performance; results are conflicting. Details: A meta-analysis of small clinical trials in healthy trained and untrained adults shows that taking L-citrulline prior to mostly anaerobic exercise marginally reduces perceived exhaustion and muscle soreness when compared with placebo (105965). Another meta-analysis including some of the same clinical studies shows that taking L-citrulline malate before exercise modestly increases performance on resistance exercises by an average of 6% when compared with placebo (105968). Individual studies show mixed benefit and mostly use a single dose of L-citrulline malate 8 grams 1 hour before exercise; other studies used L-citrulline 3.3-6 grams mixed in watermelon juice or sucrose water or L-citrulline malate 12 grams given 1-2 hours before exercise (94966,94957,97395,105965). L-citrulline has also been evaluated for use with aerobic exercise. A small study in healthy young adults taking L-citrulline 9 grams in 3 divided doses over 24 hours or as a single dose of 3 grams 3 hours before a treadmill test does not improve performance, but might reduce time to exhaustion, when compared with placebo (16473). Another small clinical study in healthy adults shows that taking about 6.8 grams (100 mg/kg) of L-citrulline daily for 5 days prior to a cycling trial does not improve time to exhaustion, oxygen uptake, or lactate levels when compared with taking 3 grams of glucose as placebo (105964). However, two small clinical trials in healthy males show that taking L-citrulline 2.4-6 grams daily for 7 days prior to a cycling test improves peak power by 9%, total work by 7%, and cycling time trial performance by 1.5% when compared with placebo (94954,94965). Differences in methods of testing athletic performance, the form and dose of L-citrulline used, and/or the duration of supplementation may explain the mixed results. L-citrulline has also been evaluated in combination with L-arginine. Research in male soccer players shows that taking L-citrulline 1.2 grams and L-arginine 1.2 grams daily for 7 days increases total power output over a 10-minute cycling test and improves subjective perceptions of exertion when compared with placebo (100956).

Sarcopenia. Oral L-citrulline does not seem beneficial for muscle strength in older adults when added to structured exercise. Details: Two small clinical studies in older adults show that taking L-citrulline in conjunction with structured exercise does not improve measures of strength, endurance, speed, or balance when compared with placebo and structured exercise (110146,110148). One study evaluated otherwise healthy adults aged 60-73 years taking L-citrulline 3 grams daily for 6 weeks (110146). The other study evaluated older adults with obesity and an average age of 68.5 years taking a specific L-citrulline product (Citrage) 10 grams daily for 12 weeks (110148).

Cardiovascular disease (CVD). Although there is interest in using oral L-citrulline for CVD, there is insufficient reliable information about the clinical effects of L-citrulline for this condition.
Dementia. Although there is interest in using oral L-citrulline for dementia, there is insufficient reliable information about the clinical effects of L-citrulline for this condition.
Diabetes. It is unclear if oral L-citrulline is beneficial in patients with diabetes. Details: A small clinical study in adults with diabetes who are taking metformin and sulfonylureas shows that adding L-citrulline (Bulk Supplements Co., Ltd.) 3 grams daily before breakfast for 8 weeks reduces average fasting blood glucose levels by 22 mg/dL and glycated hemoglobin by 0.7%, but does not affect lipid levels, when compared with taking a microcrystalline cellulose placebo (105963).
Erectile dysfunction (ED). It is unclear if oral L-citrulline is beneficial in patients with ED. Details: A small non-randomized crossover study in adults with mild ED shows that taking L-citrulline 1.5 grams daily for one month improves erection hardness from "mild dysfunction" to "normal function" in 50% of patients, compared with only 8% of patients taking placebo (94956). L-citrulline has also been evaluated in combination with other ingredients. A clinical study in middle-aged males with ED shows that taking a specific combination product (Revactin, MD Concepts LLC) containing L-citrulline, muira puama, ginger root, and guarana 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). The validity of this study is limited by the lack of a placebo control, the use of per-protocol analysis, and a high dropout rate. In fact, 44% of patients withdrew in order to resume use of phosphodiesterase type 5 (PDE5) inhibitors. Another small clinical study in adults with ED living in Japan and using PDE5 inhibitors as needed shows that taking an adjunct 50 mL drink containing L-citrulline 800 mg, a specific fenugreek extract (Testofen) 600 mg, resveratrol 300 mg, and caffeine 40 mg daily for 14 days modestly improves erectile function and satisfaction with intercourse and orgasm when compared with a placebo drink (105966). The validity of this finding may be confounded by the "as needed" use of PDE5 inhibitors, which was not reported throughout the study. Further, in both combination studies, it is unclear if these effects are due to L-citrulline, other supplement ingredients, or the combination.
Heart failure. Small clinical studies suggest that oral L-citrulline might be beneficial in patients with heart failure. Details: A very small clinical study in patients with heart failure with preserved ejection fraction (HFpEF) shows that taking L-citrulline malate 3 grams daily for 2 months decreases systolic pulmonary arterial pressure by 16% and improves the right ventricular ejection fraction after a stress test by 27% when compared to baseline (94962). The validity of this finding is limited by the lack of a control group. Another small open-label clinical study in patients with heart failure with reduced ejection fraction (HFrEF) shows that taking L-citrulline 3 grams daily for 4 months increases left ventricular ejection fraction by about 20% at rest and 13% during the stress test, and increases the right ventricular ejection fraction by about 15%, both at rest and with the stress test, when compared with no supplementation. This improved the heart failure functional class in 35% of patients (94955).
Hypertension. It is unclear if oral L-citrulline is beneficial for lowering blood pressure. Details: A small clinical trial in adults with prehypertension shows that taking L-citrulline 2 grams with grape and cranberry polyphenols 548 mg daily for 6 weeks does not reduce mean ambulatory blood pressure when compared with a cellulose placebo (105969). A small crossover study in postmenopausal females with hypertension shows that taking L-citrulline 6 grams as a single dose does not improve systolic or diastolic blood pressure at rest or during 5 minutes of plantar flexion exercise when compared with placebo (110147). The effects of using L-citrulline regularly or in other patients with diagnosed hypertension is unclear.
Lysinuric protein intolerance. Although there is interest in using oral L-citrulline for lysinuric protein intolerance, there is insufficient reliable information about the clinical effects of L-citrulline for this condition.
Muscle strength. It is unclear if oral L-citrulline can improve muscle strength when used in conjunction with resistance training. Details: A clinical study in healthy resistance-trained adults shows that taking L-citrulline malate 2 grams daily for 8 weeks in conjunction with resistance training does not further increase lean mass or muscle strength, measured by leg and bench presses, when compared with a cellulose placebo and resistance training (97394).
Muscular dystrophy. It is unclear if oral L-citrulline is beneficial in patients with Duchenne muscular dystrophy. Details: A small clinical study in adults with Becker muscular dystrophy, a milder form of Duchenne muscular dystrophy (DMD), shows that taking L-citrulline 5 grams with or without metformin 500 mg three times daily for 6 weeks improves 6-minute walking distance and decreases markers of muscle necrosis when compared to baseline (100975). A small clinical study in males aged 6.5-10 years with DMD shows that taking L-citrulline 2.5 grams with metformin 250 mg three times daily for 26 weeks does not appear to slow decline in motor function when compared with placebo. However, this combination seems to slow decline in children with more stable disease, defined as those who can walk at least 350 meters in 6 minutes (100976). The reasons for these disparate results are unclear, but they may be due to the different patient populations, disease severities, doses, and durations of therapy being studied.
Postoperative pulmonary hypertension. It is unclear if oral citrulline prevents postoperative hypertension in children undergoing heart surgery. Details: A small clinical study in children 6 years of age and younger undergoing congenital heart surgery shows that higher blood levels of L-citrulline might protect against the incidence of postoperative hypertension. L-citrulline blood levels of at least 37 micromol/L immediately after surgery, and at 12, 24, and 36 hours postoperatively, protects against its development. However, supplementation with 1.9 grams/m2 during induction of anesthesia is not necessarily protective (16467).
Post-polio syndrome. It is unclear if oral L-citrulline is beneficial for patients with this condition. Details: A small clinical study in adults with post-polio syndrome shows that taking L-citrulline 5 grams three times daily for 24 weeks does not improve 6-minute walking distance, motor function scores, muscle strength, or quality of life when compared with placebo (110149).
Pulmonary hypertension. It is unclear if oral L-citrulline is beneficial in patients with pulmonary hypertension. Details: A very small clinical study in patients with idiopathic arterial pulmonary hypertension or pulmonary hypertension due to Eisenmenger syndrome shows that taking L-citrulline malate 1 gram three times daily for 2 weeks increases 6-minute walking distance by 44 meters and reduces mean pulmonary arterial pressure by 5% when compared with baseline (94963). The validity of these findings is limited by the small study size and the lack of a comparator group.
Reye syndrome. Although there is interest in using oral L-citrulline for Reye syndrome, there is insufficient reliable information about the clinical effects of L-citrulline for this condition.
Sickle cell disease. It is unclear if oral L-citrulline is beneficial in patients with sickle cell disease. Details: A small clinical study in children ages 10-18 years shows that taking L-citrulline 90-130 mg/kg daily in 2 divided doses for up to 9 months might reduce neutrophilia and other symptoms when compared with baseline (16463). The validity of these findings is limited by the small study size and the lack of a comparator group. More evidence is needed to rate L-citrulline for these uses.

TOOTHED CLUBMOSS (Huperzia serrata Leaf, Stem Extract)

There is insufficient reliable information available about the effectiveness of toothed clubmoss.

EFFECTIVE

Phenylketonuria (PKU). Oral tyrosine as a component of medical foods is recommended in people with PKU, a disorder in which phenylalanine cannot be endogenously metabolized into tyrosine. Details: Tyrosine is used as a component of medical foods for people with phenylketonuria (PKU) (7212,7213,7232). Current guidelines recommend that people with PKU maintain a diet low in phenylalanine and incorporate tyrosine as a component of medical foods to maintain normal blood levels of tyrosine (95108). Supplementation with additional tyrosine is recommended only for patients with consistently low blood levels of tyrosine despite using tyrosine-containing medical foods (95108). Routine supplementation with free tyrosine is not recommended for most patients because it can produce wide variations in tyrosine plasma concentrations and side effects (7212,95108). Tyrosine intake does not improve neuropsychological measures in patients with PKU (81503,91471,95108).

Cognitive function. Oral tyrosine might improve cognitive function, particularly in patients exposed to stressors such as excessive cold, noise, or sleep deprivation. Details: Most research suggests that taking tyrosine orally improves cognitive function, particularly under stressful conditions. Small clinical studies in healthy adults show that taking tyrosine 100-300 mg/kg in the setting of exposure to stressors such as excessive cold, noise, or sleep deprivation improves cognitive performance measures, such as executive function and short-term memory, when compared with placebo (7215,81472,81476,81484,81501). Other small clinical studies in healthy patients show that taking tyrosine 2 grams may improve response time without detracting from performance and could improve some measures of cognitive response to conflict when compared with placebo (101082,111248). Some of these small studies may be inadequately powered to detect an effect on some cognitive function tests. Tyrosine has also been evaluated in combination with other ingredients for this purpose. A small clinical study in healthy adults with fatigue shows that taking tyrosine, serine, alanine, glutamate, and aspartate daily for 4 weeks improves measures of cognitive function including attention, spatial cognition, orientation, motivation, and time management when compared with placebo (111249). It is unclear if these effects are due to tyrosine, other ingredients, or the combination.
Memory. Taking tyrosine orally seems to improve memory in patients exposed to stressors such as cold or those having to complete multiple tasks at once. Details: Small clinical studies in healthy adults show that taking tyrosine 150-300 mg/kg prior to acute exposure to stress that is cold-induced, noise-induced, or induced by multi-tasking improves memory performance when compared with placebo (81469,81477,81499,81501). However, tyrosine 150 mg/kg does not seem to improve memory in less stressful situations such as performing one simple task or testing when not exposed to cold (81469,81499).

Athletic performance. Oral tyrosine does not improve athletic performance when taken prior to exercise. Details: Clinical studies show that taking tyrosine orally prior to participating in treadmill or cycling exercises conducted at temperate temperatures or in the heat does not improve strength, endurance, or performance when compared with placebo (81471,81474,81504,91470,104403). Another very small clinical study in healthy males shows that taking a multi-ingredient pre-workout supplement containing L-tyrosine, beta-alanine, L-citrulline maleate, arginine alpha-ketoglutarate, L-taurine, and caffeine does not increase bench press strength endurance when compared with equivalent amounts of anhydrous caffeine (111250).

Alcohol use disorder. Oral tyrosine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with alcohol use disorder shows that taking a combination of tyrosine 900 mg, D,L-phenylalanine 1.5 grams, L-glutamine 300 mg, and L-tryptophan 400 mg daily along with a multivitamin supplement reduces withdrawal symptoms and decreases stress when compared with placebo (81552). It is unclear if these effects are due to tyrosine, other ingredients, or the combination.
Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral tyrosine is beneficial for improving ADHD symptoms. Details: A very small clinical study shows that taking tyrosine does not improve symptoms of ADHD in children when compared with baseline (7209). Furthermore, another very small clinical trial in adults with ADHD shows that taking tyrosine daily for 8 weeks does not improve inattention when compared with baseline. Some patients might have transient symptom improvement after 2 weeks, but seem to acquire tolerance by 6 weeks (7210). The validity of these findings is limited by the small study size and lack of control groups.
Cocaine dependence. Oral tyrosine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in patients with cocaine dependence shows that taking L-tyrosine 1 gram in the morning and L-tryptophan 1 gram in the evening for 14 days does not reduce drug cravings or withdrawal symptoms when compared with placebo (81480).
Dementia. Oral tyrosine 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 severe Alzheimer disease or multi-infarct dementia shows that taking a combination of tyrosine 4 grams, 5-HTP 800 mg, and carbidopa 100 mg orally daily does not improve clinical or psychological parameters in most patients when compared with baseline (918). The validity of this finding is limited by the small study size and a lack of control group.
Depression. It is unclear if oral tyrosine is beneficial for improving major depressive disorder. Details: A small clinical study in patients with major depression shows that taking L-tyrosine 100 mg/kg daily for 4 weeks does not improve depressive symptoms when compared with placebo (7208).
Erectile dysfunction (ED). Although there is interest in using oral tyrosine for ED, there is insufficient reliable information about the clinical effects of tyrosine for this condition.
Fatigue. Oral tyrosine 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 fatigue shows that taking tyrosine, serine, alanine, glutamate, and aspartate daily for 4 weeks does not improve subjective or objective measures of fatigue when compared with placebo (111249).
Hypertension. It is unclear if oral tyrosine is beneficial for reducing hypertension of mild severity. Details: A very small clinical study in patients with mild essential hypertension shows that taking oral tyrosine 2.5 grams three times daily with meals for 2 weeks does not affect systolic or diastolic blood pressure when compared with control (81487).
Mitochondrial myopathies. Although there is interest in using oral tyrosine for nemaline myopathy, a type of mitochondrial myopathy, there is insufficient reliable information about the clinical effects of tyrosine for this condition.
Narcolepsy. It is unclear if oral tyrosine is beneficial for improving narcolepsy symptoms. Details: A small clinical study in patients with narcolepsy shows that taking capsules containing tyrosine 3 grams orally three times daily for 4 weeks might reduce feelings of tiredness or drowsiness when compared with placebo, but the overall effect is not clinically significant. Tyrosine also does not seem to improve sudden muscle weakness, sleep paralysis, night-time sleep, sleep latency, or speed and attention after waking when compared with placebo (81482).
Obesity. Oral tyrosine has only been evaluated for in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in overweight or obese patients shows that taking a supplement containing tyrosine 1.2 grams, cayenne 450 mg, green tea 1.5 grams, caffeine 150 mg, and calcium carbonate 3.89 grams daily for 8 weeks slightly reduces body fat mass by 0.9 kg when compared with placebo (81475). It is not clear if any potential benefit is due to tyrosine, other ingredients, or the combination.
Opioid withdrawal. Oral tyrosine has only been evaluated for heroin withdrawal in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in Chinese males undergoing detoxification for heroin addiction shows that taking a combination of tyrosine 50 mg/kg, 5-HTP 200 mg, phosphatidylcholine 1200 mg, and L-glutamine 50 mg/kg daily for 6 days can reduce insomnia and withdrawal symptoms and improve mood when compared with placebo (88178). It is not clear if this effect is due to tyrosine, other ingredients, or the combination.
Parkinson disease. Although there is interest in using oral tyrosine for Parkinson disease, there is insufficient reliable information about the clinical effects of tyrosine for this condition.
Premenstrual syndrome (PMS). Although there is interest in using oral tyrosine for PMS, there is insufficient reliable information about the clinical effects of tyrosine for this condition.
Schizophrenia. It is unclear if oral tyrosine is beneficial for improving schizophrenia symptoms. Details: A very small clinical study in patients with schizophrenia shows that taking L-tyrosine 10 grams daily in four divided doses along with molindone 150 mg daily for 3 weeks does not improve symptoms of schizophrenia when compared with taking molindone alone (81554).
Sleep deprivation. It is unclear if oral tyrosine is beneficial for improving alertness in sleep deprived adults. Details: A small clinical study shows that taking tyrosine 150 mg/kg after the loss of a night's sleep seems to delay performance decline in psychomotor tests by about 3 hours when compared with placebo (7215). Another small clinical study in sleep-deprived patients shows that taking tyrosine 150 mg/kg improves memory, reasoning, and vigilance when compared with placebo at 5.5 hours after ingestion, but not at 1.5 hours. Tyrosine was less effective than taking amphetamine, phentermine, or caffeine (81472).
Stress. Although there is interest in using oral tyrosine for stress, there is insufficient reliable information about the clinical effects of tyrosine for this condition.
Wrinkled skin. Topical tyrosine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small study in patients with photodamaged skin shows that applying a topical preparation containing 10% vitamin C, acetyl tyrosine, zinc sulfate, sodium hyaluronate, and bioflavonoids (High Potency Serum, Cellex-C International Inc.) for 3 months to the face seems to improve fine and coarse wrinkling, yellowing and sallowness, roughness, and skin tone when compared with placebo (6155). It is unclear if the benefits are due to tyrosine, other ingredients, or the combination. More evidence is needed to rate the effectiveness of tyrosine for these uses.

Safety view details

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

BETA-ALANINE

POSSIBLY SAFE ...when used orally and appropriately, short-term. Oral beta-alanine, including a specific commercial product (CarnoSyn, Natural Alternatives International), has been used with apparent safety in doses up to 6.4 grams daily for 12 weeks in younger adults (14611,16025,16439,16441,18227,94357,97972,101028,101029,104144,106717), and up to 3.2 grams daily for 12 weeks in adults aged 55 years and older (16442,97955,97961,97965).

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

CAFFEINE (Caffeine Anhydrous, ZumXR XR Caffeine)

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

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

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

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

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

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

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

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

CITICOLINE

POSSIBLY SAFE ...when used orally and appropriately, short-term (12131). Citicoline 1000-2000 mg daily has been used with apparent safety for up to 12 weeks (12130,43248,98230,104828,109015,109016). Citicoline 2500 mg daily has also been used with apparent safety for up to 7 weeks (100988). ...when citicoline is used intravenously or intramuscularly under medical supervision (12131). Citicoline has been administered intravenously with apparent safety at a dose of 500 mg daily for 7 days, or 2000 mg daily for 3 days (43229,98444,104828). ...when used topically on the eye. Citicoline 2% eye drops have been used with apparent safety for up to 3 years alone or in combination with cyanocobalamin 0.05% (98229,104824,104825,104826,104827).

CHILDREN: POSSIBLY SAFE
when citicoline is used orally and appropriately. Citicoline has been used with apparent safety for up to 1 year at a dose of 250 mg daily in children under 5 years of age and 500 mg daily in children 5-13 years of age (98442). There is insufficient reliable information available about the safety of citicoline when used intravenously in children.

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

L-CITRULLINE

POSSIBLY SAFE ...when used orally and appropriately. In clinical trials, L-citrulline has been used with apparent safety for up to 2 months at doses of 1.5-6 grams daily (94954,94956,94961,94962,100974). Doses of up to 15 grams have also been used as single doses or within a 24 hour period (16470,16473).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately. L-citrulline has been used with apparent safety in infants at a dose of 0.17 grams/kg daily (16472). It has also been used in children 6.5-10 years of age at a dose of 7.5 grams daily for 26 weeks (100976). ...when used intravenously and appropriately. An intravenous bolus dose of L-citrulline 150 mg/kg followed by 9 mg/kg/hour for 48 hours has been used safely in children under 6 years of age (16469).

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

TOOTHED CLUBMOSS (Huperzia serrata Leaf, Stem Extract)

There is insufficient reliable information available about the safety of toothed clubmoss.

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

LIKELY SAFE ...when used orally in amounts commonly found in foods. Tyrosine has Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts, short-term. Tyrosine has been used safely in doses up to 150 mg/kg daily for up to 3 months (7210,7211,7215). ...when used topically and appropriately (6155).

PREGNANCY AND LACTATION:
There is insufficient reliable information available about the safety of tyrosine during pregnancy and lactation when used in medicinal amounts. Some pharmacokinetic research shows that taking a single dose of tyrosine 2-10 grams orally can modestly increase levels of free tyrosine in breast milk. However, total levels are not affected, and levels remain within the range found in infant formulas. Therefore, it is not clear if the increase in free tyrosine is a concern (91467).

Interactions with Drugs view details

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

BETA-ALANINE

None known.

CAFFEINE (Caffeine Anhydrous, ZumXR XR Caffeine)

ADENOSINE (Adenocard)

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

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

ALCOHOL (Ethanol)

Interaction Rating = Minor Be watchful with this combination.

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

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

Details

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

ANTICOAGULANT/ANTIPLATELET DRUGS

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

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

ANTIDIABETES DRUGS

Interaction Rating = Minor Be watchful with this combination.

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

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

Details

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

BETA-ADRENERGIC AGONISTS

Interaction Rating = Moderate Be cautious with this combination.

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

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

CARBAMAZEPINE (Tegretol)

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

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

CIMETIDINE (Tagamet)

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

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

CLOZAPINE (Clozaril)

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

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

CONTRACEPTIVE DRUGS

Interaction Rating = Minor Be watchful with this combination.

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

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

Details

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

CYTOCHROME P450 1A2 (CYP1A2) INHIBITORS

Interaction Rating = Minor Be watchful with this combination.

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

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

Details

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

DIPYRIDAMOLE (Persantine)

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

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

DISULFIRAM (Antabuse)

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

Disulfiram decreases the rate of caffeine clearance (11840).

DIURETIC DRUGS

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

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

EPHEDRINE

Interaction Rating = Major Do not take this combination.

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

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

Details

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

ESTROGENS

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

Estrogen inhibits caffeine metabolism (2714,23570).

ETHOSUXIMIDE (Zarontin)

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

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

FELBAMATE (Felbatol)

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

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

FLUCONAZOLE (Diflucan)

Interaction Rating = Minor Be watchful with this combination.

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

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

Details

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

FLUTAMIDE (Eulexin)

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

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

FLUVOXAMINE (Luvox)

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

Fluvoxamine reduces caffeine metabolism (6370).

LITHIUM

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

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

METFORMIN (Glucophage)

Interaction Rating = Minor Be watchful with this combination.

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

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

Details

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

METHOXSALEN (Oxsoralen)

Interaction Rating = Minor Be watchful with this combination.

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

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

Details

Methoxsalen reduces caffeine metabolism (23572).

MEXILETINE (Mexitil)

Interaction Rating = Minor Be watchful with this combination.

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

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

Details

Mexiletine reduces caffeine metabolism (1260,11741).

MONOAMINE OXIDASE INHIBITORS (MAOIs)

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

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

NICOTINE

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, concomitant use might increase the risk of hypertension.

Details

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

PENTOBARBITAL (Nembutal)

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, caffeine might decrease the effects of pentobarbital.

Details

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

PHENOBARBITAL (Luminal)

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

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

PHENOTHIAZINES

Interaction Rating = Minor Be watchful with this combination.

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

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

Details

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

PHENYLPROPANOLAMINE

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

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

PHENYTOIN (Dilantin)

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

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

PIOGLITAZONE (Actos)

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

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

QUINOLONE ANTIBIOTICS

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

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

RILUZOLE (Rilutek)

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

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

STIMULANT DRUGS

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, concomitant use might increase stimulant adverse effects.

Details

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

TERBINAFINE (Lamisil)

Interaction Rating = Minor Be watchful with this combination.

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

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

Details

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

THEOPHYLLINE

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

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

TIAGABINE (Gabitril)

Interaction Rating = Minor Be watchful with this combination.

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

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

Details

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

TICLOPIDINE (Ticlid)

Interaction Rating = Minor Be watchful with this combination.

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

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

Details

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

VALPROATE

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

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

VERAPAMIL (Calan, others)

Interaction Rating = Moderate Be cautious with this combination.

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

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

Details

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

CITICOLINE

None known.

L-CITRULLINE

ANTIHYPERTENSIVE DRUGS

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, concomitant use of L-citrulline with antihypertensive drugs might have additive effects and increase the chance of hypotension.

Details

L-citrulline is converted to L-arginine, which can increase nitric oxide and cause vasodilation (7822,16460,16461). However, a meta-analysis of 5 small clinical studies suggests that taking L-citrulline 3-6 grams daily for 1-8 weeks does not lower blood pressure when compared with control (100974).

PHOSPHODIESTERASE-5 INHIBITORS

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, concurrent use of phosphodiesterase-5 (PDE-5) inhibitors and L-citrulline might result in additive vasodilation.

Details

L-citrulline is converted to L-arginine, which can increase nitric oxide and cause vasodilation (7822,16460,16461). Theoretically, taking L-arginine with PDE-5 inhibitors might have additive vasodilatory and hypotensive effects. However, in studies evaluating the combined use of L-arginine and sildenafil for erectile dysfunction, hypotension was not reported (105065).

TOOTHED CLUBMOSS (Huperzia serrata Leaf, Stem Extract)

ANTICHOLINERGIC DRUGS

Interaction Rating = Moderate Be cautious with this combination.

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

In animal models, toothed clubmoss and huperzine A, an active constituent of toothed clubmoss, reversed cognitive deficits induced by scopolamine (3135, 103325). Theoretically, concurrent use of anticholinergic drugs and toothed clubmoss might decrease the effectiveness of toothed clubmoss or the anticholinergic drug.

Details

Some anticholinergic drugs include atropine, benztropine (Cogentin), biperiden (Akineton), procyclidine (Kemadrin), and trihexyphenidyl (Artane).

CHOLINERGIC DRUGS

Interaction Rating = Moderate Be cautious with this combination.

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

Huperzine A, a constituent of toothed clubmoss, has demonstrated acetylcholinesterase inhibitory properties (3082,103325). Theoretically, concurrent use of toothed clubmoss with cholinergic drugs might have additive effects and increase the risk of cholinergic side effects.

Details

Cholinergic drugs include bethanechol (Urecholine), donepezil (Aricept), echothiophate (Phospholine Iodide), edrophonium (Enlon, Reversol, Tensilon), neostigmine (Prostigmin), physostigmine (Antilirium), pyridostigmine (Mestinon, Regonol), succinylcholine (Anectine, Quelicin), and tacrine (Cognex).

LEVODOPA

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, tyrosine might decrease the effectiveness of levodopa.

Details

Tyrosine and levodopa compete for absorption in the proximal duodenum by the large neutral amino acid (LNAA) transport system (2719). Advise patients to separate doses of tyrosine and levodopa by at least 2 hours.

THYROID HORMONE

Interaction Rating = Moderate Be cautious with this combination.

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

Theoretically, tyrosine might have additive effects with thyroid hormone medications.

Details

Tyrosine is a precursor to thyroxine and might increase levels of thyroid hormones (7212).

Report an Adverse Reaction to Harness Apple Pie Moonshine

Adverse Effects view details

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

BETA-ALANINE

General ...Orally, beta-alanine seems to be generally well tolerated.
Most Common Adverse Effects:
Orally: Flushing, paresthesia.

Gastrointestinal ...While rare, digestion problems have been reported with oral beta-alanine use (94341).

Neurologic/CNS ...Orally, beta-alanine can cause a dose-dependent feeling of pins and needles (paresthesias) along with skin flushing (16438,94333,94335,94338,94341,94342,94349,101028,101029,106711). This generally starts on the scalp within 20 minutes of the dose, spreading to most of the body, and lasting for about an hour. This was described as severe at a dose of 40 mg/kg, tolerable at a dose of 20 mg/kg, and very mild at a dose of 10 mg/kg. At the lowest dose it only occurred in 25% of subjects (16438). In some studies, beta-alanine has been given as frequently as 8 times per day so that each dose can be kept below 10 mg/kg (16438,16439). Other clinical research shows that taking beta-alanine in a tablet formulation eliminates the presence of parasthesias at a dose of 1.6 grams when compared with a solution made from powdered beta-alanine. This effect may be due to delayed absorption (97974,97975). Although paresthesias still occur with sustained-release formulations, their presence is less frequent when compared with immediate-release formulations (101029).

CAFFEINE (Caffeine Anhydrous, ZumXR XR Caffeine)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CITICOLINE

General ...Orally, intramuscularly, and intravenously, citicoline seems to be well-tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, back pain, blurred vision, constipation, diarrhea, edema, headache, insomnia, nausea, rash.

Cardiovascular ...Orally, citicoline may cause chest pain, palpitations, hypotension, bradycardia, tachycardia, and peripheral edema in some patients, although the incidence is likely similar to placebo (12130,12131,12132,43225).

Dermatologic ...Orally, citicoline may cause skin rash in some patients (12130,12132,43248).

Gastrointestinal ...Orally, citicoline may cause abdominal pain, constipation, diarrhea, and nausea in some patients (12130,12132,98846,100988,105730,109015).

Musculoskeletal ...Orally, citicoline may cause back pain in some patients (43225).

Neurologic/CNS ...Orally, citicoline may cause headache and insomnia in some patients (12130,43230,43273,98846,100988,109015,109016).

Ocular/Otic ...Orally, citicoline may cause blurred vision in some patients (12130,12132).

Other ...Orally, citicoline may cause edema of the extremities in some patients (43225).

L-CITRULLINE

General ...Orally, L-citrulline seems to be generally well tolerated.
Most Common Adverse Effects:
Orally: Gastrointestinal discomfort, heartburn.

Gastrointestinal ...Orally, gastrointestinal intolerance, stomach discomfort, and heartburn have been reported with L-citrulline use (94955,94963,94966).

Genitourinary ...Orally, 2 of 25 patients with pulmonary hypertension reported increased urinary frequency and edema while taking 1 gram of powdered L-citrulline in water daily (94963).

Pulmonary/Respiratory ...Orally, 2 of 25 patients with pulmonary hypertension reported cough while taking 1 gram of powdered L-citrulline in water daily (94963).

TOOTHED CLUBMOSS (Huperzia serrata Leaf, Stem Extract)

General ...No adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.
Orally, huperzine A, a constituent of toothed clubmoss, can cause dizziness, nausea, and sweating (3140).

Gastrointestinal ...Orally, huperzine A, a constituent of toothed clubmoss, can cause nausea (3140).

Neurologic/CNS ...Orally, huperzine A, a constituent of toothed clubmoss, can cause dizziness and sweating (3140).

General ...Orally, tyrosine seems to be well tolerated. No serious adverse effects have been documented; however, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Fatigue, headache, heartburn, and nausea.

Gastrointestinal ...Orally, tyrosine can cause nausea and heartburn when taken at a dose of 150 mg/kg (7211). Taking tyrosine 4 grams daily in combination with 5-hydroxytryptophan 800 mg and carbidopa 100 mg can cause diarrhea, nausea, and vomiting. These effects can be mitigated by lowering the dosage (918).

Musculoskeletal ...Orally, larger doses of tyrosine (150 mg/kg) can cause arthralgia, but this is uncommon (7211).

Neurologic/CNS ...Orally, larger doses of tyrosine (150 mg/kg) can cause headache and fatigue (7211). Taking a combination of tyrosine 4 grams, 5-hydroxytryptophan 800 mg, and carbidopa 100 mg can cause drowsiness and agitation. These effects can be mitigated by lowering the dosage (918).

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