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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral black pepper for allergic rhinitis, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Asthma. Although there has been interest in using oral black pepper for asthma, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Athletic performance. Oral black pepper has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical trial in untrained males shows that taking a supplement containing black pepper extract 10 mg, caffeine 400 mg, capsicum extract 66.7 mg, and niacin 40 mg as a single dose prior to exercise does not improve strength, time to exhaustion, or maximal oxygen consumption when compared with placebo (37873).
• Depression. Although there has been interest in using oral black pepper for depression, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Diarrhea. Although there has been interest in using oral black pepper for diarrhea, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Dysmenorrhea. Although there has been interest in using oral black pepper for dysmenorrhea, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Dyspepsia. Although there has been interest in using oral black pepper for dyspepsia, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Fall prevention. It is unclear if inhaling black pepper oil as aromatherapy is beneficial for fall prevention in older adults. Details: One small clinical study in older adults shows that applying black pepper oil near the right side of the nose as an olfactory stimulant improves stability while the eyes are closed during a one-minute trial when compared with the application of water. The improvement with black pepper oil is comparable to the improvement seen with the application of lavender oil (29160). It is unclear if any benefit persists after inhalation of black pepper oil.
• Fatigue. It is unclear if oral black pepper is beneficial in patients with fatigue. Details: One small clinical trial in adults with below-average energy levels shows that taking black pepper 2 grams as a single dose does not improve sustained attention, motivation to perform cognitive tasks, or feelings of mental energy and mental fatigue when compared with placebo (91731).
• Flatulence. Although there has been interest in using oral black pepper for flatulence, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Headache. Although there has been interest in using oral black pepper for headache, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Insect bite. Topical black pepper has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical trial shows that applying a specific product (Trikatu) containing black pepper, long pepper, and ginger, as well as camphor, eucalyptus oil, and menthol, directly to mosquito bites does not reduce papule size, erythema, edema, or pruritis when compared with a control compound containing the same base ingredients but without the pepper and ginger components (89893).
• Obesity. Although there has been interest in using oral black pepper for obesity, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Pain (chronic). Although there has been interest in using topical black pepper for chronic pain related to various etiologies, including osteoarthritis, postherpetic neuralgia, and peripheral neuropathy, there is insufficient reliable information about the clinical effects of black pepper for these conditions.
• Rhinosinusitis. Although there has been interest in using oral black pepper for rhinosinusitis, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Sexual desire. Although there has been interest in using oral black pepper for increasing sexual desire, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Smoking cessation. It is unclear if inhaling black pepper essential oil as aromatherapy is effective for smoking cessation. Details: One small clinical trial in adult male smokers who were deprived from smoking overnight shows that inhaling a vapor from the essential oil of black pepper, as needed over a 3-hour period, reduces cigarette cravings, negative feelings, and anxiety when compared with a placebo vapor (29159). Another small clinical study in patients addicted to dipping, chewing, or smoking tobacco shows that placing a drop of black pepper essential oil on tissue paper and inhaling for 2 minutes at least three times a day for 3 days reduces nicotine cravings when compared to baseline (90502).
• Swallowing dysfunction. It is unclear if inhaling black pepper oil as aromatherapy is beneficial in patients with swallowing dysfunction. Details: One small clinical study in post-stroke residents of nursing homes shows that one minute of olfactory stimulation with black pepper oil before each meal for 30 days decreases swallowing reflex latency by 11 seconds and increases the number of swallowing movements by 3.3 when compared to baseline (29161). A small clinical trial in children with neurological disorders who were on long-term enteral nutrition shows that applying black pepper oil to the nostrils or nasal cavity for one minute improves the amount of oral intake and swallowing movement in 63% of patients. Although oral intake increased, the need for enteral nutrition was not eliminated (29162).
• Vitiligo. It is unclear if topical piperine oil, a constituent of black pepper, is beneficial in patients with vitiligo. Details: A small clinical study in patients with vitiligo shows that applying piperine oil 1% daily in addition to receiving narrowband ultraviolet B (NB-UVB) light therapy every other day for 3 months improves repigmentation more rapidly when compared with using NB-UVB alone (103820). More evidence is needed to rate black pepper for these uses.

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EFFECTIVE

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

LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about CAFFEINE)

LIKELY EFFECTIVE

• Diabetic neuropathy. Applying a specific prescription patch containing capsaicin 8% or a specific cream containing capsaicin 0.075% can reduce pain in diabetic neuropathy. Details: Clinical research has evaluated the use of a specific patch (Qutenza, NeurogesX Inc.) containing capsaicin 8%, which is approved as a prescription medication by the US Food and Drug Administration (FDA) for the treatment of diabetic peripheral neuropathy. The research in this population shows that a single application of the patch on the painful parts of the feet for 30-90 minutes following pretreatment with topical anesthetics reduces pain for up to 12 weeks when compared with placebo (40719,96453). Patients using the patch experience reduced sleep interference and an average 28% reduction in pain, compared with a 21% reduction with placebo. Additionally, 50% of patients receiving the patch experience pain relief within 19 days, compared to 72 days for those receiving placebo (96453). A meta-analysis of the available clinical research for diabetic peripheral neuropathy found that one-time application of this patch is equally effective to duloxetine 20-120 mg daily, pregabalin 75-600 mg daily, and gabapentin 300-3600 mg daily in producing a 30% or 50% pain reduction. The dose of oral medication used in the evaluated studies did not impact the comparative efficacy of the capsaicin patch (96450). Other clinical research shows that applying cream containing capsaicin 0.075% four times daily for 8 weeks reduces pain intensity when compared with placebo in patients with diabetic peripheral neuropathy (40547,40592,40607). A meta-analysis of clinical research shows that applying cream containing capsaicin 0.075% reduces pain similarly to 5% lidocaine-medicated plaster (40674). Topical cream containing capsaicin 0.075% (Zostrix-HP, Link Medical Products Pty Ltd.) is FDA-approved as an over-the-counter (OTC) medication for this indication (272). However, applying a capsaicin lotion less frequently or with a lower concentration of capsaicin does not seem to be beneficial. A small clinical study in patients with diabetic neuropathy shows that applying a specific lotion (Capsika-75 lotion, Bangkok Drug Company) containing capsaicin 0.075% three times daily for 8 weeks improves pain to a similar degree as a placebo lotion (102277). This study was limited by a high dropout rate, high placebo effect, and poor adherence to therapy. Furthermore, cream or gel (such as Capsika-25 gel, Bangkok Drug Company) containing lower amounts of capsaicin do not appear to be effective for reducing diabetic peripheral neuropathy pain (92984).
• Pain (chronic). Topical cream containing capsaicin can reduce chronic pain associated with various conditions. Topical capsaicin is FDA-approved for this use. Details: Several clinical studies show that topically applying cream containing capsaicin, the active capsicum constituent, 0.05% to 0.075% temporarily relieves chronic pain from rheumatoid arthritis, osteoarthritis, back pain, jaw pain, psoriasis, and neuropathic conditions (12401,17701). Capsaicin, used in topical preparations, is FDA-approved for these uses (272). It can take up to 14 days for the full analgesic effect. For neuropathic pain, the number needed to treat using capsaicin 0.075% for eight weeks is 5.7 (12401). For musculoskeletal pain, for every 8.1 patients treated with capsaicin 0.025%, 1 patient would achieve at least a 50% reduction in pain (12401). Also, applying capsaicin 0.05% (Finalgon CPD Warmecreme) three times daily for 21 days seems to cause a 49% reduction in chronic soft tissue pain when compared with placebo (17701).
• Postherpetic neuralgia. Applying a specific prescription patch containing capsaicin can reduce postherpetic neuralgia pain, especially in patients with the lowest pain scores. Details: Clinical research has evaluated the use of a specific patch (Qutenza, NeurogesX Inc.) containing capsaicin 8%, which is approved as a prescription medication by the US Food and Drug Administration (FDA) for the treatment of postherpetic neuralgia. Research in this population shows that applying a single patch for 60-90 minutes reduces average pain over 24 hours by 27% to 37% for up to 12 weeks, compared to only 4.4% to 26% in patients in the control group (40659,40679,40686,40691,40719,40728,40800,92985,96451,96452). The number needed to treat to achieve at least a 30% or 50% reduction in pain intensity is 10 and 12, respectively; the number needed to treat to achieve an additional beneficial outcome over placebo at 8 weeks and 12 weeks is 9 and 7, respectively (40800,96451). The pain reduction with this patch has an onset of a few days after treatment and the effect lasts for about 5 months (92986). However, some evidence shows that the reduction in pain is only significant for patients who have had postherpetic neuralgia for at least 6 months (40686). Additionally, the reduction in pain and duration of response appears to be greatest for patients with lower pain scores and low sensitivity to light touch at baseline, as well as patients not using concomitant systemic neuropathic pain medications, whereas patients with high pain scores, high sensitivity to touch, or those using systemic neuropathic pain medications experience the smallest and least sustained reduction in pain (40728,96458). Also, other evidence suggests that this patch may be less effective at relieving postherpetic neuralgia when compared with 5% lidocaine-medicated plaster (40688).

POSSIBLY EFFECTIVE

• Back pain. Topical capsicum or capsaicin seems to be beneficial for reducing back pain. Details: A meta-analysis of generally low-quality clinical research, as well as individual studies, show that applying a capsicum-containing plaster providing 11 mg of capsaicin per plaster or 22 mcg of capsaicin per square centimeter of plaster to the back once daily in the morning for 4-8 hours reduces low back pain when compared with placebo (15259,15260,15261). Applying capsaicin 0.05% (Finalgon CPD Warmecreme) three times daily for 21 days seems to cause a 58% reduction in low back pain when compared with placebo (17701). Also, in a mixed group of patients with acute back or neck pain, a large clinical trial shows that four topical applications with a gel containing capsaicin 0.075% with diclofenac 2% every 12 hours modestly reduces pain on motion when compared with diclofenac alone or placebo. The number of patients with at least a 50% reduction in pain from baseline was modestly higher. Capsaicin 0.075% was similarly effective alone and when combined with diclofenac 2% (105202). However, only about half of the patients in this study had back pain.
• Cluster headache. Intranasal capsaicin seems to be beneficial for preventing cluster headaches. Its effect in the treatment of cluster headache is unclear. Details: Some clinical research shows that using the capsicum constituent capsaicin intranasally reduces the frequency of episodic or chronic cluster headache attacks (14323,14351,14352,14358). Capsaicin suspensions of 0.1 mL of a 10 mM suspension, providing 300 mcg/day of capsaicin, has been applied to the ipsilateral nostril. Applications are continued once daily until a burning sensation is no longer experienced (14351,14358). Intranasal application of capsaicin 0.025% (Zostrix, Rodlen Laboratories) might also decrease symptom severity during an acute cluster headache attack. Clinical research shows that daily treatment for 7 days decreases symptom severity over the following week (14353). Ipsilateral, or same side, nostril application of capsaicin appears to be more effective than contralateral application (14351). Due to severe pain associated with intranasal capsaicin administration, pretreatment with intranasal local anesthetic is usually used.
• Nonallergic rhinitis. Intranasal capsaicin in a dose of at least 0.1 mM seems to improve symptoms of nonallergic rhinitis. It is unclear if lower doses of capsaicin are beneficial. Details: Clinical research shows that repeated intranasal in-clinic treatments with capsaicin, the active capsicum constituent, or with capsicum oleoresin, over a period of one to three days, can significantly decrease symptoms of non-allergic, non-infectious perennial rhinitis symptoms (14328,14357,15016,40595,105204,105205). A decrease of symptoms has been observed for up to 6-9 months following these treatments (14328,14357). The following doses have been used: capsaicin 0.15 mg per dose for up to 7 doses over a 14-day period (14328), capsaicin 0.0033 mol once weekly for 5 weeks (14357), capsaicin 15 mcg/0.1 mL applied three times daily for 3 days (15016), and capsaicin 1-4 mcg per puff, applied 3 times in each nostril daily for 3 days (40595). Due to severe pain associated with intranasal capsaicin administration, pretreatment with intranasal local anesthetic is usually used. Personal use of an intranasal spray with a lower dose of capsaicin might also be effective. Clinical research shows that two 0.4 mL puffs with an intranasal spray in each nostril daily for 4 weeks providing capsaicin 0.01 mM, but not 0.001 mM, is more effective than placebo for reducing symptoms of idiopathic rhinitis. This benefit is maintained for an additional 8 weeks. This protocol was at least as effective as receiving five repeated hourly intranasal spray treatments in hospital with capsaicin 0.1 mM (105204).
• Osteoarthritis. The American College of Rheumatology (ACR) conditionally recommends topical capsaicin for knee osteoarthritis, but not for hip or hand osteoarthritis. Details: A meta-analysis of 4 preliminary clinical trials shows that using topical capsaicin 0.025% four times daily has modest benefit for osteoarthritis when compared with placebo. Using capsaicin 0.0125% doesn't seem to be effective (102408). The American College of Rheumatology (ACR) conditionally recommends topical capsaicin for knee osteoarthritis. However, it does not recommend its use for hip osteoarthritis due to the depth of the joint beneath the skin surface, nor for hand osteoarthritis, due to the risk for contamination of the eye (102114).
• Pain (acute). Topical capsicum seems to be beneficial for reducing acute pain due to trauma. Details: Clinical research in patients with trauma-related acute pain shows that topical application with a gel (Sanli Gel) containing capsaicin 0.05% three times daily for 3 days reduces pain by at least 50% in 87% of patients, compared with 63% of those using a piroxicam gel 0.5% (Felden). There was also a significantly greater number of patients with a final pain score of 4 or less. In the capsaicin group, only 12% of patients did not achieve either of these endpoints, compared with 31% in the group receiving piroxicam (105197).
• Postoperative nausea and vomiting (PONV). Applying topical capsicum to acupoints seems to be beneficial for preventing PONV. Details: Clinical research shows that applying a capsicum-containing plaster to acupoints on the hand and forearm 30 minutes prior to anesthesia and leaving in place for 6-8 hours daily for up to 3 days after surgery reduces the incidence of PONV by about 29% to 36% when compared to control (40405,40483,40610). Plasters used in these studies included Sinsin PAS (Sinsin Pharm Co.), which is standardized to contain capsicum 345.8 mg and capsicum tincture 34.58 mg per sheet (40405,40610); and Johnson's Perforated Capsicum Plaster (Johnson & Johnson Ltd.), which is standardized to contain capsicum oleoresin 1% w/w (40483).
• Postoperative pain. Applying topical capsicum-containing plaster to acupoints seems to be beneficial for reducing postoperative pain. It is unclear if a capsicum patch or capsaicin instillation prior to wound closure is beneficial for reducing postoperative pain. Details: Some clinical research shows that applying a capsicum-containing plaster to acupoints on the hands or near the knees of adults or children 30 minutes prior to anesthesia, and leaving in place for 6-8 hours daily for up to 3 days after surgery, reduces the amount of rescue analgesics needed by 29% to 39% within the first 24 hours and by 16% to 19% within the first 48 hours when compared to control (40405,40483,40520,40524,40610). The capsicum-containing plaster used in these studies (Sinsin PAS, Sinsin Pharm Co.) is standardized to contain capsicum 345.8 mg and capsicum tincture 34.58 mg per sheet (40520,40610). Other preliminary clinical research shows that applying a single patch containing the capsicum constituent capsaicin 8% (Qutenza, NeurogesX Inc.) for 30-60 minutes leads to an improvement in overall health status and an average 22% reduction in pain that lasts up to 12 weeks in patients with postoperative and posttraumatic neuropathic pain. Patches were applied to various parts of the body, including the legs, torso, feet, hands, arms, head, and neck, and the reduction in pain continued with the use of a second and third patch application. The validity of these findings is limited by the lack of a control group (96452). Other clinical evidence suggests that instilling capsaicin 15 mg during surgery immediately prior to wound closure reduces the need for pain medication for up to 2 weeks postoperatively when compared with placebo (40741).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). It is unclear if intranasal capsaicin is beneficial for preventing allergic rhinitis symptoms. Details: Preliminary clinical research shows that intranasal treatment with cotton wads soaked in the active capsicum constituent capsaicin 30 mcM, applied for 15 minutes and repeated over two days, reduces the severity of experimentally-induced allergic rhinitis. The severity of symptoms seems to be reduced for up to 2 months after treatment (14324). However, contradictory research shows that patients with allergic rhinitis caused by house dust mites do not have significantly improved symptoms after using a capsaicin solution providing 0.15 mg/dose for up to 7 doses over a 14-day period when compared with placebo (14360).
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). Although there is interest in using oral capsicum for ALS, there is insufficient reliable information about the clinical effects of capsicum for this condition.
• Athletic performance. It is unclear if oral capsaicin is beneficial for improving athletic performance; the available research is limited to small, conflicting studies. Details: Several small clinical studies in physically active young adults show that taking capsaicin might improve some measures of athletic performance, but results are mixed overall (99409,99410,102276,105191,105198,105200). A meta-analysis of these and several other small clinical studies shows that taking the capsicum constituents capsaicin or capsiate 45 minutes before exercise improves measures of muscular endurance but does not improve aerobic endurance when compared with placebo. Doses of the capsicum constituents ranged from 1.2-24 mg, with most studies assessing a single 12 mg dose (111515). The included studies have a number of methodological problems that limit the validity of the findings, such as a small sample size, short study duration, and insufficient blinding. Also, most of the study participants were male. Other small clinical studies not included in the meta-analysis also show conflicting results. One small clinical study in untrained young adults undergoing resistance training shows that taking capsiate, a capsaicin analog, 6 mg orally twice daily for 6 weeks improves upper body, but not lower body, weightlifting performance when compared with placebo (109024). However, another small clinical trial in experienced male athletes shows that taking cayenne (GNC Nature's Fingerprint Cayenne Herbal Supplement) 3 grams, providing capsaicin 25.8 mg, daily for 7 days does not improve sprint time, rate of perceived exertion, or muscle soreness over three days when compared with placebo (105206). Capsicum has also been evaluated in combination with other ingredients. One small clinical study in untrained males shows that taking a supplement containing capsicum extract 66.7 mg, caffeine 400 mg, black pepper extract 10 mg, and niacin 40 mg prior to exercising does not improve strength, time to exhaustion, or maximal oxygen consumption when compared with placebo (37873).
• Burning mouth syndrome. It is unclear if applying topical capsaicin in the mouth is beneficial for burning mouth syndrome. Details: Preliminary clinical studies show that using 15 mL of a mouth rinse containing the active capsicum constituent capsaicin 0.02% for 30 seconds daily for 7-21 days modestly decreases burning discomfort when compared to baseline in patients with burning mouth syndrome (92991,105195). Other preliminary clinical research shows that applying 0.5 mL of a gel containing capsaicin 0.01% or 0.025% to the tongue three times daily for 14 days modestly reduces pain when compared to baseline in patients with burning mouth syndrome. The gel is spread with a cotton swab, and no food or drink is consumed for 30 minutes after application (96456). The validity of these findings is limited by the lack of a control group, the small number of patients, and occasionally unclear statistical comparisons.
• Cancer. It is unclear if eating more chili is beneficial for preventing mortality due to cancer. Details: Population research has found that consuming chili more than four times weekly is not associated with a reduced odds of cancer mortality (105208). Also, other population research has found that any consumption of hot red chili peppers is not associated with a reduced odds of mortality related to cancer (105210).
• Cannabinoid hyperemesis syndrome (CHS). Preliminary clinical research suggests that topical capsaicin might be beneficial for reducing symptoms of CHS. Details: One small clinical study in adults presenting to an emergency department (ED) with CHS shows that applying 5 grams of a cream containing capsaicin 0.1% to the abdomen modestly reduces nausea severity at 60 minutes, but not 30 minutes, when compared with a placebo cream. Nausea was completely resolved in 29% of patients, compared with 0% of those using the placebo cream. However, there was no difference in vomiting at 30 or 120 minutes (105193). This study may not have been adequately powered to detect a difference in some of these outcomes. A meta-analysis of two small, low-quality studies involving the topical use of capsaicin on the abdomen, chest, and possibly back, shows that the mean time to resolution of symptoms was 326 minutes and the mean length of stay in the emergency department was 379 minutes. However, it is unclear how these times compare to the use of placebo or standard antiemetics. This study also conducted a systematic review of the available literature, which indicates that the creams most commonly used in research provide 0.025% to 0.1% capsaicin (105201). Two low-quality, retrospective reviews also suggest that capsaicin cream may be beneficial for CHS. A retrospective review of patients in the ED with CHS has found that applying capsaicin cream 0.025% is associated with a 39% shorter time to discharge when compared with control. Patients treated with capsaicin also required fewer additional rescue treatments when compared with control (109021). Another retrospective review of patients in the ED with CHS also suggests that capsaicin cream 0.025% modestly reduces abdominal pain when compared with baseline. However, 47% and 28% of patients, respectively, received additional antiemetics or an opioid after the use of the cream (105345).
• Cardiovascular disease (CVD). It is unclear if eating more chili is beneficial for preventing mortality due to CVD. Details: Population research has found that consuming chili more than four times weekly is associated with a 34% reduced odds of CVD mortality when compared with never or rarely consuming chili, as well as 44% and 61% reduced odds of ischemic heart disease and cerebrovascular death, respectively (105208). Other population research has found that consumption of hot red chili peppers is not associated with a reduced odds of mortality related to CVD when compared with not eating hot red chili peppers (105210).
• Diabetes. It is unclear if oral capsaicin is beneficial for gestational diabetes. Details: Preliminary clinical research shows that taking chili powder containing capsaicin 5 mg daily for 4 weeks modestly reduces total cholesterol levels and reduces postprandial blood glucose levels by an average of 36 mg/dL and postprandial insulin levels by an average of 14 IU/L in patients with gestational diabetes. Compared to a placebo group, these changes are significant. However, capsaicin intake does not alter fasting plasma glucose or insulin levels (96457).
• Dry skin. It is unclear if oral capsicum is beneficial for dry skin. Details: Preliminary clinical research in adult females with low skin moisture shows that taking paprika oil extract 400 mg, standardized to include 9 mg of xanthophyll, orally daily for 4 weeks improves skin moisture and viscoelasticity scores, but not the number of wrinkles, when compared with control (109026).
• Dyslipidemia. It is unclear if oral capsicum is beneficial for reducing lipid levels. Details: A meta-analysis of three or four mainly small clinical trials in healthy adults shows that taking capsicum does not improve levels of triglycerides, total cholesterol, or high-density lipoprotein (HDL) cholesterol when compared with no treatment or placebo. However, there was a small to moderate effect on levels of low-density lipoprotein (LDL) cholesterol. Freshly chopped chili or fermented red pepper were studied for 4 and 12 weeks, respectively (105194). It is unclear if capsicum can lower lipid levels in patients with dyslipidemia or hyperlipidemia.
• Dyspepsia. It is unclear if oral capsicum is beneficial for dyspepsia. Details: Preliminary clinical research shows that taking red pepper powder 2.5 grams daily in three divided doses for 5 weeks reduces symptoms of functional dyspepsia when compared with placebo. However, in some patients, there seems to be a worsening of symptoms prior to any improvement (12410).
• Fibromyalgia. It is unclear if oral capsicum is beneficial for fibromyalgia. Details: Preliminary clinical research shows that applying cream containing the active capsicum constituent capsaicin 0.025% four times daily to tender points for 4 weeks reduces localized tenderness in patients with fibromyalgia (7038). Other preliminary clinical research shows that applying capsaicin 0.075% cream (Sensedol) three times daily to tender points for 6 weeks in addition to standard therapy increases the pain threshold when compared with standard therapy in patients with severe fibromyalgia (92979). However, capsaicin does not appear to reduce overall pain or improve physical function in patients with fibromyalgia (7038,92979). Also, the long-term effects of capsaicin on fibromyalgia-related pain are unclear.
• Gastroesophageal reflux disease (GERD). Although there is interest in using oral capsicum for GERD, there is insufficient reliable information about the clinical effects of capsicum for this condition.
• HIV/AIDS-related peripheral neuropathy. It is unclear if topical capsaicin is beneficial for this condition. Details: There is conflicting evidence regarding the effects of Qutenza (NeurogesX Inc.), which contains the active constituent of capsicum, capsaicin 8%. Although some research shows it reduces pain in patients with HIV and peripheral neuropathy (22395), other research shows no significant benefit (40746). A meta-analysis of results from both of these studies shows that applying a single capsaicin 8% patch for 30-90 minutes reduces pain intensity by at least 30% in about 30% more patients when compared to control (40800). Additional meta-analyses of the results from these two studies suggests that pain reduction with capsaicin begins a few days after treatment and lasts for about 5 months, with a number needed to treat of 11 to achieve at least a 30% reduction in pain intensity (92986,96451). Reduction in pain and duration of response appears to be greatest for females with lower pain scores at baseline, whereas males with high pain scores at baseline experience the smallest and least sustained reduction in pain (96458). Some research has also evaluated topical capsaicin 0.075%. One small clinical study shows that applying this cream does not relieve symptoms of HIV-associated peripheral neuropathy when compared with placebo (3891).
• Hypertension. It is unclear if oral capsicum is beneficial for lowering blood pressure. Details: Two meta-analyses of small clinical trials show that taking capsicum as freshly chopped chili, fermented red pepper, red pepper capsules, or capsinoid capsules orally daily for 4-12 weeks does not reduce systolic or diastolic blood pressure when compared with control. However, most subjects included in these clinical trials did not have hypertension (105194,109025).
• Intermetatarsal neuroma. It is unclear if injecting capsaicin into the third intermetatarsal space is beneficial for intermetatarsal neuroma. Details: Clinical research in adults with intermetatarsal neuroma shows that a single injection of capsaicin 0.1 mg into the third intermetatarsal space 5 minutes after administration of 2 mL of lidocaine 2% with epinephrine leads to a modest reduction in pain at weeks 1 and 4, but not weeks 2 and 3, when compared with placebo. Capsaicin also reduces the extent to which pain interferes with walking and mood, but not with work, sleep, relationships, or general activity (96454).
• Irritable bowel syndrome (IBS). It is unclear if oral capsicum is beneficial for IBS. Details: Preliminary clinical research shows that taking ground guajillo chili 1 gram, containing capsaicin 0.112%, with each meal for 7 days does not reduce symptoms of IBS (12403). A small clinical study shows that taking chili (Nguan Soon Co., Ltd.) 2.1 grams, providing 2.5 mg capsaicin, daily before meals for 6 weeks does not improve abdominal burning, fecal urgency, or abdominal pain or bloating after a spicy meal. However, there was a modest reduction in abdominal burning after a spicy meal (105207). This study may not have been adequately powered to detect a difference in some of these outcomes.
• Laryngitis. Although there is interest in gargling with capsicum for laryngitis, there is insufficient reliable information about the clinical effects of capsicum for this condition.
• Motion sickness. Although there is interest in oral capsicum for motion sickness, there is insufficient reliable information about the clinical effects of capsicum for this condition.
• Myofascial pain syndrome. It is unclear if topical capsaicin is beneficial for myofascial pain syndrome. Details: Preliminary clinical research shows that applying a specific capsaicin cream (Dipental Cream, Dalim BioTech) containing capsaicin 0.25 mg/gram along with a ketoprofen 30 mg patch (KetotopVRPlaster, Pacific Pharma) to the trapezius does not reduce pain when compared with a ketoprofen patch alone in patients with myofascial pain (92983).
• Neck pain. It is unclear if topical capsaicin is beneficial for neck pain. Details: In a group of patients with acute back or neck pain, a large clinical trial shows that four topical applications with a gel containing capsaicin 0.075% with diclofenac 2% every 12 hours modestly reduces pain on motion when compared with diclofenac alone or placebo. The number of patients with at least a 50% reduction in pain from baseline was modestly higher. Capsaicin 0.075% was similarly effective alone or when combined with diclofenac 2% (105202). However, only about half of the patients in this study had neck pain.
• Neuropathic pain. It is unclear if topical capsicum is beneficial for neuropathic pain. Details: A very small study in adults with neuropathic pain secondary to spinal cord injury shows that applying a patch containing the capsicum constituent capsaicin 8% for 60 minutes daily to the affected area for 12 weeks reduces pain at weeks 2 and 4 and improves mobility, but not quality of life, for up to 12 weeks when compared with placebo (111517). The validity of these findings is limited by insufficient blinding and the small sample size.
• Obesity. It is unclear if oral capsicum is beneficial for obesity. Details: A meta-analysis of 3-5 small clinical trials shows that taking capsicum does not reduce body weight, body fat, or body mass index (BMI) in individuals with a BMI of at least 25 kg/m2 when compared with placebo or no treatment. Freshly chopped chili, fermented red pepper, or capsicum constituents were studied for 4-12 weeks (105194). In one clinical trial included in the analysis, taking capsinoids 3 mg twice daily 30 minutes prior to eating for 12 weeks reduced abdominal fat by about 1%, but did not significantly reduce body weight, when compared with placebo (40599). In overweight individuals, one small clinical trial shows that taking a specific chili extract 200 mg, formulated with fenugreek dietary fiber for sustained release (Capsifen, Akay Natural Ingredients), providing capsaicinoids 4 mg daily for 28 days reduces body weight and BMI by about 2% when compared with placebo. There was no effect on blood pressure (105196). Capsicum has also been evaluated in combination with other ingredients, with some evidence of benefit. One study evaluated a combination product (Prograde Metabolism) containing capsicum extract (Capsimax, OmniActive Health Technologies), raspberry ketone (Razberi K, Integrity Nutraceuticals), caffeine, garlic root extract, ginger root extract, bitter orange fruit (Advantra Z, Nutratech Inc), L-theanine, and black pepper fruit extract (Biperine, Sabinsa Corporation) twice daily for 8 weeks (40802).
• Overall mortality. Eating chili may be beneficial for preventing mortality. It is unclear if taking capsicum supplements is beneficial for preventing overall mortality. Details: Population research has found that consuming chili is associated with a reduced risk of overall mortality. In one study, eating chili more than four times weekly was associated with a 23% reduced odds of overall mortality when compared with never or rarely consuming chili (105208). Other population research has found that any consumption of hot red chili peppers is associated with a 13% reduced odds of mortality when compared with not eating these peppers (105210). Also, eating spicy foods at least once each week, consisting mainly of fresh chili pepper, dried chili pepper, chili sauce, or chili oil, was associated with at least a 10% reduced risk of death when compared with eating these foods less than once a week (105211).
• Peptic ulcers. It is unclear if oral capsicum is beneficial for peptic ulcers. Details: Population research has found that eating capsicum fruit (chili) an average of 24 times per month is associated with a reduced likelihood of having an ulcer when compared with eating chili an average of 8 times per month. This applies to chili in the form of chili powder, chili sauce, curry powder, and other chili-containing foods (12053). However, clinical research shows that consuming chili peppers 1 gram three times daily for 4 weeks does not improve duodenal ulcer healing when compared to control (40828).
• Peripheral neuropathy. Preliminary clinical research suggests that topical capsaicin might be beneficial for reducing peripheral neuropathy pain. Details: Preliminary clinical research shows that applying patches containing the capsicum constituent capsaicin 8% (Qutenza, NeurogesX Inc.) reduces pain in people with non-diabetic peripheral neuropathy (96452,111516). Up to four patches, applied to different painful areas, are used at one time and are left in place for 30 minutes on the feet, or 60 minutes on other parts of the body such as the legs, torso, hands, arms, head, or neck (96452). After an interval of at least 90 days, treatment can be repeated, with new patches applied for 30-60 minutes (99407). There is an average 27% reduction in pain when compared to baseline, lasting up to 12 weeks (96452). Another similar study reported a decrease of 1 point, on a 10-point pain scale, in the typical daily pain intensity (99407). The validity of these findings is limited by methodological problems, including the lack of control groups. Further research shows that using a single application of up to four capsaicin 8% patches for 30-60 minutes, or taking pregabalin orally, 150-600 mg in 2-3 divided doses daily for 8 weeks, reduces the intensity and area of dynamic mechanical allodynia (DMA, pain evoked by light brushing of the skin) in people with non-diabetic peripheral neuropathy. Complete resolution of DMA occurred in 24% of people using the patches, and 12% of those taking pregabalin (99408). The validity of these findings is limited by methodological problems, including a lack of blinding.
• Prurigo nodularis. It is unclear if topical capsaicin is beneficial for prurigo nodularis. Details: Preliminary clinical research shows that applying a cream containing the active capsicum constituent, capsaicin 0.025% to 0.3%, 4-6 times daily improves burning sensations, erythema, pruritus, and healing of skin lesions over a period of 2 weeks to 33 months when compared to baseline. Symptoms may return after discontinuation of therapy (10650).
• Sinonasal polyposis. It is unclear if intranasal capsaicin is beneficial for sinonasal polyposis. Details: Preliminary clinical research in patients with severe sinonasal polyposis shows that intranasal application of 0.5 mL of a 30 mmol/L capsaicin solution to each nostril for 3 days, followed by 0.5 mL of a 100 mmol/L capsaicin solution for 2 days, can cause significant subjective improvement in symptoms as well as objective improvement in nose/sinus air volume and endoscopy scores; however, capsaicin does not seem to significantly affect eosinophil cationic protein levels (14359).
• Swallowing dysfunction. Preliminary research shows that oral capsaicin might be beneficial for improving swallowing ability. Details: Preliminary clinical research shows that elderly patients at risk for aspiration pneumonia due to swallowing dysfunction have improved swallowing reflexes after dissolving a lozenge containing capsaicin 1.5 mcg in the mouth before each meal when compared with using a placebo lozenge (13100). Preliminary clinical research also shows that capsaicin may be beneficial in patients with swallowing dysfunction due to stroke (102278,105192). One study shows that taking 1 mL of nectar containing capsaicin 150 mcM/L with each meal daily for 3 weeks, in addition to thermal tactile stimulation, improves eating and swallowing when compared with using thermal tactile stimulation and placebo nectar (102278). Another study shows that 20 minutes of stimulation with an ice swab containing capsaicin 0.15 mM before lunch and dinner daily for three weeks modestly improves the ability to swallow water when compared with ice stimulation alone. After treatment, approximately 70% of those using the capsaicin ice were able to drink the water without choking, compared with only 33% in those using ice alone (105192). Capsaicin solution has also been administered by nebulizer. A clinical study in patients with swallowing dysfunction secondary to hemorrhagic stroke shows that inhaling capsaicin solution twice daily for one week reduces the incidence of post-swallow residue and pulmonary infection and increases number of coughs in response to capsaicin compared with placebo. However, treatment with nebulized capsaicin does not reduce the number of patients with swallow or cough reflexes compared with control (111518). More evidence is needed to rate capsicum for these uses.

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POSSIBLY EFFECTIVE

• Alzheimer disease. Oral huperzine A seems to improve memory, cognitive function, and behavior in patients with this condition. Details: Meta-analyses of small clinical studies in patients with Alzheimer disease show that, overall, huperzine A 200-800 mcg in 2-3 divided doses daily for 8-36 weeks improves cognitive function as measured on some scales, but not others, when compared with placebo (55674,93482). Improvement in cognitive function was observed consistently when measured using the Mini-Mental State Examination (MMSE) (55674,93482,93483,101469). However, results are inconsistent with other scales, such as the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), the Hasegawa Dementia Scale (HDS), and the Wechsler Memory Scale (WMS) (55674,93482). Meta-analyses also show that huperzine A improves overall behavior and performance of daily living activities when compared with placebo (55674,93482). Most research has been conducted in China, where huperzine A is an approved drug for this condition. Only one clinical trial has been conducted in the United States. This study was conducted in patients with probable mild to moderate Alzheimer disease and shows that taking huperzine A 200 mcg twice daily for at least 16 weeks does not improve cognition based on the ADAS-Cog when compared with placebo. However, this dose results in modest benefit when cognition is measured using the MMSE, and a higher dose of 400 mcg twice daily shows modest benefit when measured on both the ADAS-Cog and MMSE (93479). Long-term, large-scale clinical trials in diverse geographic locations are necessary to confirm these findings and determine which dose of huperzine A, if any, is beneficial.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Athletic performance. It is unclear if oral huperzine A is beneficial for improving athletic performance. Details: One very small, double-blind randomized crossover study in physically active adults shows that taking huperzine A 200 mcg as a single dose 30-45 minutes prior to exercise does not affect athletic performance, neuromuscular performance, or cognitive function when compared with placebo (107470). Due to the single-dose nature of this study, the effects of continued administration of huperzine A on athletic performance are unclear.
• Cocaine dependence. It is unclear if oral huperzine A is beneficial in patients with cocaine use disorder. Details: A very small clinical study in adults with cocaine use disorder shows that taking huperzine A in gradually increasing doses over 9 days, up to a dose of 200 or 400 mcg twice daily, might attenuate the stimulation and anxiety effects of an intravenous cocaine infusion when compared with placebo (93484). It is unclear if huperzine A can attenuate cravings and cocaine use in these individuals.
• Cognitive impairment. Although there is interest in using oral huperzine A for mild cognitive impairment, there is insufficient reliable information about the clinical effects of huperzine A for this condition.
• Depression. It is unclear if oral huperzine A is beneficial in patients with major depressive disorder. Details: A meta-analysis of three small, low-quality clinical studies in patients with major depressive disorder shows that taking huperzine A 100-300 mg daily in combination with antidepressants for 6-8 weeks does not further improve depressive symptoms when compared with antidepressants alone. However, huperzine A might improve cognitive functioning, based on the Wisconsin Card Sorting Test and the Wechsler Memory Scale-Revised (WMS-R) (93485). All available research has been conducted in China, so it is unclear if these findings are generalizable to other geographic locations.
• Memory. It is unclear if oral huperzine A is beneficial for improving memory in healthy adolescents. Details: A small clinical trial in Chinese adolescents around 15 years of age who complain of poor memory shows that taking huperzine A 100 mcg daily for 4 weeks improves memory quotient scores when compared with placebo (4626).
• Myasthenia gravis. It is unclear if intramuscular huperzine A is beneficial in patients with myasthenia gravis. Details: A small, open-label clinical trial in stabilized patients with myasthenia gravis shows that giving huperzine A 400 mcg intramuscularly for 10 days maintains muscle strength similarly to patients treated with intramuscular neostigmine alternating with intramuscular huperzine A. Huperzine A was reported to have a 7-hour duration of effect, compared to only 4 hours with neostigmine (3561).
• Schizophrenia. Small clinical studies suggest that oral huperzine A may modestly improve symptoms of schizophrenia in adults. Details: A meta-analysis of small, low-quality clinical trials in hospitalized patients with schizophrenia shows that taking huperzine A 150-400 mcg daily for 8-24 weeks as an adjunct to antipsychotic medications improves memory, intelligence, and positive, but not negative, psychiatric symptoms when compared with antipsychotic medications alone (93478). Limited research also suggests that huperzine A might improve outcomes in patients with resistant schizophrenia and cognitive impairment. A small, open-label clinical study in patients with treatment-resistant schizophrenia and cognitive impairment shows that adding huperzine A 300 mcg daily for 12 weeks to treatment with antipsychotics improves negative symptoms of schizophrenia by 32% and memory by 15% when compared to baseline (55665). The validity of this finding is limited by the lack of a comparator group. Furthermore, all available research has been conducted in China, so it is unclear if these findings are generalizable to other geographic locations.
• Vascular dementia. Small clinical studies suggest that oral huperzine A may modestly improve symptoms of vascular dementia in adults. Details: A meta-analysis of two small clinical trials in patients with vascular dementia shows that taking huperzine A 200-300 mcg daily for 12-24 weeks modestly improves cognitive function and activities of daily living when compared with control (93483). The validity of this meta-analysis is limited by small study size and publication bias. More evidence is needed to rate huperzine A for these uses.

(Read more about HUPERZINE A)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cancer. It is unclear if oral limonene is beneficial in patients with cancer. Details: D-limonene taken orally in 21-day cycles seems to concentrate in tumor tissue in patients with advanced cancer and may slow disease progression, but its effect on survival is uncertain (12709).
• Irritable bowel syndrome (IBS). Oral limonene has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with IBS (constipation- or diarrhea-dependent) shows that taking a combination of peppermint oil 240 mg (1.5% limonene, 40% menthol), ginger oil 50 mg, and olive oil 440 mg (Standart Zdorovya Gastro) once daily for 30 days, in combination with regular IBS therapy, decreases symptoms and reduces patients' disease categories from moderately ill to mildly ill or borderline, when compared with placebo. Treatment with limonene does not significantly alter bowel flora (110420). More evidence is needed to rate Limonene for these uses.

(Read more about LIMONENE)

POSSIBLY EFFECTIVE

• Cachexia. Intravenous MCTs can provide calories in critically ill patients and patients with refractory cachexia, but do not seem to offer any advantages over long chain triglycerides. Details: Several small clinical studies in critically ill patients and patients with refractory cachexia secondary to cancer show that receiving parenteral nutrition with a 1:1 mixture of MCTs and long chain triglycerides is similarly effective to long chain triglycerides alone for improving metabolic parameters or nutritional status (2275,2276,93739).

POSSIBLY INEFFECTIVE

• HIV/AIDS-related wasting. Oral MCTs do not seem to promote weight gain or prevent weight loss in patients with HIV infection. Details: A large clinical study in patients with HIV infection shows that taking a peptide-based supplement containing MCTs (Peptamen Oral Complete Elemental Diet, Nestlé Clinical Nutrition) with multivitamins and minerals is no more effective than taking multivitamins and minerals alone for promoting weight gain or preventing weight loss (11730).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral MCTs are beneficial in patients with age-related cognitive decline. Details: A small, single-blind clinical study in older adults residing in a nursing home shows that taking MCTs 6 grams (a 3:1 mixture of caprylic acid:capric acid), with or without L-leucine 1.2 grams and vitamin D (cholecalciferol) 20 mcg, daily for up to 3 months increases mini-mental state exam (MMSE) scores by an average of 3.5 points, compared with a 0.7-point decline in those receiving a long chain triglyceride control. MMSE scores returned to baseline 1.5 months after discontinuation of MCT supplementation (105710).
• Alzheimer disease. Small clinical studies suggest that oral MCTs do not improve cognition in patients with Alzheimer disease or mild cognitive impairment. Details: A meta-analysis of small clinical studies in patients with Alzheimer disease or mild cognitive impairment shows that taking MCTs (as combinations of caprylic acid and capric acid) in doses of 20-56 grams or 22.5-165 mL daily for up to 6 months does not improve cognition when compared with placebo or baseline (103012).
• Athletic performance. It is unclear if oral MCTs are beneficial for endurance athletic performance. Details: A very small clinical study in 10 male recreational endurance runners shows that taking a ketone supplement containing MCTs and a salt form of beta-hydroxybutyrate 60 minutes prior to a run does not improve 5-kilometer run time when compared with placebo (107738). This study may have been inadequately powered to detect a difference between groups.
• Celiac disease. Although there has been interest in using oral MCTs for celiac disease, there is insufficient reliable information about the clinical effects of MCTs for this purpose.
• Chylothorax. It is unclear if oral MCTs improve time to resolution of spontaneous congenital chylothorax in neonates. Details: A small retrospective study in neonates with spontaneous congenital chylothorax shows that administering MCTs does not improve the time to resolution of chylothorax when compared with total parenteral nutrition (11729).
• Chyluria. Although there has been interest in using oral MCTs for chyluria, there is insufficient reliable information about the clinical effects of MCTs for this purpose.
• Cystic fibrosis. Although there has been interest in using oral MCTs for cystic fibrosis, there is insufficient reliable information about the clinical effects of MCTs for this purpose.
• Diabetes. Although there has been interest in using oral MCTs for diabetes, there is insufficient reliable information about the clinical effects of MCTs for this purpose.
• Epilepsy. It is unclear if oral MCTs are beneficial in adults and adolescents aged 12 years or older with drug-resistant epilepsy. Details: A small clinical study in adults and adolescents aged 12 years or older with drug-resistant epilepsy shows that adjunctive treatment with MCTs (Stepan Lipid Nutrition) as part of a non-ketogenic diet, 47-65 mL daily (about 35% of energy intake), or a maximally tolerated dose not exceeding 100 mL, for 12 weeks reduces median seizure frequency by 46% when compared with baseline (101967). The validity of this study is limited by its small sample size and the lack of a comparator group.
• Gallbladder disease. Although there has been interest in using oral MCTs for gallbladder disease, there is insufficient reliable information about the clinical effects of MCTs for this purpose.
• Hypertriglyceridemia. Oral MCTs might improve triglyceride levels and body weight in some patients with overweight and hypertriglyceridemia, but its effect in other populations is unclear. Details: Clinical research in patients with overweight and hypertriglyceridemia shows that taking 25-30 grams of an oil containing MCTs 13% daily for 8 weeks decreases triglyceride levels by 78 mg/dL when compared with consuming oil containing only long chain fats. Body weight, body fat, and waist circumference also decreased (93740). However, this benefit may be restricted to this specific population only. Some research in patients with obesity or patients with a normal body weight shows that taking 25-30 grams of an oil containing MCTs daily for 8 weeks does not lower triglyceride levels (93741).
• Obesity. Small clinical studies suggest that oral MCTs modestly improves weight loss; however, any effects may not be clinically relevant. Details: A meta-analysis of clinical research shows that taking MCTs decreases body weight by 0.5 kg, waist circumference by 1.5 cm, and hip circumference by 0.8 cm when compared with a control group not taking MCTs. Doses used in available research have ranged from 1-54 grams daily, or 1% to 24% of energy for 4-16 weeks (93735). Most research shows that at least 4 weeks is needed before effects are seen. The greatest benefit seems to occur in patients of Asian descent, males, and patients with higher body mass indices at baseline (93730,93731,93735,93736). While MCTs may improve weight loss in some patients, the effects are generally modest and may not be clinically relevant.
• Prematurity. It is unclear if oral or topical MCTs are beneficial in preterm infants. Details: A meta-analysis of small studies involving 136 otherwise healthy preterm infants receiving full enteral diets with formula as the predominant source of nutrition shows that administration of formulas containing at least 30% of fat by weight as MCTs (ranging in concentration from 6% to 80%) for at least 7 days does not affect short-term growth, including weight, length, and head circumference, when compared with formulas containing less than 30% of fat by weight as MCTs. Due to small study sizes, it is unclear whether either type of formula was better tolerated. The validity of this analysis is limited by the presence of unclear risk of potential bias in the included studies (105711). MCT oil has also been evaluated for the prevention of gastrointestinal Candida infections. A very small clinical study in preterm infants shows that adding MCT oil (Nestlé Health Science) 0.5 mL per ounce of formula or breast milk for 1 week reduces Candida colonization when compared with no MCT oil (101968). Topical use of MCT oil has also been evaluated for growth in preterm infants. A small clinical study in preterm infants weighing 1500-2000 grams shows that massage with MCT oil, consisting of tactile and kinesthetic stimulation, three times daily for 7 days increases weight gain when compared with no massage (107739). The validity of this finding is limited by unclear reporting. Also, it is unclear if this effect is due to MCT oil, massage, or the combination.
• Primary intestinal lymphangiectasia. It is unclear if oral MCTs are beneficial for the management of primary intestinal lymphangiectasia. Details: A review of 55 case reports suggests that taking MCTs as part of a low-fat, high-protein diet resolves symptoms in 63% of patients with primary intestinal lymphangiectasia, compared with 36% of patients receiving no treatment or other treatments such as diuretic therapy, albumin transfusions, resection of isolated segments of affected bowels, etc. Mortality is also reduced by 79% in patients treated with diet restrictions and MCTs when compared with those receiving no treatment or other treatments (93733).
• Sarcopenia. It is unclear if oral MCTs are beneficial in frail older adults. Details: A small clinical study in older adults residing in a nursing home shows that taking MCTs 6 grams, leucine 1.2 grams, and vitamin D (cholecalciferol) 20 mcg daily for 3 months increases body weight by 1.1 kg, right-hand grip strength by 13%, and peak expiratory flow by 28% when compared with baseline. These improvements are also significant when compared with patients receiving no supplementation (93729). In a second study in this same population conducted by the same research group, taking MCTs 6 grams, with or without leucine 1.2 grams and vitamin D (cholecalciferol) 20 mcg, daily for 3 months does not increase body weight or hand grip strength. There were small to moderate improvements in opening and closing the legs, repetitive swallowing, and measures of functional independence (101970). The validity of these findings is limited by the single-blind nature of the studies and the large number of endpoints. It is also unclear if any benefits are due to MCTs, other ingredients, or the combination.
• Short bowel syndrome. Although there has been interest in using oral MCTs for short bowel syndrome, there is insufficient reliable information about the clinical effects of MCTs for this purpose. More evidence is needed to rate MCTs for these uses.

(Read more about MEDIUM CHAIN TRIGLYCERIDES (MCTs))

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Abortion. Although there has been interest in using oral parsley to induce abortion, there is insufficient reliable information about the clinical effects of parsley for this purpose.
• Constipation. Although there has been interest in using oral parsley for constipation, there is insufficient reliable information about the clinical effects of parsley for this purpose.
• Diabetes. Although there has been interest in using oral parsley for diabetes, there is insufficient reliable information about the clinical effects of parsley for this purpose.
• Dry skin. Although there has been interest in using topical parsley for dry skin, there is insufficient reliable information about the clinical effects of parsley for this purpose.
• Dyspepsia. Although there has been interest in using oral parsley for dyspepsia, there is insufficient reliable information about the clinical effects of parsley for this purpose.
• Hypertension. Although there has been interest in using oral parsley for hypertension, there is insufficient reliable information about the clinical effects of parsley for this purpose.
• Insect bite. Although there has been interest in using topical parsley for insect bites, there is insufficient reliable information about the clinical effects of parsley for this purpose.
• Kidney stones (nephrolithiasis). Although there has been interest in using oral parsley for kidney stones, there is insufficient reliable information about the clinical effects of parsley for this purpose.
• Melasma. It is unclear if topical parsley is beneficial for melasma. Details: A small clinical study in adults with melasma shows that applying a brewed parsley water to the face with a cotton ball on 6 days of each week for 8 weeks is as effective as hydroquinone 4% cream for improving dark spots (96828).
• Nonmelanoma skin cancer. Although there has been interest in using topical parsley to prevent nonmelanoma skin cancer, there is insufficient reliable information about the clinical effects of parsley for this purpose.
• Osteoarthritis. Although there has been interest in using oral parsley for osteoarthritis, there is insufficient reliable information about the clinical effects of parsley for this purpose.
• Urinary tract infections (UTIs). Although there has been interest in using oral parsley for UTIs, there is insufficient reliable information about the clinical effects of parsley for this purpose. More evidence is needed to rate parsley for these uses.

(Read more about PARSLEY)

POSSIBLY EFFECTIVE

• Memory. Oral rosemary seems to improve memory in young adults. It is unclear if rosemary aromatherapy improves memory. Details: Clinical research in healthy adults shows that taking rosemary 500 mg orally twice daily for one month improves memory by approximately 14% when compared with placebo (98536). Other preliminary clinical research shows that applying four drops of pure rosemary essential oil (Tisserand Aromatherapy) to an aromatherapy diffuser pad 5 minutes before a single test period can improve the quality, but not the speed, of memory recall, and increase alertness and contentment more than lavender aromatherapy or no aroma (18323). Rosemary aromatherapy has also been evaluated for improving memory in adults with kidney failure. A small clinical study in patients (mean age 53 years) undergoing hemodialysis shows that aromatherapy with rosemary essential oil three times weekly for 1 month does not improve medication adherence or measures of prospective and retrospective memory when compared with a control group. In this study, five drops of rosemary essential oil were applied to gauze, which was then placed 10 cm from the patient's nose for 30 minutes starting 1 hour after hemodialysis (109559).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Abortion. Although there has been interest in the use of oral rosemary as an abortifacient, there is insufficient reliable information about the clinical effects of rosemary for this purpose.
• Age-related cognitive decline. It is unclear if oral rosemary is beneficial for age-related cognitive decline. Details: A small clinical study in healthy individuals aged 65-90 years shows that a single 750 mg dose of powdered rosemary leaf in tomato juice may improve memory speed. However, higher single doses of 1500-6000 mg seem to have a deleterious effect on memory speed. For other measures of attention and memory, there were no clear benefits across the range of doses from 750-6000 mg (18246). Oral rosemary has also been evaluated in combination with other ingredients. A small clinical study in healthy adults aged 62 years or younger shows that taking a combination product containing equal parts rosemary, lemon balm, and sage twice daily for 2 weeks modestly improves word recall when compared with placebo. However, it does not appear to have benefit in adults aged 63 years and older (97277). It is unclear if any benefit is due to rosemary, other ingredients, or the combination.
• Alopecia areata. Topical rosemary oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that rosemary oil 114 mg, in combination with lavender oil 108 mg, thyme oil 88 mg, and cedarwood oil 94 mg, mixed with jojoba oil 3 mL and grapeseed oil 20 mL and applied topically to the scalp, improves hair growth in 44% of patients, compared with 15% of those receiving placebo. This combination was massaged into the scalp for a minimum of 2 minutes, followed by wrapping the head in a warm towel, every night for 7 months (5177).
• Androgenic alopecia. It is unclear if topical rosemary is beneficial for androgenic alopecia. Details: Preliminary clinical research shows that applying rosemary oil (Barij Essence Pharmaceutical Company) 1 mL to the scalp twice daily for 6 months is as effective as minoxidil 2% for increasing hair count in patients with androgenic alopecia (91729).
• Depression. It is unclear if oral rosemary is beneficial for major depressive disorder. Details: A small clinical trial among adults newly diagnosed with major depressive disorder and recent initiation of antidepressant medication shows that taking rosemary dried leaf extract 650 mg twice daily for 8 weeks might reduce some symptoms of depression and anxiety when compared with placebo (112141). However, the validity of these findings is limited by differences in baseline depression symptom scores between groups.
• Diabetes. It is unclear if oral rosemary is beneficial for improving glycemic control in patients with type 2 diabetes. Details: In patients with type 2 diabetes, preliminary clinical research shows that taking rosemary tea daily for 90 days decreases glycated hemoglobin levels by 15% and waist and hip circumference by 6% and improves insulin resistance. However, there was no effect on fasting blood glucose, lipid profile, body weight, or body mass index (BMI). The tea was made by adding rosemary 2 grams to a liter of boiling water for 3 minutes and then passing through a sieve (105323). Other preliminary clinical research in adults with type 2 diabetes shows that taking rosemary powder 3 grams daily for 4 weeks does not reduce fasting blood glucose levels or improve lipid profile when compared with baseline. These endpoints were improved in a group of healthy adults (105327). The validity of the findings from these studies is limited by the lack a comparator group.
• Diabetic nephropathy. Oral rosemary has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific combination product (Canephron N, Bionorica) containing 18 mg each of rosemary leaf, centaury herb, and lovage root per tablet, as two tablets three times daily for 6 months along with standard antidiabetes treatment and enalapril (Vasotec), decreases microalbuminuria by 73%, decreases albumin:creatinine ratio by 46%, increases high-density lipoprotein (HDL) cholesterol by 25%, and lowers triglyceride levels by 43%, but does not improve glomerular filtration rate, when compared to baseline. Improvements were greater in those taking the combination product than in those treated only with standard antidiabetes therapy and enalapril. However, the combination product does not appear to improve reductions in total cholesterol or low-density lipoprotein (LDL) cholesterol (91726).
• Dysmenorrhea. It is unclear if oral rosemary is beneficial for dysmenorrhea. Details: In patients with moderate primary dysmenorrhea, clinical research shows that taking rosemary extract 220 mg every 8 hours for the first three days of the menstrual cycle, repeated for two menstrual cycles, is as effective as mefenamic acid for reducing average pain and bleeding when compared with two baseline cycles (105328).
• Fatigue. Oral rosemary has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in healthy young adults with below-average energy levels shows that taking a single dose of a mixture of rosemary from Albania (Rosmarinus officinalis) and Morocco (Rosmarinus eriocalyx) 1.7 grams does not consistently improve sustained attention, motivation to perform cognitive tasks, mental energy, or mental fatigue when compared with placebo (91731).
• Fibromyalgia. Oral rosemary has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with fibromyalgia shows that taking an oral product containing rosemary leaf extract, oleanolic acid from olive leaf, and rho iso-alpha acids from hops (Meta050, Metagenics), at a dose of 440 mg three times daily for 4 weeks, then 880 mg twice daily for 4 weeks, does not improve symptoms when compared to baseline (18327).
• Gingivitis. A mouth rinse containing rosemary has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with mild to moderate gingivitis and mild plaque shows that rinsing the mouth with 10 mL of mouthwash containing 5% v/v of a combined alcoholic extract of rosemary, calendula, and ginger for 30 seconds twice daily after meals for 2 weeks decreases plaque formation, gingival inflammation, and gingival bleeding similarly to chlorhexidine gluconate 0.2% mouthwash and better than a placebo mouthwash (93555).
• Hypertension. Although there is interest in using oral rosemary for hypertension, there is insufficient reliable information about the clinical effects of rosemary for this condition.
• Hypotension. It is unclear if oral rosemary is beneficial for hypotension. Details: Preliminary clinical research in patients with primary hypotension shows that taking rosemary essential oil (Metapharmaceutical) 1 mL every 8 hours for 44 weeks increases systolic blood pressure by 13 mmHg and diastolic blood pressure by 7 mmHg when compared to baseline. However, blood pressure returned to near baseline values after treatment discontinuation (91730).
• Mental alertness. It is unclear if rosemary aromatherapy is beneficial for improving mental alertness. Details: Preliminary clinical research in nurses working on a night shift shows that placing one drop of rosemary oil on a surgical mask that is worn for 2 hours with a 10-minute on/15-minute off cycle modestly increases alertness and reduces sleepiness when compared with a water drop control (105324).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral rosemary leaf is beneficial in patients with NAFLD. Details: A small clinical study in patients with NAFLD shows that taking rosemary leaf powder 2 grams twice daily for 8 weeks, in conjunction with diet and exercise recommendations, does not improve measures of liver function, glycemic control, cholesterol, or body weight when compared with placebo (109561).
• Opioid withdrawal. It is unclear if oral rosemary is beneficial for opioid withdrawal when used in combination with methadone. Details: Preliminary clinical research shows that taking rosemary leaf along with methadone for 2 weeks improves symptoms of opioid withdrawal and the ability to sleep when compared with methadone alone after 3 and 7 days of treatment, but not after 2 weeks. Rosemary leaf was provided in capsules containing 300 mg each (Barij Essence Pharmaceutical Company) at a dose of 16 capsules daily for the first 3 days, 12 capsules daily for the next 4 days, and eight capsules daily for the next 7 days, in divided doses (91727).
• Osteoarthritis. Oral rosemary has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows subjective reductions in pain associated with osteoarthritis when oral formulations containing rosemary leaf extract, oleanolic acid from olive leaf, and rho iso-alpha acids from hops (NG440-2, Metagenics; Meta050, Metagenics) are used (18326,18327). The formulation used in one of these studies (Meta050, Metagenics) was taken in a dose of 440 mg three times daily for 4 weeks, then 880 mg twice daily for 4 weeks (18327). The formulation used in the other study, which was taken daily for 4 weeks, contained rosemary leaf extract 112.5 mg, oleanolic acid from olive leaf 1 mg, and rho iso-alpha acids from hops 225 mg per tablet (18326).
• Raynaud syndrome. It is unclear if topical rosemary essential oil is beneficial in patients with Raynaud syndrome. Details: A very small, open-label study in patients with Raynaud syndrome caused by systemic scleroderma shows that applying 10 drops of rosemary 10% essential oil to the hands does not increase skin temperature or improve warmth perception when compared with olive oil (109560). However, this study may have been inadequately powered to detect a difference between groups.
• Rheumatoid arthritis (RA). Oral rosemary has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows subjective decreases in pain associated with RA when oral formulations containing rosemary leaf extract, oleanolic acid from olive leaf, and rho iso-alpha acids from hops (NG440-2, Metagenics; Meta050, Metagenics) are used (18326,18327). The formulation used in one of these studies (Meta050, Metagenics) was taken in a dose of 440 mg three times daily for 4 weeks, then 880 mg twice daily for 4 weeks (18327). The formulation used in the other study, which was taken daily for 4 weeks, contained rosemary leaf extract 112.5 mg, oleanolic acid from olive leaf 1 mg, and rho iso-alpha acids from hops 225 mg per tablet (18326).
• Stress. It is unclear if rosemary aromatherapy is beneficial for stress. Details: Preliminary clinical research on the use of rosemary aromatherapy for anxiety and stress is conflicting. In a group of graduate nursing students, perceived stress associated with taking a test was lower when inhalers containing rosemary or lavender oil were used. Three drops of rosemary essential oil were added to an inhaler and inhaled before and during the test. Pulse rates, but not blood pressure, were also reduced (18324). In contrast, a small clinical study in adults aged 18-30 years shows that the aroma from diluted rosemary essential oil applied to the wrist during timed crossword puzzle completion actually increases subjective feelings of anxiety and tension when compared with placebo (18325).
• Sunburn. Oral rosemary has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination of rosemary and grapefruit extracts in a 1:1 ratio (NutroxSun, Monteloeder, Inc.), 250 mg orally once daily for 12 weeks, increases the amount of UV radiation needed to cause sunburn by 34% after 8 weeks and 56% after 12 weeks when compared to baseline (91728). The validity of these findings is limited by the lack of a comparator group.
• Upper respiratory tract infection (URTI). Oral rosemary has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial among healthy adults shows that taking a combination product containing rosemary leaf extract, aloe gel powder, and poria mushroom extract daily for 8 weeks does not reduce the frequency, duration, or severity of URTI-related symptoms when compared with placebo. However, in patients receiving an influenza vaccine midway through the study, this product does seem to improve some immune response biomarkers when compared with placebo (111921). The amount of rosemary leaf extract in the supplement was not disclosed.
• Wound healing. It is unclear if topical rosemary cream is beneficial for wound healing. Details: A moderate-sized clinical trial among primiparous adults with medio-lateral episiotomy shows that applying a cream containing rosemary extract to the wound twice daily for 10 days improves episiotomy wound healing and reduces redness and discharge when compared with placebo cream (112143). More evidence is needed to rate rosemary for these uses.

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POSSIBLY EFFECTIVE

• Hypercholesterolemia. Several small studies suggest that oral safflower oil, as a substitute for coconut oil, butter, or other animal fats in the diet, may reduce total and low-density lipoprotein (LDL) cholesterol levels in patients with or without hypercholesterolemia. Details: Three small clinical studies in patients with or without hypercholesterolemia show that substituting coconut oil, butter, or other animal fats in the diet with safflower oil (36% of total daily calories) for 4-6 weeks can lower levels of total and LDL cholesterol, but has no beneficial effects on high-density lipoprotein (HDL) cholesterol or triglycerides (25391,25393,72310).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Coronary heart disease (CHD). Safflower oil, which is high in oleic acid, may be beneficial for reducing the risk of CHD when used to replace other dietary oils. Details: Some safflower oil products contain high quantities of oleic acid. In 2018, the US Food and Drug Administration (FDA) determined that it would allow a qualified health claim stating that consuming 1.5 tablespoons daily of oils containing at least 70% oleic acid may reduce the risk of CHD. In order to obtain any benefit, this oil must be used to replace fats and oils higher in saturated fat. However, the FDA has determined that this statement is based on supporting, rather than conclusive, evidence (98563).
• Cystic fibrosis. It is unclear if oral safflower oil is beneficial in children with cystic fibrosis. Details: A very small clinical study in children with cystic fibrosis shows that taking safflower oil 1 gram/kg daily for one year does not affect sweat chloride concentrations or disease severity when compared with age-matched controls (72281).
• Diabetes. Small clinical studies of oral safflower oil for improving glycemic control in patients with diabetes have yielded mixed results. Details: One very small clinical trial in patients with type 2 diabetes shows that taking safflower oil 10 grams daily for 3 weeks increases fasting blood glucose by 11% when compared to baseline. Insulin levels, insulin sensitivity, and lipid levels were not affected (13146). However, another small clinical study in obese, postmenopausal patients with type 2 diabetes shows that taking safflower oil 2 grams four times daily for 16 weeks decreases HbA1c by 0.64% and increases high-density lipoprotein (HDL) cholesterol by about 5 mg/dL when compared with conjugated linoleic acid (CLA) 2 grams four times daily. Insulin sensitivity and fasting blood glucose levels do not appear to be affected (94039). These differing outcomes may be due to the small study sizes and varied patient populations.
• Diabetic nephropathy. Small clinical studies suggest that intravenous safflower yellow, a component of safflower flower, might improve symptoms and markers of diabetic nephropathy. Details: A meta-analysis of 14 small and low-quality clinical studies in adults with diabetic nephropathy shows that intravenous administration of safflower yellow as an adjunct to conventional treatment reduces urinary albumin excretion rate, fasting blood glucose, serum creatinine, and blood urea nitrogen when compared with conventional treatment alone. Overall, patients receiving safflower yellow were more likely to experience a clinical improvement in symptoms when compared with conventional treatment alone (102381).
• Familial hypercholesterolemia. Small clinical studies suggest that substituting safflower oil in place of butter in the diet may modestly reduce cholesterol levels in patients with familial hypercholesterolemia. Details: Two very small clinical studies in patients with familial hypercholesterolemia show that substituting safflower oil in place of butter in the diet (contributing 36% of daily calories) for 3 weeks decreases total and low-density lipoprotein (LDL) cholesterol levels when compared with butter (72246,72267).
• Hepatitis C. Oral safflower oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small, open-label clinical study in patients with chronic hepatitis C shows that taking a specific combination product containing safflower, pumpkin seeds, plantain seeds, and Japanese honeysuckle (EH0202) 1 gram daily for 3 months modestly reduces general discomfort, abdominal bloating, nausea, and vomiting when compared to baseline. However, hepatitis C RNA and hepatitis C virus antibody levels are not affected (72238).
• Hypertension. It is unclear if oral safflower oil is beneficial for reducing blood pressure; the available research is conflicting. Details: A very small clinical study in patients with hypertension shows that taking safflower oil 10 mL twice daily for 6-8 weeks reduces diastolic blood pressure when compared with placebo (72304). However, another small clinical study in patients with mild hypertension shows that taking safflower oil 30 mL daily for 6 weeks does not affect blood pressure when compared to baseline (72268).
• Low birth weight. It is unclear if oral safflower oil is beneficial in infants with low birth weight. Details: A small clinical study in low birth weight infants shows that fortifying formula or breast milk with a specific safflower oil product (Safola, Marico Industries Ltd.) does not improve weight gain or skin thickness when compared with coconut oil or unfortified formula or breast milk (72229).
• Metabolic syndrome. It is unclear if oral safflower oil is beneficial in patients with metabolic syndrome. Details: A small clinical study in patients with metabolic syndrome shows that taking safflower oil 2 grams four times daily for 12 weeks reduces waist circumference by 3.4 cm, systolic blood pressure by 7 mmHg, diastolic blood pressure by 3 mmHg, and fasting blood glucose by 8 mg/dL when compared with placebo. However, body weight, body mass index (BMI), and lipid levels were not affected (108889).
• Obesity. Although there has been interest in using oral safflower oil for obesity, there is insufficient reliable information about the clinical effects of safflower oil for this purpose.
• Myocardial infarction. Intravenous safflower yellow, a component of safflower flower, might improve outcomes when used as an adjunct to conventional therapy for the treatment of acute coronary syndrome (ACS). Details: A meta-analysis of 16 small, low-quality clinical trials in patients with ACS, including myocardial infarction and unstable angina, shows that intravenous administration of safflower yellow 20-40 mL daily for 10-15 days as an adjunct to conventional therapy improves clinical outcomes, electrocardiogram measures, and left ventricular ejection fraction when compared with placebo (108891).
• Phrynoderma. It is unclear if oral safflower oil is beneficial in patients with phrynoderma. Details: A small clinical study in patients with phrynoderma shows that taking 30 mL of safflower oil containing vitamin E 116 mg and linoleic acid 68% daily for more than 8 weeks can partially improve skin dryness and roughness when compared to baseline (72269). The validity of these findings is limited by the lack of a comparator group.
• Scarring. Topical safflower oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with non-hypertrophic scars and striae shows that applying an oil containing safflower oil 55.9%, olive oil 42%, grapefruit oil 2%, and tocopherol 0.1% (Kneipp Bio Skin Oil, Kneipp GmbH) to the scars and striae twice daily for 8 weeks improves scores on the Patient Scar Assessment Scale (PSAS) by 20%, compared to a 6% improvement in untreated areas (95938).
• Stroke. Small clinical studies suggest that intravenous safflower yellow, a constituent of safflower flower, as an adjunct to conventional treatments, may improve neurological outcomes post-stroke. Details: A meta-analysis of seven small, low-quality clinical studies in Chinese patients with acute ischemic stroke shows that intravenous administration of safflower yellow 100-150 mg as an adjunct to conventional treatments, starting within 72 hours of stroke onset and continuing once daily for 14 days thereafter, increases the odds of neurological improvement by about 3-fold when compared with conventional treatments alone (94038).
• Unstable angina. Intravenous safflower yellow, a component of safflower flower, might improve outcomes when used as an adjunct to conventional therapy for the treatment of unstable angina. Details: A meta-analysis of seven low-quality clinical studies in Chinese patients with unstable angina shows that intravenous safflower yellow 50-150 mg daily for 14-15 days in addition to conventional treatment modestly improves electrocardiogram (ECG) measures and symptoms of angina when compared with conventional treatment alone (94041). Another meta-analysis of 16 small, low-quality clinical trials in patients with acute coronary syndrome (ACS), including unstable angina and myocardial infarction, shows that intravenous administration of safflower yellow 20-40 mL daily for 10-15 days as an adjunct to conventional therapy improves clinical outcomes, ECG measures, and left ventricular ejection fraction when compared with placebo (108891). More evidence is needed to rate safflower for these uses.

(Read more about SAFFLOWER)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Athletic performance. Preliminary clinical research shows that theacrine does not improve measures of athletic performance. However, these studies were small, and may have been underpowered. Details: One small clinical trial in elite male and female soccer players shows that taking theacrine (TeaCrine, Compound Solutions, Inc.) 275 mg alone or 125 mg in combination with caffeine 150 mg 30 minutes prior to exercise does not improve time to exhaustion, control of heart rate, or perceived exertion when compared with placebo (99950). Another small clinical trial in resistance trained males shows that taking theacrine (TeaCrine, Compound Solutions, Inc.) 300 mg alone or 150 mg in combination with caffeine 150 mg 90 minutes prior to exercise does not improve endurance or rowing time trial performance when compared with placebo (103274).
• Cognitive function. Oral theacrine has mostly been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking theacrine does not improve concentration or most other measures of cognitive function (88784,99950,99952). Studies have used single doses of 200-275 mg of a specific theacrine product (TeaCrine; Compound Solutions, Inc.) alone, in combination with caffeine 150 mg, or in a proprietary combination with caffeine 150 mg, white willow bark, SAMe, Rauwolfia vomitoria, vitamin B12, and citrus bioflavonoids (TheaTrim, Purus Labs). However, the validity of these results is limited because the studies were likely underpowered. Furthermore, some research shows that taking theacrine 200 mg daily for 7 days might improve subjective measures of cognitive function, such as increased energy, reduced fatigue, and improved concentration, in some healthy individuals (88784). A small clinical study in young males shows that taking a combination product containing theacrine 50mg, caffeine 125 mg, and methylliberine 75mg as a single dose orally before a video game test improves inhibitory control, attention to internal processing, reaction times, and self-reported alertness when compared with either caffeine 125 mg alone or placebo. Caffeine alone is associated with increased anxiety and headache when compared with taking the combination product (109926).
• Fatigue. Although there is interest in using oral theacrine for fatigue, there is insufficient reliable information about the effects of theacrine for this purpose.
• Mental alertness. Oral theacrine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in males aged 18-63 years who are current or former law enforcement or military personnel shows that taking theacrine 50 mg, caffeine 150 mg, and methylliberine 100 mg immediately before two 75-minute consecutive computerized tests of reaction times, vigilance, and marksmanship, improves reaction times and vigilance in the second test when compared with the first. Similar improvements are seen with the combination product and with subjects taking caffeine 300 mg alone. All three groups, including placebo, show improvements in decision making and in subjective feelings of arousal when compared with baseline, but not marksmanship scores (109927).
• Muscle strength. Oral theacrine has only been evaluated in combination with caffeine; its effect when used alone is unclear. Details: A small clinical study in resistance trained males shows that taking theacrine (TeaCrine, Compound Solutions, Inc.) 300 mg alone or 150 mg in combination with caffeine 150 mg 90 minutes prior to resistance training does not improve muscle strength or power, measured by bench press and squat exercises, when compared with placebo (103274). However, the study has been inadequately powered to detect a difference between groups. More evidence is needed to rate theacrine for these uses.

(Read more about THEACRINE)

EFFECTIVE

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

LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Antidepressant-induced sexual dysfunction. It is unclear if oral yohimbine, a constituent of yohimbe, is beneficial for patients with antidepressant-induced sexual dysfunction. Details: Small clinical trials suggest that taking yohimbine, a constituent of yohimbe, improves sexual dysfunction associated with selective serotonin reuptake inhibitors (SSRIs) (3305,3306,3307,3311,3313,3970,3971,3972,3973). It is unclear if yohimbe bark is beneficial.
• Anxiety. There is limited evidence on the oral use of yohimbine, a constituent of yohimbe, for the management of various phobias. Details: A small clinical study in healthy adults with a fear of flying shows that taking yohimbine hydrochloride 10 mg as an adjunct to virtual reality exposure therapy (VRET) does not improve anxiety measures when compared with VRET alone (86819). However, another small clinical study in healthy adults with claustrophobia shows that taking yohimbine hydrochloride 10.8 mg prior to exposure-based treatment reduces peak fear after one week when compared with exposure-based treatment alone (86794). The effect of yohimbe bark has not been investigated in clinical research.
• Athletic performance. It is unclear if oral yohimbine, a constituent of yohimbe, is beneficial for athletic performance. Details: A small clinical study in professional soccer players shows that taking yohimbine, a constituent of yohimbe, 20 mg daily for 3 weeks does not improve exercise performance or build muscle mass when compared with placebo (86785). However, a small crossover study in physically active females undergoing an anaerobic exercise test shows that taking a single dose of oral yohimbine 2.5 mg 20 minutes prior to repeated sprints increases average power output, total work, and heart rate and decreases average fatigue index when compared with placebo. Additionally, taking yohimbine decreases lactic acid levels and increases epinephrine levels when compared with baseline or placebo (107849). Due to the single-dose nature of this study, the effects of continued administration of yohimbine on athletic performance are unclear. The effects of yohimbe bark have not been investigated in clinical research.
• Depression. It is unclear if oral yohimbine, a constituent of yohimbe, is beneficial in patients with depression. Details: A very small clinical study in patients with treatment-resistant major depressive disorder shows that taking yohimbine, a constituent of yohimbe, 30 mg daily for 10 days along with desipramine does not improve symptoms of depression when compared with desipramine alone (86834). Also, a small crossover trial in patients with major depressive disorder and/or a history of adverse childhood experiences shows that taking yohimbine 10 mg once does not alter approach-avoidance behaviors normally associated with depression when compared with placebo (111402). The effects of yohimbe bark have not been investigated in clinical research.
• Dry mouth. It is unclear if oral yohimbine, a constituent of yohimbe, is beneficial for dry mouth. Details: A very small clinical study shows that taking yohimbine, a constituent of yohimbe bark, 18 mg daily for 5 days improves symptoms of dry mouth in individuals treated with antidepressants when compared with placebo (86886). The effect of yohimbe bark has not been investigated in clinical research.
• Erectile dysfunction (ED). It is unclear if oral yohimbine, a constituent of yohimbe, is beneficial for ED. Details: The effects of yohimbe bark have not been investigated in clinical research. Most small clinical studies suggest that taking yohimbine, a constituent in yohimbe bark, seems to improve symptoms in adults with various types of ED, including organic, psychogenic, mixed, and others (3305,3307,3309,3311,3312,3313,10629,86827,86831,86878)(86882,86888,86896). A meta-analysis in patients with ED shows that taking 5-100 mg of oral yohimbine for 2-10 weeks increases the probability of erectile function improvement when compared with placebo. Also, the use of yohimbine in combination with either L-arginine or trazodone, but not as monotherapy, improves sexual function when compared with placebo (107848). These findings are limited by the high heterogeneity of the included studies. Due to insufficient data, guidelines from the American Urological Association do not recommend yohimbine as a treatment option for ED (86881).
• Fatigue. Although there is interest in using oral yohimbe for fatigue, there is insufficient reliable information about the clinical effects of yohimbe for this purpose.
• Obesity. Although there is interest in using oral yohimbe for obesity, there is insufficient reliable information about the clinical effects of yohimbe for this condition.
• Orthostatic hypotension. It is unclear if oral yohimbine, a constituent of yohimbe, is beneficial in patients with orthostatic hypotension. Details: Some preliminary clinical research shows that taking a single dose of yohimbine 5.4 mg increases systolic blood pressure and standing diastolic blood pressure in patients with orthostatic hypotension when compared with placebo or pyridostigmine (86811,86890). However, other preliminary clinical research shows that taking yohimbine does not improve blood pressure in patients with orthostatic hypotension due to autonomic failure when compared with placebo (86821). The effect of yohimbe bark has not been investigated in clinical research. More evidence is needed to rate yohimbe for these uses.

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

POSSIBLY SAFE ...when black pepper oil is applied topically. Black pepper oil is nonirritating to the skin and is generally well tolerated (11). ...when black pepper oil is inhaled through the nose or as a vapor through the mouth, short-term. Black pepper oil as a vapor or as an olfactory stimulant has been used with apparent safety in clinical studies for up to 3 days and 30 days, respectively (29159,29160,29161,90502). There is insufficient reliable information available about the safety of black pepper when used orally in medicinal amounts.

CHILDREN: LIKELY SAFE
when used orally in amounts commonly found in foods (11).

CHILDREN: POSSIBLY UNSAFE
when used orally in large amounts. Fatal cases of pepper aspiration have been reported in some patients (5619,5620). There is insufficient reliable information available about the safety of topical pepper oil when used in children.

PREGNANCY: LIKELY SAFE
when used orally in amounts commonly found in foods (11).

PREGNANCY: LIKELY UNSAFE
when used orally in large amounts. Black pepper might have abortifacient effects (11,19); contraindicated. There is insufficient reliable information available about the safety of topical pepper when used during pregnancy.

LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (11). There is insufficient reliable information available about the safety of black pepper when used in medicinal amounts during breast-feeding.

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

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

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

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

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

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

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

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

(Read more about CAFFEINE)

LIKELY SAFE ...when used orally in amounts typically found in food. Capsicum has Generally Recognized as Safe (GRAS) status in the US (4912). ...when used topically and appropriately (7038,10650,105345). The active capsicum constituent capsaicin is an FDA-approved ingredient used in certain over-the-counter, topical preparations (272).

POSSIBLY SAFE ...when used orally and appropriately, short-term in medicinal amounts. A specific sustained-release chili extract (Capsifen) has been used safely in doses of up to 200 mg daily, for up to 28 days (105196). ...when used intranasally and appropriately, short-term. Capsicum-containing nasal sprays, suspensions, and swabs seem to be safe when applied multiple times over 24 hours or when applied daily or every other day for up to 14 days. Although no serious side effects have been reported in clinical trials, intranasal application of capsicum-containing products can be very painful (14322,14324,14328,14329,14351,14352,14353,14356,14357) (14358,14359,14360,15016,105204). POSSIBLY UNSAFE when used orally, long-term or in high doses. There is concern that long-term use or use of excessive doses might be linked to hepatic or kidney damage, as well as hypertensive crisis (12404,40569,40606). There is insufficient reliable information available about the safety of capsicum when injected.

CHILDREN: POSSIBLY UNSAFE
when used topically in children under 2 years old (272). There is insufficient reliable information available about the safety of capsicum when used orally in children.

PREGNANCY: LIKELY SAFE
when used topically and appropriately (272).

PREGNANCY: POSSIBLY SAFE
when used orally and appropriately, short-term. Capsicum 5 mg daily has been used for up to 28 days during the latter half of the second trimester and the third trimester (96457).

LACTATION: LIKELY SAFE
when used topically and appropriately (272).

LACTATION: POSSIBLY UNSAFE
when used orally. Dermatitis can sometimes occur in infants when foods heavily spiced with capsicum peppers are ingested during lactation (739). Also, observational research suggests that intake of raw capsicum peppers during pregnancy is associated with an increased risk of sensitization to inhalant allergens in children by the age of 2 years (41021).

(Read more about CAPSICUM)

POSSIBLY SAFE ...when used orally and appropriately, short-term. Huperzine A 200-800 mcg daily has been used with apparent safety in clinical trials lasting up to 6 months (3171,3561,4626,93478,93479,93480,93481,93482,93483,93485).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. Huperzine A has been used with apparent safety in clinical research lasting for 1 month (4626).

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

(Read more about HUPERZINE A)

LIKELY SAFE ...when consumed in amounts commonly found in foods. Limonene has Generally Recognized As Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts. Limonene has been safely used in doses of up to 8 mg/m2 in one trial for up to a year (12709). ...when used topically in amounts found in fragrances and personal hygiene products. Limonene is a common ingredient in fragrances and personal hygiene products (99871,99873). It can cause allergic contact dermatitis in some people (99871,99872,99873).

PREGNANCY AND LACTATION: LIKELY SAFE
when consumed in amounts commonly found in foods. Limonene has Generally Recognized As Safe (GRAS) status in the US (4912). There is insufficient reliable information available about using limonene in medicinal amounts during pregnancy or breast-feeding; avoid using.

(Read more about LIMONENE)

LIKELY SAFE ...when used orally and appropriately (11726,11727,11728,11729,11730,93729). ...when used parenterally and appropriately (2275,2276,2278,11726,11727,11728,11729). There is insufficient reliable information available about the safety of MCTs when used topically.

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

(Read more about MEDIUM CHAIN TRIGLYCERIDES (MCTs))

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

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts, short-term (12,13173).

LIKELY UNSAFE ...when used orally in very large doses e., 200 grams). Parsley oil contains significant amounts of the potentially toxic constituents, apiole and myristicin (11). Apiole can cause blood dyscrasias, kidney toxicity, and liver toxicity; myristicin can cause giddiness and hallucinations (4). ...when parsley seed oil is used topically. Applying parsley seed oil to the skin can cause photodermatitis upon sun exposure (4). There is insufficient reliable information available about the safety of the topical use of parsley leaf and root.

PREGNANCY: LIKELY UNSAFE
when used orally in medicinal amounts. Parsley has been used orally as an abortifacient and to stimulate menstrual flow (4,12,515,19104,92873). Population evidence suggests that maternal intake of An-Tai-Yin, an herbal combination product containing parsley and dong quai, during the first trimester increases the risk of congenital malformations of the musculoskeletal system, connective tissue, and eyes (15129).

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about PARSLEY)

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

POSSIBLY SAFE ...when the leaf is used orally and appropriately in medicinal amounts (18). Powdered rosemary leaf has been used with apparent safety as a single dose of up to 1.5 grams (18246,91731) or at a dose of 1-4 grams daily for up to 8 weeks (91727,98536,105327,109561). ...when the essential oil is used topically and appropriately for up to 7 months (5177,91729,109560). ...when the essential oil is used by inhalation as aromatherapy, short-term (7107,18323,105324,109559).

LIKELY UNSAFE ...when the essential oil or very large quantities of rosemary leaf are used orally. Ingestion of undiluted rosemary oil or very large quantities of rosemary leaf can cause serious adverse effects (18,515).

PREGNANCY: POSSIBLY UNSAFE
when used orally in medicinal amounts. Rosemary might have uterine and menstrual flow stimulant effects (4,12,18), and might increase metabolism of estradiol and estrone (18331); avoid using. There is insufficient reliable information available about the safety of rosemary when used topically during pregnancy.

LACTATION:
There is insufficient reliable information available about the safety of using rosemary in medicinal amounts during lactation; avoid using.

(Read more about ROSEMARY)

LIKELY SAFE ...when safflower oil is used orally as part of the diet (6,13146,72238).

POSSIBLY SAFE ...when safflower oil is used topically for up to 8 weeks (95938). ...when safflower oil is administered intravenously in recommended doses by a health care professional. A specific safflower oil emulsion (Liposyn) 10% to 20% has been used intravenously for up to 2 weeks (72300,72301). ...when safflower yellow, a component of safflower flower, is administered intravenously and appropriately. Safflower yellow has been used with apparent safety in doses up to 150 mg daily for up to 5 weeks (94038,94041,102381).

CHILDREN: POSSIBLY SAFE
when safflower oil is administered intravenously in recommended doses by a healthcare professional. A specific safflower oil emulsion (Liposyn) 20% has been used intravenously in infants and children for up to 2 weeks (72284,72295). ...when safflower oil is used orally in medicinal amounts. Safflower oil 2.5 mL daily has been taken safely for 8 weeks (94042). There is insufficient reliable information available about the safety of safflower flower in children.

PREGNANCY: LIKELY SAFE
when safflower oil is used orally as part of the diet (6,13146,72238).

PREGNANCY: POSSIBLY SAFE
when safflower oil is administered intravenously in recommended doses by a healthcare professional (20529).

PREGNANCY: LIKELY UNSAFE
when safflower flower is used due to its abortifacient, menstrual stimulant, and uterine stimulant effects (11,12).

LACTATION: LIKELY SAFE
when safflower oil is used orally as part of the diet (6,13146,72238). There is insufficient reliable information available about the safety of safflower flower during lactation; avoid using.

(Read more about SAFFLOWER)

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

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

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

(Read more about VITAMIN B12)

POSSIBLY UNSAFE ...when used orally. Yohimbine, a constituent of yohimbe, has been associated with serious adverse effects including cardiac arrhythmia, agitation, myocardial infarction, seizure, and others (17465). Some research shows that yohimbine can be safely used under close medical supervision for up to 10 weeks (3305,3307,3311,3313). However, due to safety concerns, yohimbe should not be used without medical supervision.

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally. Yohimbe might have uterine relaxant effects and also cause fetal toxicity (19).

(Read more about YOHIMBE)

AMOXICILLIN (Amoxil, Trimox) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the effects and side effects of amoxicillin.  Details Animal research shows that taking piperine, a constituent of black pepper, with amoxicillin increases plasma levels of amoxicillin (29269). This has not been reported in humans.

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the risk of bleeding when taken with antiplatelet or anticoagulant drugs.  Details In vitro research shows that piperine, a constituent of black pepper, seems to inhibit platelet aggregation (29206). This has not been reported in humans.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Animal research shows that piperine, a constituent of black pepper, can reduce blood glucose levels (29225). Monitor blood glucose levels closely. Dose adjustments might be necessary.

ATORVASTATIN (Lipitor) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase blood levels of atorvastatin.  Details Animal research shows that taking piperine, a constituent of black pepper, 35 mg/kg can increase the maximum serum concentration of atorvastatin three-fold (104188). This has not been reported in humans.

CARBAMAZEPINE (Tegretol) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, black pepper might increase blood levels of carbamazepine, potentially increasing the effects and side effects of carbamazepine.  Details One clinical study in patients taking carbamazepine 300 mg or 500 mg twice daily shows that taking a single 20 mg dose of purified piperine, a constituent of black pepper, increases carbamazepine levels. Piperine may increase carbamazepine absorption by increasing blood flow to the GI tract, increasing the surface area of the small intestine, or inhibiting cytochrome P450 3A4 (CYP3A4) in the gut wall. Absorption was significantly increased by 7-10 mcg/mL/hour. The time to eliminate carbamazepine was also increased by 4-8 hours. Although carbamazepine levels were increased, this did not appear to increase side effects (16833). In vitro research also shows that piperine can increase carbamazepine levels by 11% in a time-dependent manner (103819).

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the effects and side effects of cyclosporine.  Details In vitro research shows that piperine, a constituent of black pepper, increases the bioavailability of cyclosporine (29282). This has not been reported in humans.

CYTOCHROME P450 1A1 (CYP1A1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of drugs metabolized by CYP1A1.  Details In vitro research suggests that piperine, a constituent of black pepper, inhibits CYP1A1 (29213). This has not been reported in humans.

CYTOCHROME P450 2B1 (CYP2B1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of drugs metabolized by CYP2B1.  Details In vitro research suggests that piperine, a constituent of black pepper, inhibits CYP2B1 (29332). This has not been reported in humans.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of drugs metabolized by CYP2D6.  Details In vitro research suggests that some constituents of black pepper inhibit CYP2D6 (29207,29212,38375). This has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of drugs metabolized by CYP3A4.  Details In vitro research shows that piperine, a constituent of black pepper, as well as the pepper fruit seem to inhibit CYP3A4 (14375,29212). This has not been reported in humans.

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, black pepper might increase blood levels of lithium due to its diuretic effects. The dose of lithium might need to be reduced.  Details Black pepper is thought to have diuretic properties (11).

NEVIRAPINE (Viramune) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Black pepper might increase blood levels of nevirapine.  Details Clinical research shows that piperine, a constituent of black pepper, increases the plasma concentration of nevirapine. However, no adverse effects were observed in this study (29209).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of P-glycoprotein substrates.  Details In vitro research shows that piperine, a constituent of black pepper, seems to inhibit P-glycoprotein (14375,29281,29283).

PENTOBARBITAL (Nembutal) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the sedative effects of pentobarbital.  Details Animal research shows that piperine, a constituent of black pepper, increases pentobarbital-induced sleeping time (29214).

PHENYTOIN (Dilantin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Black pepper might increase blood levels of phenytoin.  Details Clinical research shows that piperine, a constituent of black pepper, seems to increase absorption, slow elimination, and increase levels of phenytoin (537,14442). Taking a single dose of black pepper 1 gram along with phenytoin seems to double the serum concentration of phenytoin (14375). Consuming a soup with black pepper providing piperine 44 mg/200 mL of soup along with phenytoin also seems to increase phenytoin levels when compared with consuming the same soup without black pepper (14442).

PROPRANOLOL (Inderal) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Black pepper might increase blood levels of propranolol.  Details Clinical research shows that piperine, a constituent of black pepper, seems to increase absorption and slow elimination of propranolol (538).

RIFAMPIN (Rifadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Black pepper might increase blood levels of rifampin.  Details Clinical research shows that piperine, a constituent of black pepper, seems to increase absorption and serum levels of rifampin (14375,29284).

THEOPHYLLINE Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Black pepper might increase blood levels of theophylline.  Details Clinical research shows that piperine, a constituent of black pepper, seems to increase absorption and slow elimination of theophylline (538).

(Read more about BLACK PEPPER)

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 (6024,8646,114662).

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 Abrupt caffeine withdrawal might increase the levels and adverse effects of lithium.  Details Caffeine has diuretic activity. When abruptly discontinued, caffeine may alter the clearance of lithium (609). There are two case reports of lithium tremor that worsened upon abrupt coffee withdrawal (610) and 6 case reports of elevated serum lithium levels after reducing or eliminating caffeine intake (114665). In one case, a male with schizoaffective disorder stabilized on lithium had an elevated lithium level after reducing his caffeine intake by 87%. At a later date, he increased his caffeine intake by 6-fold, resulting in a subtherapeutic lithium level and a recurrence of psychiatric symptoms (114665).

METFORMIN (Glucophage) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, metformin might increase the levels and adverse effects of caffeine.  Details Animal research suggests that metformin can reduce caffeine metabolism (23571). However, this effect has not been reported in humans.

METHOXSALEN (Oxsoralen) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, methoxsalen might increase the levels and adverse effects of caffeine.  Details Methoxsalen reduces caffeine metabolism (23572).

MEXILETINE (Mexitil) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, mexiletine might increase the levels and adverse effects of caffeine.  Details Mexiletine reduces caffeine metabolism (1260,11741).

MONOAMINE OXIDASE INHIBITORS (MAOIs) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the risk of a hypertensive crisis.  Details Caffeine has been shown to inhibit monoamine oxidase (MAO) A and B in laboratory studies (37724,37877,37912,38108). Concomitant intake of large amounts of caffeine with MAOIs might precipitate a hypertensive crisis (15). In a case report, a patient that consumed 10-12 cups of caffeinated coffee and took the MAOI tranylcypromine presented with severe hypertension (91086). Hypertension was resolved after the patient switched to drinking decaffeinated coffee.

NICOTINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, concomitant use might increase the risk of hypertension.  Details Concomitant use of caffeine and nicotine has been shown to have additive cardiovascular effects, including increased heart rate and blood pressure. Blood pressure was increased by 10.8/12.4 mmHg when the agents were used concomitantly (36549).

PENTOBARBITAL (Nembutal) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, caffeine might decrease the effects of pentobarbital.  Details Caffeine might negate the hypnotic effects of pentobarbital (13742).

PHENOBARBITAL (Luminal) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, caffeine might reduce the effects of phenobarbital and increase the risk for convulsions.  Details Animal research suggests that caffeine can decrease the anticonvulsant activity of phenobarbital (23558,23559,23561). However, the exact mechanism of this interaction is unclear.

PHENOTHIAZINES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, phenothiazines might increase the levels and adverse effects of caffeine.  Details Phenothiazines, including perazine, chlorpromazine, levomepromazine, and thioridazine, can reduce the metabolism of caffeine by inhibiting cytochrome P450 1A2 (CYP1A2) (23573,23574).

PHENYLPROPANOLAMINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, phenylpropanolamine might increase the risk of hypertension, as well as the levels and adverse effects of caffeine.  Details Concomitant use of phenylpropanolamine and caffeine might cause an additive increase in blood pressure (11738). Phenylpropanolamine also seems to increase caffeine serum levels (13743).

PHENYTOIN (Dilantin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, caffeine might reduce the effects of phenytoin and increase the risk for convulsions.  Details Animal research suggests that caffeine can decrease the anticonvulsant activity of phenytoin (23559,23561). The effect does not seem to be related to the seizure threshold-lowering effects of caffeine. However, the exact mechanism of this interaction is unclear.

PIOGLITAZONE (Actos) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, caffeine might increase the levels and clinical effects of pioglitazone.  Details Animal research suggests that caffeine can modestly increase the maximum concentration, area under the curve, and half-life of pioglitazone, and also reduce its clearance. This increased the antidiabetic effects of pioglitazone (108812). However, the exact mechanism of this interaction is unclear.

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, quinolone antibiotics might increase the levels and adverse effects of caffeine.  Details Quinolones (also called fluoroquinolones) can decrease caffeine clearance by inhibiting cytochrome P450 1A2 (CYP1A2) enzyme (606,607,608,23554,23555,23556).

RILUZOLE (Rilutek) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the levels and adverse effects of both caffeine and riluzole.  Details Caffeine and riluzole are both metabolized by cytochrome P450 1A2 (CYP1A2), and concomitant use might reduce the metabolism of one or both agents (11739).

STIMULANT DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Theoretically, concomitant use might increase stimulant adverse effects.  Details Due to the central nervous system (CNS) stimulant effects of caffeine, concomitant use with stimulant drugs can increase the risk of adverse effects (11832).

TERBINAFINE (Lamisil) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, terbinafine might increase the levels and adverse effects of caffeine.  Details Terbinafine decreases the clearance of intravenous caffeine by 19% (11740).

THEOPHYLLINE Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = C Theoretically, caffeine might increase the levels and adverse effects of theophylline.  Details Large amounts of caffeine might inhibit theophylline metabolism (11741).

TIAGABINE (Gabitril) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, caffeine might increase the levels and adverse effects of tiagabine.  Details Animal research suggests that chronic caffeine administration can increase the serum concentrations of tiagabine. However, concomitant use does not seem to reduce the antiepileptic effects of tiagabine (23561).

TICLOPIDINE (Ticlid) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, ticlopidine might increase the levels and adverse effects of caffeine.  Details In vitro evidence suggests that ticlopidine can inhibit caffeine metabolism (23557). However, this effect has not been reported in humans.

VALPROATE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, caffeine might reduce the effects of valproate and increase the risk for convulsions.  Details Animal research suggests that caffeine can decrease the anticonvulsant activity of valproate (23558,23559,23561,37882). However, the exact mechanism of this interaction is unclear.

VERAPAMIL (Calan, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, verapamil might increase the levels and adverse effects of caffeine.  Details Verapamil increases plasma caffeine concentrations by 25% (11741).

(Read more about CAFFEINE)

ACE INHIBITORS (ACEIs) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, using topical capsaicin may increase the risk of ACE inhibitor-induced cough.  Details There is one case report of a topically applied capsaicin cream contributing to the cough reflex in a patient using an ACEI (12414). However, it is unclear if this interaction is clinically significant.

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, capsicum may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details In vitro research shows that capsicum might increase the effects of antiplatelet drugs (12406,12407). Also, population research shows that capsicum is associated with an increased risk of self-reported bleeding in patients taking warfarin (12405,20348). However, clinical research shows that taking a single dose of capsaicin (Asian Herbex Ltd.), the active ingredient in capsicum, 400-800 mcg orally in combination with aspirin 500 mg does not decrease platelet aggregation when compared with taking aspirin 500 mg alone. Also, there was no notable effect on measures of platelet aggregation with capsaicin (92990). It is unclear whether capsaicin must be used in more than a single dose to affect platelet aggregation.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking capsicum with antidiabetes drugs might increase the risk of hypoglycemia.  Details Preliminary clinical research shows that consuming capsicum 5 grams along with a glucose drink attenuates the rise in plasma glucose after 30 minutes by 21%, decreases the 2-hour postprandial area under the curve of plasma glucose by 11%, and increases the 2-hour postprandial area under the curve of plasma insulin by 58% in healthy individuals when compared with placebo (40453,40614). Other clinical research shows that taking capsicum 5 mg daily for 28 days significantly reduces postprandial blood glucose and insulin levels, but not fasting blood glucose and insulin levels, in patients with gestational diabetes (96457).

ASPIRIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking capsicum with aspirin might reduce the bioavailability of aspirin.  Details Animal research shows that acute or chronic intake of capsicum pepper reduces oral aspirin bioavailability (22617). This has not been shown in humans.

CIPROFLOXACIN (Cipro) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking capsicum with ciprofloxacin might increase levels and adverse effects of ciprofloxacin.  Details Animal research shows that concomitant use of capsaicin, the active constituent of capsicum, and ciprofloxacin increases the bioavailability of ciprofloxacin by up to 70% (22613).

THEOPHYLLINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking capsicum with theophylline might increase the levels and adverse effects of theophylline.  Details In animal research, oral administration of capsicum reduced excretion of theophylline (12405). However, capsicum does not seem to affect the pharmacokinetics of theophylline when administered intravenously (22616).

(Read more about CAPSICUM)

ANTICHOLINERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, huperzine A might decrease the effects of anticholinergic drugs.  Details Huperzine A has acetylcholinesterase (AChE) inhibiting effects. In animal models, huperzine A reversed cognitive deficits induced by scopolamine, an anticholinergic drug (3134,3135,55692).

CHOLINERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concurrent use of huperzine A with cholinergic drugs might increase the effects and side effects of these medications.  Details Huperzine A can inhibit acetylcholinesterase (AChE) and might cause cumulative effects if used with cholinergic drugs (3131).

(Read more about HUPERZINE A)

(Read more about LIMONENE)

(Read more about MEDIUM CHAIN TRIGLYCERIDES (MCTs))

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, parsley might increase the risk of bleeding when taken with anticoagulant or antiplatelet drugs.  Details Animal research suggests that parsley has antiplatelet effects (68209).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, parsley might increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Animal research suggests that parsley might decrease blood glucose (13174,68131,68153,68162). Monitor blood glucose levels closely. Dose adjustments might be necessary.

ASPIRIN Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, aspirin might increase the severity of allergic reactions to parsley.  Details In one case, severe urticaria and swelling were reported after taking aspirin with parsley in an individual with a known mild parsley allergy (5054).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, parsley might increase serum levels of CYP1A2 substrates.  Details Laboratory research suggests that parsley can inhibit CYP1A2 (68176).

DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, parsley might enhance or interfere with the effects of diuretic drugs.  Details Animal research suggests that parsley seed extract increases urine elimination (68119). Parsley leaf and root might also interfere with diuretic therapy due their purported aquaretic effects (512).

PENTOBARBITAL (Nembutal) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, parsley might increase the duration of pentobarbital effects.  Details Animal research suggests that parsley juice prolongs the action of pentobarbital, perhaps by decreasing cytochrome P450 levels (25362). It is not known if this occurs in humans or if this applies to other barbiturates or sedatives.

SIROLIMUS (Rapamune) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, large quantities of parsley might increase sirolimus levels.  Details In one case report, an adult female with a history of kidney transplant presented with elevated blood sirolimus levels, approximately 4-7 times greater than previous measures, after daily consumption of a juice containing approximately 30 grams of parsley for 7 days. Sirolimus levels returned to normal a week after the parsley juice was discontinued (106010).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, large amounts of parsley leaf and root might decrease the effects of warfarin.  Details Parlsey contains vitamin K (19).

(Read more about PARSLEY)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, rosemary may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details In vitro and animal research suggests that rosemary inhibits platelet aggregation (18334,18335,18336,18337).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking rosemary with antidiabetes drugs might increase the risk of hypoglycemia.  Details Animal research shows that rosemary extract can decrease blood glucose levels in diabetic models (71821,71923). However, research in humans is conflicting. Although rosemary powder decreased blood glucose levels in healthy adults (105327), no change in blood glucose levels was seen in adults with type 2 diabetes, most of whom were taking antidiabetes drugs (105323,105327).

ASPIRIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, rosemary might have additive effects with salicylate-containing drugs such as aspirin.  Details Rosemary is reported to contain salicylates (18330).

CHOLINE MAGNESIUM TRISALICYLATE (Trilisate) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, rosemary might have additive effects with salicylate-containing drugs such as choline magnesium trisalicylate.  Details Rosemary is reported to contain salicylate (18330).

CYTOCHROME P450 1A1 (CYP1A1) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, rosemary might decrease the levels and clinical effects of CYP1A1 substrates.  Details In vitro research shows that rosemary induces CYP1A1 enzymes (18332,18333). This effect has not been reported in humans.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, rosemary might decrease the levels and clinical effects of CYP1A2 substrates.  Details In vitro research shows that rosemary induces CYP1A2 enzymes (18332,18333). This effect has not been reported in humans.

SALSALATE (Disalcid) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, rosemary might have additive effects with salicylate-containing drugs such as salsalate.  Details Rosemary is reported to contain salicylate (18330).

(Read more about ROSEMARY)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B High doses of safflower oil might increase the risk of bleeding when taken with anticoagulant or antiplatelet drugs.  Details Small clinical studies show that taking safflower oil, approximately 55 grams daily for 2-3 weeks, decreases platelet aggregation (72241,72303). However, taking lower doses of safflower oil, such as 5 grams daily for 4 weeks, does not seem to affect platelet function (66267). In one case report, a 74-year-old male stabilized on warfarin developed urinary tract bleeding and an elevated INR after taking a safflower extract 20 grams daily for 14 days (95939).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, safflower oil might alter the effects of antidiabetes drugs.  Details Some clinical research shows that taking safflower oil 10 grams daily for 3 weeks can increase fasting blood glucose in patients with type 2 diabetes (13146). However, clinical research in patients with metabolic syndrome with or without impaired glucose tolerance shows that taking safflower oil 8 grams daily for 12 weeks reduces fasting glucose levels by around 8 mg/dL (108889). Some clinical research also shows that taking safflower oil 8 grams daily for 16 weeks does not affect fasting glucose levels in patients with type 2 diabetes (94039).

WARFARIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, safflower oil might increase the risk of bleeding when taken with warfarin.  Details In one case report, a 74-year-old male stabilized on warfarin developed urinary tract bleeding and an elevated INR after taking a safflower extract 20 grams daily for 14 days (95939).

(Read more about SAFFLOWER)

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, theacrine might alter the effects of CNS depressants.  Details Animal research shows that low doses of theacrine have sedating effects, whereas high doses might have stimulant effects (88778). Depending on the dose of theacrine used, it might increase or decrease the effects of CNS depressants. However, these effects have not yet been reported in humans.

(Read more about THEACRINE)

(Read more about VITAMIN B12)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, combining yohimbe bark with antiplatelet or anticoagulant drugs might have additive effects; however, this has not been reported in clinical research.  Details Research in healthy adults shows that taking yohimbine, a constituent of yohimbe bark, in doses of 8 mg or more, seems to inhibit platelet aggregation in vitro by binding to the alpha-2 adrenoceptor (86773,86806,86835,86853). The effects of yohimbe bark itself are unclear; yohimbe bark contains 0.6% to 1.38% yohimbine, but it is unclear how much is absorbed (86862,89263).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, yohimbe might reduce the effects of antihypertensive drugs.  Details Yohimbine, a constituent of yohimbe, is an alpha-2 adrenoceptor antagonist and has been reported to increase blood pressure in clinical research. Theoretically, concomitant use of yohimbe and antihypertensive drugs can interfere with blood pressure control (11,17465).

CLONIDINE (Catapres) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, yohimbe might precipitate clonidine withdrawal.  Details Chronic clonidine use can downregulate alpha-2 adrenoreceptors. Animal research and one human case report suggest that concomitant administration of yohimbine, an alpha-2 adrenoceptor antagonist, may precipitate clonidine withdrawal and lead to sympathomimetic toxicity, including hypertensive crisis (111406).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, yohimbe might decrease the levels and clinical effects of CYP1A2 substrates.  Details In vitro research shows that yohimbe extract induces CYP1A2 enzymes (111404).

CYTOCHROME P450 2D6 (CYP2D6) INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B CYP2D6 inhibitors may increase the levels and adverse effects of yohimbine, a constituent of yohimbe.  Details In vitro and clinical research shows that the yohimbe bark constituent, yohimbine, is metabolized by CYP2D6 isoenzymes (105688,105697,105698). Paroxetine, a cytochrome P450 (CYP) 2D6 inhibitor, increases the maximum serum concentration of yohimbine and reduces the clearance of yohimbine compared to yohimbine alone in patients who are extensive CYP2D6 metabolizers. (114932).

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, yohimbe might increase the levels and adverse effects of CYP2D6 substrates.  Details In vitro research suggests that yohimbine, a constituent of yohimbe bark, inhibits CYP2D6 enzyme activity (23117).

CYTOCHROME P450 3A4 (CYP3A4) INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, CYP3A4 inhibitors might increase the levels and adverse effects of yohimbine, a constituent of yohimbe bark.  Details In vitro and clinical research shows that the yohimbe bark constituent, yohimbine, is metabolized by CYP3A4 enzymes (105688,105698). Theoretically, drugs that inhibit CYP3A4 might increase the levels and adverse effects of yohimbine.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, yohimbe might decrease the levels and clinical effects of CYP3A4 substrates.  Details In vitro research shows that yohimbe extract induces CYP3A4 enzymes (111404).

MONOAMINE OXIDASE INHIBITORS (MAOIs) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = D Concomitant use of MAOIs with yohimbe can result in additive effects.  Details Yohimbine, a constituent of yohimbe, has MAO inhibitory effects. At high doses, yohimbine is a non-selective inhibitor of MAO (11,12).

PAROXETINE (Paxil) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Paroxetine decreases the clearance of yohimbine and may increase its effects.  Details Paroxetine, a cytochrome P450 (CYP) 2D6 inhibitor, increases the maximum serum concentration of yohimbine by about 350% and reduces the clearance of yohimbine by about 80% compared to yohimbine alone in patients who are extensive CYP2D6 metabolizers. No significant changes in pharmacokinetic parameters of yohimbine were observed with coadministration of paroxetine in patients who are poor CYP2D6 metabolizers (114932).

PHENOTHIAZINES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, using yohimbine with phenothiazines might have additive effects.  Details Yohimbine, a constituent of yohimbe, has alpha-2 adrenergic antagonist effects. Theoretically, combining it with phenothiazines can cause additive alpha-2 adrenergic antagonism (19).

STIMULANT DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking yohimbe with stimulant drugs can have additive effects.  Details Yohimbine, a constituent of yohimbe, has sympathomimetic effects and increases blood pressure in a dose-dependent manner. Theoretically, taking yohimbe with stimulant drugs can have additive stimulant and hypertensive effects (11,12,105698).

TRICYCLIC ANTIDEPRESSANTS (TCAs) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking yohimbe with TCAs can increase adverse effects.  Details A small clinical study in patients taking TCAs for at least 4 weeks shows that receiving doses of intravenous yohimbine 2.5-20 mg daily for up to 7 days precipitates severe anxiety, agitation, and tremor (105881). The effects of yohimbe bark itself are unclear; oral yohimbe bark contains 0.6% to 1.38% yohimbine, but it is unclear how much is absorbed (86862,89263).

(Read more about YOHIMBE)

General ...Orally, black pepper seems to be well tolerated when used in the amounts found in food or when taken as a medicine as a single dose. Topically and as aromatherapy, black pepper oil seems to be well tolerated.
Most Common Adverse Effects:
Orally: Burning aftertaste, dyspepsia, and reduced taste perception.
Inhalation: Cough.
Serious Adverse Effects (Rare):
Orally: Allergic reaction in sensitive individuals.

Gastrointestinal ...Orally, black pepper can cause a burning aftertaste (5619) and dyspepsia (38061). Single and repeated application of piperine, the active constituent in black pepper, to the tongue and oral cavity can decrease taste perception (29267). By intragastric route, black pepper 1.5 grams has been reported to cause gastrointestinal microbleeds (29164). It is not clear if such an effect would occur with oral administration.

Immunologic ...In one case report, a 17-month-old male developed hives, red eyes, facial swelling, and a severe cough following consumption of a sauce containing multiple ingredients. Allergen skin tests were positive to both black pepper and cayenne, which were found in the sauce (93947).

Ocular/Otic ...Topically, ground black pepper can cause redness of the eyes and swelling of the eyelids (5619).

Pulmonary/Respiratory ...When inhaled through the nose as an olfactory stimulant, black pepper oil has been reported to cause cough in one clinical trial (29162).

(Read more about BLACK PEPPER)

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 (98807,114658).

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).

(Read more about CAFFEINE)

General ...Orally, capsicum is generally well tolerated in amounts typically found in food or when the extract is used in doses of up to 200 mg daily. Topically and intranasally, capsaicin, a constituent of capsicum, is generally well tolerated.
Most Common Adverse Effects:
Orally: Belching, bloating, burning, diarrhea, dyspepsia, gas, headache, mild constipation, nausea, rhinorrhea, skin flushing, and sweating.
Serious Adverse Effects (Rare):
Orally: Cases of myocardial infarction and hypertensive crisis have been reported.

Cardiovascular ...Orally, palpitation was reported in one clinical trial (105196).
One case of myocardial infarction has been reported in a 41-year-old male without cardiovascular risk factors; the event was attributed to the use of an oral capsicum pepper pill that the patient had been taking for weight loss (40768). Another case of coronary vasospasm and acute myocardial infarction has been reported for a healthy 29-year-old male; the event was attributed to the use of a topical capsicum-containing patch that the patient had been applying to the middle of the back for 6 days (40658). Two cases of arterial hypertensive crisis have been reported for individuals who ingested a large amount of peppers and chili peppers the day before. One of the patients also had an acute myocardial infarction, and the other had high levels of thyroid stimulating hormone (40569,40606).

Dermatologic ...Orally, capsicum or its constituent capsaicin may cause urticaria and skin wheals in rare cases (96457,105203).
Topically, capsicum can cause a prickling sensation, itching, pain, burning, edema, stinging, irritation, rash, and erythema. About 1 in 10 patients who use capsaicin topically discontinue treatment because of adverse effects. These effects seem to occur more often with topical formulations containing higher concentrations of capsaicin, the active constituent of capsicum. Side effects tend to diminish with continued use (12401,15260,15261,40358,40439,40483,40547,40676,40682,40719)(40784,40847,92979,92983,92984,96453,105193,105197,105202,111514). In one case, application of a capsaicin 8% patch (Qutenza) for 60 minutes caused a second-degree burn, characterized by burning, erythema, severe pain, and blistering at the administration site. The burn was treated with topical corticosteroids, but 9 months later neuropathic pain persisted, resulting in limited mobility. It is unclear whether the mobility sequalae were caused by topical capsaicin or the patient's pre-existing neurological disorders (111514). Skin contact with fresh capsicum fruit can also cause irritation or contact dermatitis (12408).
Intranasally, capsaicin can cause nasal burning and pain in most patients. It also often causes lacrimation, sneezing, and excessive nasal secretion; however, these side effects appear to diminish with repeat applications (14323,14329,14358). In some cases, the burning sensation disappears after 5-8 applications (14351,14358). In some cases, patients are pretreated with intranasal lidocaine to decrease the pain of intranasal capsaicin treatment. However, even with lidocaine pretreatment, patients seem to experience significant pain (14324).

Gastrointestinal ...Orally, capsicum can cause upper abdominal discomfort, including irritation, fullness, dyspepsia, gas, bloating, nausea, epigastric pain and burning, anal burning, diarrhea, mild constipation, and belching (12403,12410,40338,40427,40456,40503,40560,40584,40605,40665)(40718,40725,40745,40808,40828,96456,96457,105194,105196). There is a case report of a 3-year-old female who experienced a burning and swollen mouth and lips after touching the arm of a parent that had been treated with a capsaicin patch and then placing the fingers in the mouth (105199). Excessive amounts of capsaicin can lead to gastroenteritis and hepatic necrosis (12404). In a case report, a 40-year-old male with diabetes consumed white wine daily and chewed cayenne which was thought to result in black teeth stains and loss of enamel (40809). Some preliminary research links ingestion of capsaicin with stomach and gallbladder cancer; however the link may be due to contamination of capsaicin products with carcinogens (40771).
Topically, capsaicin can cause diarrhea and vomiting (105202).

Immunologic ...In a case report, a 34-year-old female had anaphylaxis involving difficulty breathing and stupor and also urticaria after consuming a red bell pepper, which is in the capsicum genus. The causal chemical was theorized to be 1,3-beta-glucanase (92978). In another case report, a 33-year-old female experienced angioedema, difficulty breathing and swallowing, and urticaria after ingesting raw green and red peppers (92982).

Neurologic/CNS ...Orally, capsicum can cause sweating and flushing of the head and neck, lacrimation, headache, faintness, and rhinorrhea (7005,12410,105196,105203). Topically, applying capsaicin can cause headache (96450,105202). Injection of capsaicin into the intermetatarsal space has also been associated with headache (96454).

Ocular/Otic ...Topically, capsicum can be extremely irritating to the eyes and mucous membranes. Capsicum oleoresin, an oily extract in pepper self-defense sprays, causes intense eye pain. It can also cause erythema, blepharospasm, tearing, shortness of breath, and blurred vision. In rare cases, corneal abrasions have occurred (12408,12409,40345,40348,40383,40720,40857).
Inhalation of capsicum can cause eye irritation, and allergic alveolitis (5885). In a case report, a 38-year-old female had acute anterior uveitis that developed about 12 hours after using a specific patch (Isola Capsicum N Plus) that contained capsaicin 1.5 mg per patch and methyl salicylate 132 mg per patch for neck pain. The uveitis was controlled with topical steroids and did not recur (92977).

Oncologic ...Population research suggests that moderate to high intake of capsaicin, the active constituent of capsicum, is associated with an increased risk of gastric cancer, while low intake is associated with a decreased risk. It is not clear from the study what amount of capsaicin is considered high versus low intake (92988). Additionally, some research suggests that any link may be due to contamination of capsaicin products with carcinogens (40771).

Pulmonary/Respiratory ...Orally, difficulty breathing was reported in a clinical trial (105196).
Topically, nasopharyngitis related to the use of a cream containing capsaicin has been reported (105202).
Inhalation of capsicum and exposure to capsicum oleoresin spray can cause cough, dyspnea, pain in the nasal passages, sneezing, rhinitis, and nasal congestion (5885,15016,40522,40546,40647). In rare cases, inhalation of the capsicum oleoresin or pepper spray has caused cyanosis, apnea, respiratory arrest and death in people. Death was caused by asphyxiation probably due to acute laryngeal edema and bronchoconstriction from inhalation of the capsicum oleoresin spray (40546,40672,40837,40879).
In a case report, a 47-year-old female who was exposed to capsaicin gas for more than 20 minutes experienced acute cough, shortness of breath, short-term chest pain, wheezing, and difficulty breathing for months afterwards (92980). In rare cases, exposure to capsicum oleoresin spray resulted in apnea, pulmonary injury, cyanosis, and even respiratory arrest (40383,40546).

(Read more about CAPSICUM)

General ...Orally, huperzine A seems to be well tolerated. There is currently a limited amount of information about the tolerability of intramuscular huperzine A.
Most Common Adverse Effects:
All ROAs: Huperzine A can cause dose-dependent cholinergic side effects such as blurred vision, constipation, diarrhea, dizziness, dry mouth, insomnia, nausea, sweating, and vomiting.

Cardiovascular ...Orally, huperzine A might cause decreased heart rate (3138,93482). There are two cases reported where consumption of a tea mistakenly brewed from Lycopodium selago, a source of huperzine A, has resulted in significant cholinergic toxicity, including hypertension (13193).

Gastrointestinal ...Orally, huperzine A can cause cholinergic side effects such as nausea, vomiting, diarrhea, and anorexia (93480,93481,93482,93483). Constipation and thirst have also been reported (93482,93483). In two case reports, consumption of a tea mistakenly brewed from Lycopodium selago, a source of huperzine A, has resulted in significant cholinergic toxicity, including vomiting and diarrhea (13193).

Musculoskeletal ...In two case reports, consumption of a tea mistakenly brewed from Lycopodium selago, a source of huperzine A, has resulted in significant cholinergic toxicity, including leg cramps (13193).

Neurologic/CNS ...Orally, huperzine A can cause cholinergic side effects such as dizziness (3140,55613,93481,93482) and sweating (93482). Huperzine A can also cause hyperactivity and insomnia (3138,3140,55613,93482). Fainting has also been reported (4624). In two case reports, consumption of a tea mistakenly brewed from Lycopodium selago, a source of huperzine A, has resulted in significant cholinergic toxicity, including sweating and slurred speech (13193).

(Read more about HUPERZINE A)

General ...Orally, limonene is generally well tolerated. It can cause nausea, vomiting, and diarrhea (12709). Topically, limonene can cause contact dermatitis (12715,12716,99871,99872,99873). Observational research has found that increased exposure to ambient air limonene from household cleaning products is associated with wheezing and asthma, particularly in children (99870).

Dermatologic ...Topically, limonene can cause contact dermatitis (12715,12716,99871,99872,99873). Observational studies have found that 8% to 9.4% of patients with a suspected fragrance allergy have allergic skin reactions to limonene hydroperoxides (99871,99873). In one case, a 35-year-old female presented with lymphomatoid contact dermatitis, characterized by a pruritic skin eruption that covered her abdomen and lower limbs, after exposure to limonene in various personal hygiene and household cleaning products. Patch testing showed a positive reaction to limonene hydroperoxides. The patient's skin lesions cleared with topical corticosteroids, sun exposure, and avoidance of limonene-containing products (99872).

Gastrointestinal ...Orally, limonene can cause nausea, vomiting, and diarrhea (12709).

Pulmonary/Respiratory ...When inhaled, limonene has been linked to wheezing and asthma. Observational research has found that a 100% increase in exposure to ambient air limonene from fragrances and household cleaning products is associated with 17% and 18% greater odds of wheezing and asthma, respectively. This link appears to be even stronger in children (99870).

(Read more about LIMONENE)

General ...Orally, MCTs can cause significant gastrointestinal upset, especially with higher doses.
Most Common Adverse Effects:
Abdominal discomfort, diarrhea, essential fatty acid deficiency, intestinal gas noises, irritability, nausea, reflux, vomiting. Gastrointestinal disturbances are thought to be associated with higher doses of MCT. Since MCTs are fats, excessive consumption can result in weight gain.

Cardiovascular ...There is some concern that MCTs may further increase the risk for hypertriglyceridemia in some preterm infants due to immature lipoprotein lipase activity in these infants. A case of extremely elevated triglyceride levels of 4,736 mg/dL and associated lipemia retinalis has been reported at 43 weeks post-menstrual age (PMA) for a preterm infant born at 30 weeks' gestational age. It was discovered that the baby had been receiving MCT supplements in addition to breast milk starting at 42 weeks' PMA. MCT supplements were discontinued. One month later triglycerides were reduced to 287 mg/dL, and the retinal vasculature had a normal hue. However, at 2-month follow-up, triglyceride levels were elevated to levels higher than normal for age despite MCT discontinuation. Investigators speculated that a genetic disorder of lipid metabolism may also have contributed to the elevated triglyceride levels in addition to use of MCTs (96330).

Gastrointestinal ...Orally, MCTs can cause significant gastrointestinal upset. Diarrhea is the most commonly reported side effect (11723,93737,93738,101967). Other reported side effects include vomiting, irritability, nausea, reflux, abdominal discomfort, intestinal gas noises, and essential fatty acid deficiency (11723,93738,101967). Taking MCTs with food can reduce these adverse effects (93737). Gastrointestinal disturbances are thought to be associated with higher doses of MCT, such as 85 grams (93731).

Other ...Excessive consumption of MCTs can result in weight gain. MCT oil contains 6-8.5 calories per gram. One tablespoon provides about 14 grams and about 115 calories (11724).

(Read more about MEDIUM CHAIN TRIGLYCERIDES (MCTs))

General ...Orally, parsley seems to be well tolerated when used low to moderate doses. Large doses may be unsafe.
Serious Adverse Effects (Rare):
Orally, Hallucinations, hemolytic anemia, hypotension, hepatic impairment, kidney impairment, nephrotic syndrome, paralysis, and thrombocytopenia purpura when taken in very high doses (200 grams parsley oil or 10 grams or more of parsley's apiole or myristicin constituents).

Cardiovascular ...Parsley contains the potentially toxic constituent, myristicin, which can cause significant adverse effects at high doses (11). Adverse effects specifically associated with myristicin include hypotension and bradycardia (4).

Dermatologic ...Orally, parsley oil can cause contact photodermatitis with sun exposure (4).
Topically, parsley can cause contact photodermatitis (4).

Hematologic ...Parsley contains the potentially toxic constituent apiole, which can cause significant adverse effects at high doses (11). Adverse effects specifically associated with more than 10 grams of the constituent apiole include hemolytic anemia and thrombocytopenia purpura (4).

Hepatic ...Parsley contains the potentially toxic constituents, apiole and myristicin, which can cause significant adverse effects at high doses (11). Adverse effects specifically associated with more than 10 grams of the constituent apiole include hepatic dysfunction (4). Adverse effects specifically associated with the constituent myristicin include fatty degeneration of the liver (4).

Immunologic ...A case of anaphylaxis involving severe angioedema leading to unconsciousness has been reported in a woman who consumed parsley 45 minutes prior to symptoms. The patient responded to epinephrine, antihistamines, intravenous fluids, oxygen therapy, and 1 mg/kg methylprednisolone. The woman had consumed one cup of chopped parsley nearly every day for several years, but upon skin testing, the patient tested positive to parsley (92869). There is also a report of lip angioedema after consumption of raw parsley. The patient had anaphylaxis to raw arugula, and reported itchy red lesions after contact with the leaves of either raw parsley or arugula. The patient had positive skin prick tests to both plants. The reaction may have been due to oral allergy syndrome, as the patient could tolerate cooked arugula and parsley, but not raw (92870).

Ocular/Otic ...Parsley contains the potentially toxic constituent, myristicin, which can cause significant adverse effects at high doses (11). An adverse effect specifically associated with the constituent myristicin includes deafness (4).

Psychiatric ...Parsley contains the potentially toxic constituent, myristicin, which can cause significant adverse effects at high doses (11). Adverse effects specifically associated with the constituent myristicin include giddiness and hallucinations (4).

Renal ...Parsley contains the potentially toxic constituents, apiole and myristicin, which can cause significant adverse effects at high doses (11). Adverse effects specifically associated with more than 10 grams of the constituent apiole include nephrosis and kidney irritation (4). Adverse effects specifically associated with the constituent myristicin include fatty degeneration of the kidneys (4).

(Read more about PARSLEY)

General ...Orally, rosemary seems to be well tolerated when used in appropriate medicinal amounts. Undiluted rosemary oil or very large quantities of rosemary leaf should not be consumed. Topically and as aromatherapy, rosemary seems to be well tolerated.

Dermatologic ...Topically, rosemary use can lead to photosensitivity, erythema, dermatitis, and cheilitis in hypersensitive individuals (4,6).

Immunologic ...Topically, allergic reactions can occur. When used in the mouth, lip and gum edema have occurred (101173). When used on the skin, allergic contact dermatitis has occurred, likely due to the constituent carnosol (71715,71924,71926).
Rosemary might also cause occupational asthma. A case of occupational asthma caused by several aromatic herbs including thyme, rosemary, bay leaf, and garlic has been reported. The diagnosis was confirmed by inhalation challenges. Although all of the herbs caused immediate skin reactivity, a radioallergosorbent test (RAST) showed that garlic was the most potent allergen by weight, with rosemary and the other herbs showing less reactivity (783).

Neurologic/CNS ...Orally, the undiluted oil, as well as the camphor constituent of rosemary, might cause seizures (4,5,6,12868).

(Read more about ROSEMARY)

General ...Orally and intravenously, safflower oil seems to be well tolerated.
Serious Adverse Effects (Rare):
Orally: Liver failure.

Dermatologic ...Intravenously, safflower yellow, a constituent of safflower flower, can cause skin rash (94038,94041). In one case, adjusting the rate of the drip improved the rash (94041).

Hepatic ...Orally, safflower oil has been associated with liver failure. There are at least 7 case reports of acute liver failure requiring liver transplant that are probably associated with over-use of safflower oil, usually for weight loss purposes. However, it is not clear what dose or duration of safflower use led to liver failure in these cases (99138).

Immunologic ...Safflower can cause an allergic reaction in individuals sensitive to the Asteraceae/Compositae family. Members of this family include ragweed, chrysanthemums, marigolds, daisies, and many other herbs.

(Read more about SAFFLOWER)

General ...Orally, theacrine seems to be well tolerated. No adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.

(Read more about THEACRINE)

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

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

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

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

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

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

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

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

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

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

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

(Read more about VITAMIN B12)

General ...Orally, there is limited information available about the adverse effects of yohimbe. Yohimbine, a constituent of yohimbe, might be unsafe; most reported adverse effects are dose-related.
Most Common Adverse Effects:
Orally: Yohimbine, a constituent of yohimbe, has been associated with anxiety, agitation, diaphoresis, diarrhea, flushing, headache, hypertension, increased urination, nausea, tachycardia, tremors, vertigo, and vomiting.
Serious Adverse Effects (Rare):
Orally: Yohimbine, a constituent of yohimbe, has been associated with atrial fibrillation, hypertensive crisis, myocardial infarction, and QT interval prolongation.

Cardiovascular ...Orally, yohimbine, a constituent of yohimbe, has been associated with hypertension, especially at higher doses (3312,17465,86801,86802,86804,86811,86820,86822,86834,86856)(86786,86896). A case of hypertensive crisis was reported in a 63-year-old male taking a yohimbine-containing herbal product once daily for one month. The patient was successfully managed with intravenous nitroprusside followed by clonidine (91521). Tachycardia, fluid retention, palpitations, and chest discomfort have also been reported (3312,17465,86786,86793,86801,86802,86804,86822,86843,86854)(86856,86866,86867,86869,86871,86874,86875). Conduction abnormalities have also been reported (86856,86786). There have been some reports of myocardial infarction, atrial fibrillation, and QT interval prolongation (17465). In theory, these effects may also occur with the use of yohimbe bark extract.

Dermatologic ...Orally, yohimbine, a constituent of yohimbe, may cause rash, erythrodermic skin eruption, and exanthema (3312,3971,86804,86896,86878).

Gastrointestinal ...Orally, yohimbine, a constituent of yohimbe, may cause nausea, vomiting, increased salivation, diarrhea, and gastrointestinal distress (3970,17465,49902,86780,86781,86786,86801,86804,86824,86827)(86828,86829,86863,86878,86882,86896).

Genitourinary ...Orally, yohimbine may cause dartos contraction or decreased libido in some patients (86786,86882). A case of severe intractable priapism has been reported for a 42-year-old male who took a supplement containing yohimbe extract the previous day for sexual enhancement. Treatment with phenylephrine 400 mcg was unsuccessful at resolving the priapism, so surgical insertion of a proximal cavernosal spongiosum shunt was needed (86804).

Hematologic ...A case of drug-induced agranulocytosis has been reported following prolonged use of oral yohimbine, a constituent of yohimbe (86877).

Immunologic ...There is one report of a hypersensitivity reaction including fever; chills; malaise; itchy, scaly skin; progressive renal failure; and lupus-like syndrome associated with ingestion of a one-day dose of yohimbine, a constituent of yohimbe (6169).

Musculoskeletal ...Orally, yohimbine, a constituent of yohimbe, may cause muscle aches (86850).

Neurologic/CNS ...Orally, yohimbine, a constituent of yohimbe, has been associated with reports of general central nervous system (CNS) and autonomic excitation, tremulousness, head twitching, seizure threshold changes, enhanced brain norepinephrine release, decreased energy, dizziness, vertigo, and headache (3312,3971,86774,86779,86786,86804,86827,86857,86870,86882)(86883). Cold feet and chills have also been reported with yohimbine (86827,86896). Other adverse reactions include flushing and diaphoresis (17465). Excessive doses of yohimbine can also cause paralysis (11,18). A case of acute neurotoxicity characterized by malaise, vomiting, loss of consciousness, and seizures has been reported for a 37-year-old bodybuilder who ingested a single dose of yohimbine 5 grams. Improvement was seen within 12 hours following treatment with furosemide, labetalol, clonidine, urapidil, and gastrointestinal decontamination (86801).

Psychiatric ...Orally, yohimbine, a constituent of yohimbe, may increase malaise, fatigue, insomnia, restlessness, agitation, and anxiety (3312,3970,3971,17465,86786,86801,86804,86822,86827,86834)(86868,86878,86882,86896). In a clinical study of healthy subjects, administration of yohimbine increased impulsivity, with larger doses increasing impulsivity more than 50% (86784,86810).

Pulmonary/Respiratory ...Orally, yohimbine, a constituent of yohimbe, may cause bronchospasm, tachypnea, cough, and rhinorrhea (17465,86825,86850). A case of sinusitis characterized by pain and discomfort above both eyes has been reported for a 59-year-old male taking yohimbine 5.4 mg three times daily to treat erectile dysfunction. Symptoms resolved within 24 hours of discontinuing yohimbine. The effect was attributed to the alpha-2 adrenergic antagonist effects of yohimbine (94112). Excessive doses of yohimbine can cause respiratory depression (1118).

Renal ...Orally, yohimbine, a constituent of yohimbe, may increase urinary frequency (3312,3970,3971,17465,86804,86827,86850,86861,86882). A case of acute renal failure has been reported for a 42-year-old male taking yohimbine. Normalization of renal function was achieved following 2 weeks of treatment with corticosteroids. The renal dysfunction was attributed to yohimbine-induced systemic lupus erythematosus (6169).

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