Innoshred by INNOSUPPS

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral bitter orange for allergic rhinitis, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Androgenic alopecia. Although there has been interest in using topical bitter orange for androgenic alopecia, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Anxiety. It is unclear if oral bitter orange or aromatherapy with bitter orange is beneficial in patients with anxiety. Details: Aromatherapy with bitter orange has been evaluated for anxiety in hospitalized or recently hospitalized patients. A clinical study in conscious patients admitted to the intensive care unit shows that inhaling bitter orange as aromatherapy for 30 minutes is associated with lower anxiety scores immediately and 3 hours after the intervention, but not at 1 hour after, when compared with placebo. It is unclear if the improvement from baseline differed between groups; baseline anxiety scores were significantly higher in the placebo group (108752). Another clinical study in adults with acute coronary syndrome shows that aromatherapy with bitter orange essential oil 30% for the 2 days immediately after hospitalization improves anxiety scores by 19%, compared with a 6% improvement in those inhaling placebo (101710). Oral bitter orange has also been evaluated in patients with anxiety. A small clinical study in postmenopausal adults with moderate anxiety shows that taking dried bitter orange flower powder 500 mg orally twice daily for 8 weeks reduces anxiety symptoms by about 4% when compared with placebo, as measured on the State-Trait Anxiety Inventory Scale (97256). However, this improvement is not likely to be considered clinically significant.
• Athletic performance. Several small, short-term clinical studies suggest that oral bitter orange does not improve athletic performance, although some conflicting findings exist. Details: One small clinical study in young males who were former athletes shows that taking 100 mg of p-synephrine from bitter orange extract (Advantra Z, Nutratech Inc.), with or without caffeine 100 mg, daily for 4 days increases the number of total repetitions and volume load by 11% during resistance squat exercise performance when compared with placebo. However, there was no difference in ratings of perceived exertion, and only the p-synephrine plus caffeine group showed an increase in mean power and velocity measures (95683). Other small studies have failed to show a benefit, with or without caffeine. One small study of physically active males with habitual caffeine use shows that taking caffeine 100 mg and bitter orange 100 mg once before exercise does not affect peak power, mean power, total work, or perceived effort or fatigue when compared with placebo (101709). Another small clinical study shows that taking p-synephrine (Synephrine HCL 99%, Nutrition Power) 3 mg/kg orally 60 minutes before exercise does not improve jump tests, 60-meter sprints, or 100-meter sprints in healthy sprint athletes (95655). A small clinical study shows that taking a specific caffeine-containing pre-workout supplement (Cellucor C4 Pre-Workout, Nutrabolt) along with bitter orange extract (Nutratech Inc.) as a single dose 30 minutes before exercise does not improve athletic performance during anaerobic cycling or leg and bench press exercises (95657). Also, taking this combination daily for 8 weeks does not improve strength or body composition when compared with placebo (95656).
• Cancer. Although there has been interest in using oral bitter orange to prevent cancer, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Chronic kidney disease (CKD). Although there has been interest in using oral bitter orange for CKD and other kidney and bladder conditions, there is insufficient reliable information about the clinical effects of bitter orange for these conditions.
• Conjunctivitis. Although there has been interest in using topical bitter orange for conjunctivitis, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Constipation. Although there has been interest in using oral bitter orange for constipation, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Diabetes. Oral bitter orange has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in patients with type 2 diabetes shows that drinking a tea made from the leaves of Indian snakeroot and the fruit of bitter orange for 4 months decreases fasting and postprandial glucose levels and glycated hemoglobin (HbA1c) levels when compared with placebo (35751). However, it is unclear if these effects are due to bitter orange, Indian snakeroot, or the combination.
• Diarrhea. Although there has been interest in using oral bitter orange for diarrhea, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Dyspepsia. It is unclear if oral bitter orange is beneficial in patients with dyspepsia. Details: One small clinical trial in patients with functional dyspepsia shows that taking a specific product containing bitter orange in combination with other ingredients (Zhizhu) three times daily for 4 weeks improves symptoms of functional dyspepsia in 67% of patients, compared with 45% of patients taking a similar product containing sweet orange instead of bitter orange (35757).
• Fatigue. Although there has been interest in using oral bitter orange for fatigue, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Flatulence. Although there has been interest in using oral bitter orange for flatulence, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Frostbite. Although there has been interest in using oral bitter orange to prevent frostbite, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Gallbladder disease. Although there has been interest in using oral bitter orange for gallbladder disease, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Headache. Although there has been interest in using topical bitter orange for headache, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Hyperlipidemia. Although there has been interest in using oral bitter orange for hyperlipidemia, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Insomnia. It is unclear if using bitter orange aromatherapy for sleep disturbances is beneficial in postmenopausal or pregnant adults. Details: A small clinical study in postmenopausal adults with sleep disturbances shows that inhaling essential oil of bitter orange 10% as aromatherapy for 5 minutes twice daily for 4 consecutive days each week for 4 weeks does not improve sleep quality when compared with odorless sweet almond oil (108642). Other clinical research in pregnant adults with sleep disturbances shows that inhaling bitter orange essential oil as aromatherapy for 20 minutes twice daily for 1 month improves sleep scores, including sleep duration, latency, and efficiency, when compared with sweet almond oil (110043).
• Obesity. It is unclear if oral bitter orange, or its constituent p-synephrine, is beneficial for obesity. Details: A meta-analysis of clinical trials in adults with or without obesity shows that taking p-synephrine, a constituent of bitter orange, 6-214 mg orally daily for up to 8 weeks does not reduce body weight or fat mass, or alter blood glucose levels, when compared with placebo (109950). Bitter orange has also been studied in combination with other ingredients. One small clinical trial in overweight adults shows that taking a combination of bitter orange 975 mg, caffeine 528 mg, and St. John's wort 900 mg daily along with calorie restriction and exercise reduces body weight when compared with caloric restriction and exercise alone (11268). Another small clinical study in overweight adults shows that taking a specific combination product (Prograde Metabolism, Prograde Nutrition) containing bitter orange, raspberry ketone, caffeine, capsaicin, garlic, ginger, black pepper, cayenne pepper, and chromium along with diet and exercise for 8 weeks reduces body weight, fat mass, and hip and waist girth and increases lean body mass and energy levels when compared with placebo (91291). However, a small clinical trial in overweight and obese adults shows that taking a different combination product (Charge, Labrada), containing bitter orange 150 mg, providing 9 mg synephrine, plus caffeine and several other ingredients twice daily for 8 weeks does not reduce body weight (15381). The effects of bitter orange alone on body weight are unclear.
• Pain (acute). It is unclear if aromatherapy with bitter orange essential oil is beneficial in hospitalized patients with pain. Details: One small clinical trial in conscious patients in intensive care units shows that aromatherapy with bitter orange essential oil for 30 minutes does not reduce pain when compared with placebo (104187).
• Peptic ulcers. Although there has been interest in using oral bitter orange for peptic ulcers, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Premenstrual syndrome (PMS). It is unclear if aromatherapy with bitter orange essential oil is beneficial in patients with PMS. Details: One small clinical trial in healthy female students with PMS shows that inhaling bitter orange blossom 0.5% essential oil as aromatherapy for 5 minutes twice daily for 5 days, starting about one week before menstruation and repeating for two menstrual cycles, improves psychological but not physical symptoms of PMS when compared with aromatherapy with odorless sweet almond oil (98331).
• Pre-procedural anxiety. It is unclear if oral bitter orange or aromatherapy with bitter orange is beneficial for reducing anxiety before surgery. Details: One small clinical study in patients undergoing minor operations shows that taking bitter orange blossom distillate 1 mL/kg two hours prior to surgery reduces preoperative anxiety when compared to baseline. No significant improvements in anxiety were reported in patients taking placebo before surgery (35759). Another small clinical study in patients undergoing coronary angiography shows that inhaling bitter orange essential oil for 15-20 minutes about one hour prior to the procedure reduces anxiety when compared with placebo (104186).
• Pressure ulcers. Although there has been interest in using topical bitter orange for pressure ulcers, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Rheumatoid arthritis (RA). Although there has been interest in using topical bitter orange for RA, there is insufficient reliable information about the clinical effects of bitter orange for this condition.
• Rhinosinusitis. Although there has been interest in using oral bitter orange for rhinosinusitis, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Sexual dysfunction. It is unclear if topical bitter orange oil is beneficial in postmenopausal adults with sexual dysfunction. Details: Preliminary clinical research in postmenopausal adults with sexual dysfunction shows that inhaling bitter orange essential oil 10% as aromatherapy for 5 minutes twice daily, 4 days per week for 4 weeks, improves sexual dysfunction scores by 58% when compared with almond oil. Patients reported improvements in the domains of desire, arousal, lubrication, orgasm, pain, and satisfaction (110042).
• Tinea corporis. It is unclear if topical bitter orange oil is beneficial in patients with tinea corporis. Details: In one small clinical study of patients with either tinea corporis, tina cruris, or tinea pedis, 80% of patients applying a bitter orange oil 25% emulsion three times daily experienced a cure within 1-2 weeks, and 20% experienced a cure within 2-3 weeks. For those applying a solution of bitter orange oil 20% in alcohol, 50% experienced a cure in 1-2 weeks, 30% in 2-3 weeks, and 20% in 3-4 weeks (6972). The validity of these findings is limited by the lack of a comparator group.
• Tinea cruris. It is unclear if topical bitter orange oil is beneficial in patients with tinea cruris. Details: In one small clinical study of patients with either tinea corporis, tina cruris, or tinea pedis, 80% of patients applying a bitter orange oil 25% emulsion three times daily experienced cure within 1-2 weeks, and 20% experienced a cure within 2-3 weeks. For those applying a solution of bitter orange oil 20% in alcohol, 50% experienced a cure in 1-2 weeks, 30% in 2-3 weeks, and 20% in 3-4 weeks (6972). The validity of these findings is limited by the lack of a comparator group.
• Tinea pedis. It is unclear if topical bitter orange oil is beneficial in patients with tinea pedis. Details: In one small clinical study of patients with either tinea corporis, tina cruris, or tinea pedis, 80% of patients applying a bitter orange oil 25% emulsion three times daily experienced cure within 1-2 weeks, and 20% experienced a cure within 2-3 weeks. For those applying a solution of bitter orange oil 20% in alcohol, 50% experienced a cure in 1-2 weeks, 30% in 2-3 weeks, and 20% in 3-4 weeks (6972). The validity of these findings is limited by the lack of a comparator group. More evidence is needed to rate bitter orange 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.

(Read more about CAPSICUM)

POSSIBLY EFFECTIVE

• Hypertension. Oral CLA seems to modestly reduce blood pressure when used along with ramipril. However, oral CLA alone does not seem to reduce blood pressure. Details: A meta-analysis of small clinical trials shows that taking CLA in doses of 1 gram to 10.8 grams daily does not lower systolic or diastolic blood pressure when compared with placebo or a control diet (111053). However, this analysis is limited by the heterogeneous populations in the individual studies. Only one study was specifically conducted in individuals with hypertension (45569). This small clinical trial in individuals with stage one uncontrolled hypertension shows that taking CLA 4.5 grams daily along with ramipril 37.5 mg daily for 8 weeks modestly reduces systolic and diastolic blood pressure when compared with ramipril alone (45569).
• Obesity. In adults and children, oral CLA seems to decrease fat mass by a small amount, including abdominal fat mass. However, it is unclear if oral CLA is beneficial for weight loss, body mass index (BMI) reduction, or improvement of metabolic measures. Details: Taking CLA 3-6.8 grams daily seems to decrease body fat mass, increase lean body mass, and reduce waist and hip circumference in some patients (2819,3153,4947,13137,45295,45303,45685,45799,97003,105809). A meta-analysis of clinical research in adults with overweight or obesity also undergoing an exercise program shows a small effect on body fat reduction, but not body weight or plasma lipids (111056). Most research suggests that doses greater than 3.4 grams daily do not seem to offer any additional benefit when compared with lower doses (2819,2821,3153,4947,10410,11327,13137,45295,45799). Also, supplementing milk with CLA 3 grams daily seems to reduce total fat mass in individuals with overweight when compared with placebo (45331). CLA also seems to reduce hunger and improve satiety and feelings of fullness, but this appetite suppression does not necessarily result in a lower energy intake or improved body weight maintenance (11327). In children with overweight aged 6-10 years, taking CLA 3 grams daily for approximately 7 months seems to reduce body fat, abdominal fat, and peripheral fat percentages when compared with placebo (45713). There is inconsistent evidence regarding the effects of CLA on body weight and BMI, with most research suggesting that CLA does not reduce total body weight or BMI (2819,2821,3153,10410,13137,45007,45679,45790,97003,97006). Also, taking CLA in combination with omega-3 fatty acids or chromium picolinate does not seem to improve BMI and body weight in individuals with overweight or obesity (42627,45431). Although one meta-analysis of clinical research shows that taking CLA 2.4-6 grams daily for 6-12 months increases weight loss by 0.7 kg and fat loss by 1.3 kg when compared with placebo, this effect is small and may not be clinically significant (91585). Also, taking CLA 3.4 grams daily for 1 year does not seem to prevent weight or body fat regain in individuals with overweight who previously lost some of their initial body weight (45083,45221). However, one study shows that taking CLA 8 grams daily for 16 weeks seems to reduce BMI in obese, postmenopausal adults with type 2 diabetes (45614). Some studies have evaluated the consumption of CLA-enriched fatty foods. In males with overweight, consuming butter enriched with CLA does not seem to have beneficial metabolic effects (45192). Also, in individuals with overweight or obesity, consuming a goat cheese naturally enriched in CLA and omega-3 fatty acids for 12 weeks does not seem to improve BMI, fat mass, or weight, or most metabolic measures, including fasting glucose, blood pressure, or inflammatory factors, when compared to a control goat cheese. However, there was an increase in total cholesterol, possibly related to an increase in high-density lipoprotein (HDL) cholesterol, and reduced levels of C-reactive protein (CRP) (105808). There is evidence that the isolated trans-10,cis-12 isomer of CLA can increase hyperproinsulinemia and insulin resistance in patients with abdominal obesity (2821,13026,13137). Hyperproinsulinemia is an independent risk factor for type 2 diabetes and cardiovascular disease. Therefore, CLA might not be a good choice for obese patients. However, most commercial CLA products contain a mixture of CLA isomers. It is not known if these mixed CLA isomer products carry this risk. One meta-analysis of clinical research shows that insulin resistance is modestly reduced when a CLA supplement is taken by adults undergoing an exercise program when compared with exercise alone (111056).

POSSIBLY INEFFECTIVE

• Common cold. Oral CLA does not seem to be beneficial for common cold prevention or treatment. Details: Some clinical research shows that taking CLA 2 grams daily does not reduce the risk of developing a cold or reduce cough or sore throat severity in individuals with a common cold when compared with placebo (45577).
• Diabetes. Oral CLA does not seem to be beneficial for diabetes. Details: Some clinical research shows that taking CLA 6.4 grams daily for 16 weeks does not improve fasting glucose, postprandial glucose, or insulin in individuals with type 2 diabetes when compared with safflower oil (45614,45835).
• Hyperlipidemia. Oral CLA does not seem to be beneficial for hyperlipidemia. Details: A meta-analysis and individual clinical trials show that taking CLA as supplements or fortified foods does not improve levels of cholesterol or triglycerides (45790,97006,111054). One meta-analysis of small clinical trials in heterogenous populations shows that taking CLA does not improve levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, or triglycerides, and modestly DECREASES levels of high-density lipoprotein (HDL) cholesterol, when compared with taking placebo or a control diet (111054). CLA has generally been taken in doses of 1.4 to 6.8 grams daily for up to 24 weeks (45790,97006,111054). However, research in patients with hyperlipidemia is limited. Most studies have included general populations of healthy adults, patient with type 2 diabetes, or populations with obesity.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). It is unclear if oral CLA is beneficial for reducing symptoms of allergic rhinitis. Details: Clinical research shows that taking CLA 2 grams daily for 12 weeks improves overall well-being in patients with birch pollen allergy when compared with placebo, but does not improve eye or total allergy symptoms (45395).
• Asthma. It is unclear if oral CLA is beneficial for reducing symptoms of asthma. Details: A small clinical trial in patients with mild asthma shows that taking CLA 4.5 grams daily for 12 weeks improves airway hypersensitivity and tolerance to strenuous exercise when compared with placebo, but without significantly reducing the need to use rescue bronchodilators or improving lung capacity (45787). In addition, a small clinical trial in children 6-18 years of age with allergic asthma shows that taking CLA 3 grams daily for 12 weeks does not reduce the use of emergency bronchodilators or improve peak expiratory flow, forced expiratory volume (FEV1), or vital lung capacity when compared with placebo (97005).
• Atherosclerosis. Although there is interest in using oral CLA for preventing atherosclerosis, there is insufficient reliable information about the clinical effects of CLA for this purpose.
• Athletic performance. It is unclear if oral CLA is beneficial for improving athletic performance. Details: Some preliminary clinical research in student athletes shows that taking CLA powder (CLAce Powder, The Nisshin OilliO Group, Ltd.) 900 mg daily for 14 days increases time to exhaustion during exercise by an average of 179 seconds, but does not reduce rate of perceived exertion, when compared with placebo (97002). Other small clinical trials show that taking a specific product containing CLA oil (Clarinol A-80, Stepan Specialty Products, LLC) 5.63 grams daily for 6 weeks in combination with aerobic training does not improve muscle endurance, muscle power, peak oxygen uptake, or cardiorespiratory fatigue threshold when compared with placebo in untrained to moderately trained males (91587,91588).
• Breast cancer. It is unclear if dietary CLA is beneficial for preventing breast cancer. Details: Some observational research has found that a higher intake of CLA in foods, particularly cheese, is linked with a lower risk of developing breast cancer in postmenopausal individuals (5058). However, other population research has found that intake of CLA is not associated with a reduced risk of breast cancer (45609). Furthermore, some epidemiological evidence has found that CLA intake might be weakly associated with an increased risk of breast cancer (45048).
• Cognitive function. It is unclear if oral CLA is beneficial for improving cognitive function in older adults. Details: Preliminary clinical research in older adults shows that taking CLA 1.75 grams twice daily for 6 weeks may modestly improve verbal learning and recall in males, but not females, when compared with placebo (97008).
• Colorectal cancer. It is unclear if dietary CLA is beneficial for preventing colorectal cancer. Details: Epidemiological research has found that high dietary intake of CLA might reduce the risk of colorectal cancer in females by up to 39% (13775). It is not known if taking CLA supplements is associated with a reduced risk of colorectal cancer.
• Metabolic syndrome. It is unclear if oral CLA is beneficial for metabolic syndrome. Details: Evidence from a small clinical trial shows that taking CLA 3 grams daily orally for 90 days, along with a hypocaloric diet, decreases body fat mass by approximately 3% when compared to baseline in females with metabolic syndrome. However, this reduction does not appear to be significant when compared with placebo treatment, and CLA does not lower blood lipid levels or blood pressure (91586).
• Muscle strength. It is unclear if oral CLA is beneficial for increasing muscle strength. Details: Some preliminary clinical research shows that adding CLA 6 grams to supplementation with creatine 9 grams and whey protein 36 grams daily for 12 weeks modestly enhances strength improvement and lean tissue mass when compared with placebo in adults participating in strength training (45596). However, other clinical research shows that taking CLA 5 grams daily for 7 weeks does not improve most measures of strength in adults participating in resistance training when compared with placebo, although bench press strength was modestly improved in males, and lean tissue mass and fat mass were also improved (45222). Other clinical research shows that taking CLA 6 grams daily for 4 weeks does not improve body composition or strength in resistance-trained athletes (45041). The reasons for these discrepancies are unclear, but may be related to the duration of treatment.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral CLA is beneficial for NAFLD. Details: Preliminary clinical research shows that taking CLA (Nutrifit, Nutricentury) 1 gram three times daily in conjunction with a weight loss diet for 8 weeks reduces fat mass, low-density lipoprotein (LDL) cholesterol levels, and alanine aminotransferase (ALT) levels and increases muscle mass when compared with a weight loss diet alone in obese adults with NAFLD. CLA was also associated with a reduction in glycated hemoglobin, but with no corresponding reduction in fasting plasma glucose (97004).
• Physical performance. It is unclear if oral CLA is beneficial for improving physical performance in older adults. Details: Preliminary clinical research in adults 65-85 years of age shows that taking CLA 1.75 grams twice daily for 6 weeks does not improve handgrip strength or hand discomfort when compared with placebo (97008).
• Rheumatoid arthritis (RA). It is unclear if oral CLA is beneficial for RA. Details: Preliminary clinical research shows that taking CLA 2.5 grams daily with or without vitamin E 400 mg daily for 12 weeks reduces pain and morning stiffness and reduces erythrocyte sedimentation rate in patients with RA when compared to baseline (45730). The validity of these findings is limited by the lack of a comparator group. More evidence is needed to rate conjugated linoleic acid for these uses.

(Read more about CONJUGATED LINOLEIC ACID (CLA))

There is insufficient reliable information available about the effectiveness of grains of paradise.

(Read more about GRAINS OF PARADISE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alzheimer disease. Although there has been interest in using oral green coffee for Alzheimer disease, there is insufficient reliable information about the clinical effects of green coffee for this condition.
• Diabetes. Although there has been interest in using oral green coffee for diabetes, there is insufficient reliable information about the clinical effects of green coffee for this condition.
• Hypercholesterolemia. It is unclear if oral green coffee is beneficial for hypercholesterolemia. Details: A meta-analysis of small clinical trials shows that taking green coffee extract modestly reduces levels of total and low-density lipoprotein (LDL) cholesterol, and increases levels of high-density lipoprotein (HDL), when compared to placebo. There was no effect on triglyceride levels (111048). These changes are unlikely to be clinically significant. In addition, this analysis is limited by the significant heterogeneity of the patient populations and any effect of green coffee extract in patients with hyperlipidemia is unclear. A small preliminary clinical study included in this meta-analysis in patients with hypercholesterolemia shows that drinking a beverage containing soluble green coffee 0.7 grams and soluble roasted coffee 1.3 grams (containing chlorogenic acids 148.4 mg per serving) three times daily for 8 weeks reduces LDL cholesterol, total cholesterol, and triglycerides when compared with baseline (103957). The validity of this finding is limited by the lack of a comparator group. Furthermore, it is unclear if the benefits are due to green coffee, roasted coffee, or the combination.
• Hypertension. It is unclear if oral green coffee extract is beneficial for lowering blood pressure. Details: Two small clinical studies in Japanese adults with mild, untreated hypertension show that taking green coffee extracts providing 50-140 mg chlorogenic acids daily for 4-12 weeks reduces systolic blood pressure by 5-10 mmHg and diastolic blood pressure by 3-7 mmHg when compared with placebo (17971,17972).
• Metabolic syndrome. Oral green coffee extract seems to improve some, but not all, measures of metabolic syndrome. Details: In patients with metabolic syndrome, clinical research shows that taking green coffee extract (Arjuna Natural Extracts Ltd) 400 mg twice daily for 8 weeks improves some measures of metabolic syndrome when compared with placebo. Systolic blood pressure, fasting blood glucose, insulin resistance, and waist circumference were reduced by a small amount, but there was no effect on glycated hemoglobin, lipid profile, or diastolic blood pressure (104831).
• Obesity. Oral green coffee extract may have a small effect on weight loss. Details: A meta-analysis of 13 clinical studies in patients with overweight or obesity shows that taking either green coffee extract 90-1000 mg, containing chlorogenic acids 30-500 mg, or pure chlorogenic acid 1200 mg daily for 8-12 weeks reduces weight by about 2 kg and body mass index (BMI) by 0.56 kg/m2 when compared with placebo (103954). Individual clinical studies have used a specific green coffee extract (Svetol, Naturex) (17982,17983). In the meta-analysis, there was no clear dose-response relationship (103954). This weight loss is unlikely to be clinically significant. In addition, this analysis is limited by the significant heterogeneity of the included studies and patient populations. In 2014 a trial reporting efficacy of a green coffee extract for treatment of obesity was determined to be "seriously flawed" by the Federal Trade Commission (FTC), resulting in its retraction by the authors and payment of a significant fine by the sponsoring company (Applied Food Sciences, Inc.) (88168,88169). This flawed study was not included in the 2020 meta-analysis (103954). In contrast to these findings, some clinical research has shown that taking green coffee does not reduce body weight. In one study, taking polyphenols 300 mg twice daily alone or in combination with oat-derived beta-glucans does not affect body weight or body composition when compared to baseline (109208). Also, in overweight or obese patients with breast cancer, a small clinical trial shows that taking green coffee extract (Arjuna Natural Extracts Ltd) 400 mg twice daily for 12 weeks does not affect body weight, body composition, or glycemic indices, when compared with placebo (111046).
• Polycystic ovary syndrome (PCOS). It is unclear if oral green coffee extract is beneficial for PCOS. Details: A small clinical trial in patients with PCOS shows that taking green coffee extract (Bonyan Salamat Kasra Company, Iran) 400 mg daily for 6 weeks modestly decreases total cholesterol and triglyceride levels when compared with taking placebo. However, there was no effect on glycemic indices, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or body weight (111047). More evidence is needed to rate green coffee for these uses.

(Read more about GREEN COFFEE)

LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Athletic performance. Although there has been interest in using oral rauwolscine for improving athletic performance, there is insufficient reliable information about the clinical effects of rauwolscine for this use.
• Sexual arousal. Although there has been interest in using oral rauwolscine for sexual arousal, there is insufficient reliable information about the clinical effects of rauwolscine for this condition.
• Obesity. Although there has been interest in using oral rauwolscine for obesity and weight loss, there is insufficient reliable information about the clinical effects of rauwolscine for this condition. More evidence is needed to rate rauwolscine for these uses.

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LIKELY SAFE ...when used orally in amounts commonly found in foods. Bitter orange has Generally Recognized as Safe (GRAS) status in the US (4912,35751).

POSSIBLY SAFE ...when bitter orange essential oil is used topically or by inhalation as aromatherapy (6972,7107,98331,104186,104187,108642).

POSSIBLY UNSAFE ...when used orally for medicinal purposes. Although single doses of synephrine, or low daily doses used short-term, may be safe in healthy adults (2040,11269,15381,35757,35759,91681,97256,98332), laboratory analyses raise concerns that many marketed bitter orange products contain higher amounts of synephrine and other natural and synthetic amines than on the label, increasing the risk for serious stimulant-related adverse effects (104185). Additionally, there is a lack of agreement regarding a safe daily dose of synephrine. Health Canada has approved 50 mg of p-synephrine daily when used alone, or 40 mg of p-synephrine in combination with up to 320 mg of caffeine daily in healthy adults (91684). The Federal Institute for Risk Assessment in Germany recommends that supplements should provide no more than 6.7 mg of synephrine daily. This recommendation is meant to ensure that patients who frequently consume synephrine in conventional foods will receive no more than 25.7 mg daily (91290). These limits are intended to reduce the risk for serious adverse effects. There have been several case reports of ischemic stroke and cardiotoxicity including tachyarrhythmia, cardiac arrest, syncope, angina, myocardial infarction, ventricular arrhythmia, and death in otherwise healthy patients who have taken bitter orange extract alone or in combination with other stimulants such as caffeine (2040,6979,12030,13039,13067,14326,14342,91680).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in the amounts found in foods. Bitter orange has Generally Recognized as Safe (GRAS) status in the US (4912).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally for medicinal purposes. There are case reports of cardiotoxicity including tachyarrhythmia, syncope, and myocardial infarction in otherwise healthy adults who have taken bitter orange extract alone or in combination with other stimulants such as caffeine (2040,6979,12030,13039,13067,14326,14342,91680). The effects of bitter orange during lactation are unknown; avoid use.

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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)

LIKELY SAFE ...when used orally in amounts found in foods. CLA occurs naturally in milk fat, beef, and the meat of other ruminant animals (5924,5925,5932,5933).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts of up to 6. 8 grams daily, short-term (2819,2821,3153,4947,10410,11327,111056).

CHILDREN: LIKELY SAFE
when used orally in amounts found in foods. CLA occurs naturally in milk fat, beef, and the meat of other ruminant animals (5924,5925,5932,5933).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately in medicinal amounts. Some evidence suggests that CLA 3 grams daily can be taken safely for up to 7 months (45713).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts found in foods (5924,5932,5933). There is insufficient reliable information available about the safety of CLA when used in medicinal amounts during pregnancy or lactation; avoid using.

(Read more about CONJUGATED LINOLEIC ACID (CLA))

POSSIBLY SAFE ...when used orally and appropriately, short-term (12). Grains of paradise seed extract 100 mg daily has been used with apparent safety for up to 4 weeks (99890). There is insufficient reliable information available about the safety of grains of paradise when used orally, long-term.

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

(Read more about GRAINS OF PARADISE)

POSSIBLY SAFE ...when used orally and appropriately. Green coffee extracts taken in doses up to 1000 mg daily, providing up to 500 mg chlorogenic acid, have been used with apparent safety for up to 12 weeks in clinical research (17971,17972,103954). A specific green coffee extract (Svetol, Naturex) has been used with apparent safety in doses up to 200 mg five times daily for up to 12 weeks (17981,17982,17983). Green coffee also contains caffeine, although in lower amounts than regular coffee. One cup of green coffee contains about 20-50 mg of caffeine, compared with about 100 mg in one cup of regular coffee. 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). Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine found in ingredients such as green coffee, which naturally contains caffeine, does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product.

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

(Read more about GREEN COFFEE)

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

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

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

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

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

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

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

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

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

(Read more about GREEN TEA)

POSSIBLY UNSAFE ...when used orally. There is insufficient reliable information available about the safety of rauwolscine. However, it is structurally similar to yohimbine, which has been associated with serious adverse effects including cardiac arrhythmia, agitation, myocardial infarction, seizure, and others (17465).

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

(Read more about RAUWOLSCINE)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, bitter orange might increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Some clinical research shows that drinking a tea containing bitter orange and Indian snakeroot reduces fasting and postprandial glucose levels in patients with type 2 diabetes who are using antidiabetes drugs (35751). However, it is unclear if these effects are due to bitter orange, Indian snakeroot, or the combination. An animal study also shows that p-synephrine in combination with gliclazide , a sulfonylurea, causes an additional 20% to 44% decrease in glucose levels when compared with gliclazide alone (95658).

CAFFEINE Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Bitter orange might increase blood pressure and heart rate when taken with caffeine.  Details Small clinical studies show that taking bitter orange in combination with caffeine can increase blood pressure and heart rate in otherwise healthy normotensive adults (13657,95659). Theoretically, this might increase the risk of serious cardiovascular adverse effects.

COLCHICINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Bitter orange might affect colchicine levels.  Details Colchicine is a substrate of P-glycoprotein and cytochrome P450 3A4 (CYP3A4). Bitter orange has been reported to inhibit CYP3A4 and increase levels of CYP3A4 substrates (7029,11362,93470). However, one small clinical study in healthy adults shows that drinking bitter orange juice 240 mL twice daily for 4 days and taking a single dose of colchicine 0.6 mg on the 4th day decreases colchicine peak serum levels by 24%, time to peak serum level by 1 hour, and overall exposure to colchicine by 20% (35762). The clinical significance of this finding is unclear.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, bitter orange might increase levels of drug metabolized by CYP2D6.  Details In vitro research shows that octopamine, a constituent of bitter orange, weakly inhibits CYP2D6 enzymes (91878). This effect 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 = B Bitter orange might increase levels of drugs metabolized by CYP3A4.  Details Small clinical studies suggest that single or multiple doses of freshly squeezed bitter orange juice 200-240 mL can inhibit CYP3A4 metabolism of drugs (7029,11362,93470), causing increased drug levels and potentially increasing the risk of adverse effects. However, the extent of the effect of bitter orange on CYP3A4-mediated drug interactions is unknown. Some evidence suggests that bitter orange selectively inhibits intestinal CYP3A4, but not hepatic CYP3A4. Its effect on P-glycoprotein, which strongly overlaps with CYP3A4 interactions, is unclear (7029,11269,11270,11362). One small clinical study shows that drinking 8 ounces of freshly squeezed bitter orange juice has no effect on cyclosporine, which seems to be more dependent on hepatic CYP3A4 and P-glycoprotein than intestinal CYP3A4 (11270).

DEXTROMETHORPHAN (Robitussin DM, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Bitter orange might increase blood levels of dextromethorphan.  Details One small clinical study shows that bitter orange juice increases dextromethorphan levels, likely through cytochrome P450 3A4 (CYP3A4) inhibition (11362). Theoretically, bitter orange might increase the risk for dextromethorphan-related adverse effects.

FELODIPINE (Plendil) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Bitter orange might increase blood levels of felodipine.  Details One small clinical study shows that bitter orange juice increases felodipine levels, likely through cytochrome P450 3A4 (CYP3A4) inhibition (7029). Theoretically, bitter orange might increase the risk for felodipine-related adverse effects.

INDINAVIR (Crixivan) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Bitter orange might increase blood levels of indinavir.  Details One small clinical study shows that bitter orange juice slightly increases indinavir levels, but this effect is likely to be clinically insignificant. Bitter orange selectively inhibits intestinal cytochrome P450 3A4 (CYP3A4); however, the metabolism of indinavir seems to be more dependent on hepatic CYP3A4 (11269). The effect of bitter orange on other protease inhibitors has not been studied.

MIDAZOLAM (Versed) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Bitter orange might increase blood levels of midazolam.  Details One small clinical study shows that bitter orange juice can increase midazolam levels, likely through inhibition of cytochrome P450 3A4 (CYP3A4) (7029). Theoretically, bitter orange might increase the risk of midazolam-related adverse effects.

MONOAMINE OXIDASE INHIBITORS (MAOIs) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, taking MAOIs with synephrine-containing bitter orange preparations might increase the hypertensive effects of synephrine, potentially leading to hypertensive crisis.  Details Bitter orange contains tyramine, octopamine, and synephrine, which are MAO substrates (11267,11995,12378).

QT INTERVAL-PROLONGING DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, bitter orange might have an additive effect when combined with drugs that prolong the QT interval, potentially increasing the risk of ventricular arrhythmias.  Details One case report suggests that taking bitter orange in combination with other stimulants such as caffeine might prolong the QT interval in some patients (13039).

SILDENAFIL (Viagra) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Bitter orange juice might increase blood levels of sildenafil.  Details A small clinical study in healthy adult males shows that drinking freshly squeezed bitter orange juice 250 mL daily for 3 days and taking a single dose of sildenafil 50 mg on the 3rd day increases the peak plasma concentration of sildenafil by 18% and the overall exposure to sildenafil by 44%. Theoretically, this may be due to inhibition of cytochrome P450 3A4 by bitter orange (93470).

STIMULANT DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, bitter orange might increase the risk of hypertension and adverse cardiovascular effects when taken with stimulant drugs.  Details Bitter orange appears to have stimulant effects (2040,6979).

(Read more about BITTER ORANGE)

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)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, CLA may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Some clinical evidence suggests that intake of CLA reduces platelet aggregation by approximately 10% (45607). The clinical significance of this effect is unclear.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = A Theoretically, taking CLA with antihypertensive drugs might increase the risk of hypotension.  Details Animal research suggests that a particular form of CLA reduces systolic blood pressure (45081). Also, some clinical research shows that CLA enhances the blood pressure-lowering effects of ramipril, an antihypertensive drug (45569).

RAMIPRIL (ALTACE) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = A Theoretically, taking black seed with ramipril might increase the risk of hypotension.  Details Some clinical research shows that CLA enhances the blood pressure-lowering effects of ramipril (45569).

(Read more about CONJUGATED LINOLEIC ACID (CLA))

(Read more about GRAINS OF PARADISE)

ADENOSINE (Adenocard) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, green coffee might decrease the vasodilatory effects of adenosine and interfere with its use prior to stress testing.  Details Green coffee can contain caffeine. Caffeine is a competitive inhibitor of adenosine at the cellular level. However, 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 such as caffeine, as well as 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, alcohol might increase the levels and adverse effects of caffeine.  Details Green coffee can contain caffeine. Concomitant use of alcohol can increase caffeine serum concentrations and the risk of caffeine adverse effects. Alcohol reduces caffeine metabolism (6370,24693).

ALENDRONATE (Fosamax) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, green coffee may decrease the levels and effects of alendronate.  Details In human research, drinking coffee with alendronate reduces the bioavailability of alendronate by 60% (11735). Whether green coffee reduces the bioavailability of alendronate has not been investigated. Separate green coffee ingestion and alendronate administration by two hours.

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, green coffee may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Green coffee can contain caffeine. Caffeine is reported to have antiplatelet activity (8028,8029). Theoretically, caffeine in green coffee might increase the risk of bleeding when used concomitantly with these agents. However, this interaction has not been reported in humans. There is some evidence that caffeinated coffee might increase the fibrinolytic activity in blood (8030).

ANTIDIABETES DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, taking green coffee and antidiabetes drugs might interfere with blood glucose control.  Details In clinical research, green coffee extract results in modest reductions in blood glucose levels in various populations (17982,19327,111049). However, other reports claim that caffeine might increase or decrease blood sugar levels (6024,8646,19329,19330,19331,19332).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking green coffee with antihypertensive drugs might increase the risk of hypotension.  Details Clinical studies have shown that green coffee extract decreases blood pressure (17971,17972). When used with antihypertensive drugs, green coffee might have additive blood pressure-lowering effects. However, this has not been shown in clinical research.

BETA-ADRENERGIC AGONISTS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use of large amounts of green coffee might increase cardiac inotropic effects of beta-agonists.  Details Green coffee can contain caffeine. Caffeine can increase cardiac inotropic effects of beta-agonists (15).

CIMETIDINE (Tagamet) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = B Theoretically, cimetidine might increase the effects and adverse effects of caffeine in green coffee.  Details Green coffee can contain caffeine. Cimetidine can reduce caffeine clearance by 31% to 42% (11736,24700).

CLOZAPINE (Clozaril) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, green coffee might increase the levels and adverse effects of clozapine and acutely exacerbate psychotic symptoms.  Details Green coffee can contain caffeine. Caffeine can increase the effects and toxicity of clozapine. Caffeine doses of 400-1000 mg daily inhibit clozapine metabolism (5051). Clozapine is metabolized by cytochrome P450 1A2 (CYP1A2). Researchers speculate that caffeine might inhibit CYP1A2. However, 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).

CONTRACEPTIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, concomitant use might increase the effects and adverse effects of caffeine found in green coffee.  Details Green coffee can contain caffeine. Oral contraceptives decrease the rate of caffeine clearance by 40% to 65% (2714,11737).

DIPYRIDAMOLE (Persantine) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, green coffee might decrease the vasodilatory effects of dipyridamole and interfere with its use prior to stress testing.  Details Green coffee can contain caffeine. Caffeine is a methylxanthine that may inhibit dipyridamole-induced vasodilation (11770,11772,24974,37985,53795). It is recommended that methylxanthines such as caffeine, as well as methylxanthine-containing products such as green coffee, 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 might increase the levels and adverse effects of caffeine.  Details Green coffee can contain caffeine. In human research, disulfiram decreases the clearance and increases the half-life of caffeine (11840).

DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the risk of hypokalemia.  Details Green coffee can contain caffeine. 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 of stimulant adverse effects.  Details Green coffee can contain caffeine. 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 (1275,6486,9740,10307). Tell patients to avoid taking caffeine with ephedrine and other stimulants.

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 Green coffee can contain caffeine. Estrogen inhibits caffeine metabolism (2714).

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 Green coffee can contain caffeine. Fluconazole decreases caffeine clearance by approximately 25% (11022,24978).

FLUVOXAMINE (Luvox) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, fluvoxamine might increase the levels and adverse effects of caffeine.  Details Green coffee can contain caffeine. Fluvoxamine reduces caffeine metabolism (6370,38287).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, abrupt green coffee withdrawal might increase the levels and adverse effects of lithium.  Details Green coffee can contain caffeine. Abrupt caffeine withdrawal can increase serum lithium levels (609). Two cases of lithium tremor that worsened with abrupt coffee withdrawal have been reported (609,610).

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 Green coffee can contain caffeine. Mexiletine can decrease caffeine elimination by 50% (1260,11741,24981).

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 Green coffee can contain caffeine. 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).

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 Green coffee can contain caffeine. 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, green coffee might reduce the effects of pentobarbital.  Details Green coffee can contain caffeine. Theoretically, caffeine might negate the hypnotic effects of pentobarbital (13742).

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

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 Green coffee contains caffeine. 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 = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, quinolone antibiotics might increase the levels and adverse effects of caffeine.  Details Green coffee can contain caffeine. Concomitant use of quinolones can decrease caffeine clearance and increase effects and risk of adverse effects (606,607,608,23554,23555,23556,24695,24696,24697).

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 Green coffee can contain caffeine. Caffeine and riluzole are both metabolized by cytochrome P450 1A2 (CYP1A2), and concomitant use might reduce 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 Green coffee can contain caffeine. 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 Green coffee can contain caffeine. 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 = B Theoretically, green coffee might increase the levels and adverse effects of theophylline.  Details Green coffee can contain caffeine. Large amounts of caffeine might inhibit theophylline metabolism (11741).

VERAPAMIL (Calan, others) 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 caffeine.  Details Green coffee can contain caffeine. Verapamil increases plasma caffeine concentrations by 25% (11741).

(Read more about GREEN COFFEE)

5-FLUOROURACIL Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, high doses of green tea might increase the effects and side effects of 5-fluorouracil.  Details Animal research shows that taking green tea in amounts equivalent to about 6 cups daily in humans for 4 weeks prior to receiving a single injection of 5-fluorouracil increases the maximum plasma levels of 5-fluorouracil by about 2.5-fold and the area under the curve by 425% (98424).

ADENOSINE (Adenocard) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, green tea might decrease the vasodilatory effects of adenosine and interfere with its use prior to stress testing.  Details Green tea contains caffeine. Caffeine is a competitive inhibitor of adenosine at the cellular level. However, caffeine doesn't 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, alcohol might increase the levels and adverse effects of caffeine.  Details Green tea contains caffeine. Concomitant use of alcohol and caffeine can increase caffeine serum concentrations and the risk of caffeine adverse effects. Alcohol reduces caffeine metabolism (6370).

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, green tea may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Conflicting reports exist regarding the effect of green tea on bleeding risk when used with anticoagulant or antiplatelet drugs; however, most evidence suggests that drinking green tea in moderate amounts is unlikely to cause a significant interaction. Green tea contains small amounts of vitamin K, approximately 7 mcg per cup (100524). Some case reports have associated the antagonism of warfarin with the vitamin K content of green tea (1460,1461,1463,4211,6048,8028,20868). However, these reports are rare, and very large doses of green tea (about 8-16 cups daily) appear to be needed to cause these effects. Furthermore, the catechins and caffeine in green tea are reported to have antiplatelet activity (733,8028,8029,12882,100524).

ANTIDIABETES DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, taking green tea with antidiabetes drugs might interfere with blood glucose control.  Details Concomitant use of green tea and antidiabetes drugs might interfere with blood glucose control. The data are conflicting. Reports claim that green tea and/or caffeine, a constituent of green tea, might increase or decrease blood sugar (6024,8646,54011,54035,54068,90154).

ATORVASTATIN (Lipitor) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Green tea extract seems to reduce the levels and clinical effects of atorvastatin.  Details In healthy humans, taking green tea extract 300 mg or 600 mg along with atorvastatin reduces plasma levels of atorvastatin by approximately 24%. The elimination of atorvastatin is not affected (102714). Atorvastatin is a substrate of organic anion-transporting polypeptides (OATPs). Research shows that two of the major catechins found in green tea, epicatechin gallate (ECG) and epigallocatechin gallate (EGCG), inhibit OATPs. Some OATPs are expressed in the small intestine and are responsible for the uptake of drugs and other compounds, which may have resulted in reduced plasma levels of atorvastatin (19079). It is not clear if drinking green tea alters the absorption of atorvastatin.

BORTEZOMIB (Velcade) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, green tea might interfere with the effects of bortezomib.  Details In vitro research shows that green tea polyphenols, such as epigallocatechin gallate (EGCG), interact with bortezomib and block its proteasome inhibitory action. This prevents the induction of cell death in multiple myeloma or glioblastoma cancer cell lines (17212). Advise patients taking bortezomib, not to take green tea.

CARBAMAZEPINE (Tegretol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, green tea might reduce the effects of carbamazepine and increase the risk for convulsions.  Details Green tea contains caffeine. 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).

CELIPROLOL (Celicard) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, green tea might reduce the levels and clinical effects of celiprolol.  Details In a small human study, taking green tea daily for 4 days appears to decrease blood and urine levels of celiprolol by at least 98% (104607). This interaction is possibly due to the inhibition of organic anion transporting polypeptide (OATP). Green tea catechins have been shown to inhibit organic anion transporting polypeptides (OATP), one of which, OATP1A2, is found in the intestine (19079,19080,98461) The interaction is thought to be due primarily to the epigallocatechin gallate (EGCG) content of green tea (98461).

CIMETIDINE (Tagamet) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = B Theoretically, concomitant use might increase the effects and adverse effects of caffeine in green tea.  Details Green tea contains caffeine. Cimetidine can reduce 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 Theoretically, green tea might increase the levels and adverse effects of clozapine and acutely exacerbate psychotic symptoms.  Details Animal research suggests that, although green tea extract does not affect the elimination of clozapine, it delays the time to reach peak concentration and reduces the peak plasma levels (90173). Also, concomitant administration of green tea and clozapine might theoretically cause acute exacerbation of psychotic symptoms due to the caffeine in green tea. Caffeine can increase the effects and toxicity of clozapine. Caffeine doses of 400-1000 mg daily inhibit clozapine metabolism (5051). Clozapine is metabolized by cytochrome P450 1A2 (CYP1A2). Researchers speculate that caffeine might inhibit CYP1A2. However, there is no reliable evidence that caffeine affects CYP1A2. There is also speculation that genetic factors might make some patients be more sensitive to the interaction between clozapine and caffeine (13741).

CONTRACEPTIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, concomitant use might increase the effects and adverse effects of caffeine found in green tea.  Details Green tea contains caffeine. Oral contraceptives can decrease caffeine clearance by 40% to 65% (8644).

CYTOCHROME P450 1A2 (CYP1A2) INHIBITORS 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 caffeine.  Details Green tea contains caffeine. Caffeine is metabolized by cytochrome P450 1A2 (CYP1A2) (3941,5051,11741,23557,23573,23580,24958,24959,24960,24962), (24964,24965,24967,24968,24969,24971,38081,48603). Theoretically, drugs that inhibit CYP1A2 may decrease the clearance rate of caffeine from green tea and increase caffeine levels.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Green tea is unlikely to produce clinically significant changes in the levels and clinical effects of CYP3A4 substrates.  Details In vitro and in vivo research suggests that green tea can inhibit intestinal CYP3A and induce hepatic CYP3A4 enzymes (20896,53747,53835,90170). However, this effect is unlikely to be clinically significant, as green tea does not appear to affect CYP3A4 activity in humans (14429,90170).

DIPYRIDAMOLE (Persantine) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, green tea might decrease the vasodilatory effects of dipyridamole and interfere with its use prior to stress testing.  Details Green tea contains caffeine. Caffeine might inhibit 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 might increase the risk of adverse effects from caffeine.  Details In human research, disulfiram decreases the clearance and increases the half-life of caffeine (11840).

DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, using green tea with diuretic drugs might increase the risk of hypokalemia.  Details Green tea contains caffeine. In excessive amounts, caffeine 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 Green tea contains caffeine. 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 (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 Green tea contains caffeine. Estrogen inhibits caffeine metabolism (2714).

ETHOSUXIMIDE (Zarontin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, green tea might reduce the effects of ethosuximide and increase the risk for convulsions.  Details Green tea contains caffeine. 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, green tea might reduce the effects of felbamate and increase the risk for convulsions.  Details Green tea contains caffeine. 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.

FEXOFENADINE (Allegra) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Green tea can decrease blood levels of fexofenadine.  Details Clinical research shows that green tea can significantly decrease blood levels and excretion of fexofenadine. Taking green tea extract with a dose of fexofenadine decreased bioavailability of fexofenadine by about 30%. In vitro, green tea inhibits the cellular accumulation of fexofenadine by inhibiting the organic anion transporting polypeptide (OATP) drug transporter (111029). Research shows that two of the major catechins found in green tea, epicatechin gallate (ECG) and epigallocatechin gallate (EGCG), inhibit OATPs, specifically OATP1A2, OATP1B1, and OATP2B1. In addition, green tea has been shown to reduce the absorption of some drugs that are OATP substrates (19079,102714,102730).

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

FLUTAMIDE (Eulexin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, green tea might increase the levels and adverse effects of flutamide.  Details Green tea contains caffeine. In vitro evidence suggests that caffeine can inhibit the metabolism of flutamide (23553). Theoretically, concomitant use of caffeine and flutamide might increase serum concentrations of flutamide and increase the risk adverse effects.

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 Green tea contains caffeine. Fluvoxamine reduces caffeine metabolism (6370).

HEPATOTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, concomitant use might have additive adverse hepatotoxic effects.  Details Green tea extract supplements have been linked to several cases of hepatotoxicity and might have additive hepatotoxic effects with other drugs. (14136,14310,53740,53742,53746,53752,53775,54016,15026,54027)(93256,102722,111644).

IMATINIB (Gleevec) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, green tea might reduce the levels and clinical effects of imatinib.  Details In animal research, a single dose of green tea extract reduces the area under the curve (AUC) of imatinib by up to approximately 64% and its main metabolite N-desmethyl imatinib by up to approximately 81% (104600). This interaction has not been shown in humans. The mechanism of action is unclear but may involve multiple pathways.

LISINOPRIL Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, green tea might reduce the levels and clinical effects of lisinopril.  Details Preliminary clinical research shows that a single dose of green tea extract reduces plasma concentrations of lisinopril. Compared to a control group, peak levels and area under the curve (AUC) of lisinopril were reduced by approximately 71% and 66%, respectively (104599). This may be due to inhibition of organic anion transporting polypeptides (OATP) by green tea catechins (19079,19080,98461) The interaction is thought to be due primarily to the epigallocatechin gallate (EGCG) content of green tea (98461).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, abrupt green tea withdrawal might increase the levels and adverse effects of lithium.  Details Green tea contains caffeine. Abrupt caffeine withdrawal can increase serum lithium levels (609). Two cases of lithium tremor that worsened with abrupt coffee withdrawal have been reported (610).

METFORMIN (Glucophage) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, metformin might increase the levels and adverse effects of caffeine.  Details Green tea contains caffeine. Animal research suggests that metformin can reduce caffeine metabolism (23571). Theoretically, concomitant use can increase caffeine serum concentrations and the risk of caffeine adverse effects.

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 Green tea contains caffeine. Methoxsalen can reduce caffeine metabolism (23572). Concomitant use can increase caffeine serum concentrations and the risk of caffeine adverse effects.

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 Green tea contains caffeine. Mexiletine can decrease caffeine elimination by 50% (1260).

MIDAZOLAM (Versed) Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, green tea might increase the levels and adverse effects of midazolam.  Details Animal research suggests that green tea extract can increase the maximum plasma concentration, but not the half-life, of oral midazolam. This effect has been attributed to the inhibition of intestinal cytochrome P450 3A4 (CYP3A4) and induction of hepatic CYP3A4 enzymes by green tea constituents (20896). However, it is unlikely that this effect is clinically significant, as the dose used in animals was 50 times greater than what is commonly ingested by humans.

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 Green tea contains caffeine. 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.

NADOLOL (Corgard) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Green tea seems to reduce the levels and clinical effects of nadolol.  Details Preliminary clinical research shows that green tea consumption reduces plasma concentrations of nadolol. Compared to a control group, both peak levels and total drug exposure (AUC) of nadolol were reduced by approximately 85% in subjects who drank green tea daily for two weeks. Drinking green tea with nadolol also significantly reduced nadolol's systolic blood pressure lowering effect (19071). Other clinical research shows that a single dose of green tea can affect plasma nadolol levels for at least one hour (102721). Green tea catechins have been shown to inhibit organic anion transporting polypeptides (OATP), one of which, OATP1A2, is involved in the uptake of nadolol in the intestine (19071,19079,19080,98461) The interaction is thought to be due primarily to the epigallocatechin gallate (EGCG) content of green tea (98461).

NICARDIPINE (Cardene) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, green tea might increase the levels and adverse effects of nicardipine.  Details Green tea contains EGCG. Animal research shows that EGCG increases the area under the curve (AUC) and absolute oral bioavailability of nicardipine. The mechanism of action is thought to involve inhibition of both intestinal P-glycoprotein and hepatic cytochrome P450 3A (90136). The effect of green tea itself on nicardipine is unclear.

NICOTINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use might increase the risk of hypertension.  Details Green tea contains caffeine. 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).

NINTEDANIB (Ofev) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Green tea seems to reduce the levels of nintedanib.  Details Clinical research shows that green tea can significantly decrease blood levels of nintedanib. Taking green tea extract twice daily for 7 days 30 minutes prior to a meal along with nintedanib with the meal decreased the 12-hour area under the curve (AUC) values for nintedanib by 21%. There was no effect on the maximum concentration of nintedanib (111028).

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, green tea might reduce the absorption of organic anion-transporting polypeptide (OATP) substrates.  Details OATPs are expressed in the small intestine and liver and are responsible for the uptake of drugs and other compounds. Research shows that two of the major catechins found in green tea, epicatechin gallate (ECG) and epigallocatechin gallate (EGCG), inhibit OATPs, specifically OATP1A2, OATP1B1, and OATP2B1. In addition, green tea has been shown to reduce the absorption of some drugs that are OATP substrates, including lisinopril, and celiprolol (19079,102714,102730).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Green tea might increase the levels and adverse effects of P-glycoprotein (P-gp) substrates.  Details In vitro research and case reports suggest that green tea inhibits drug efflux by P-gp, potentially increasing serum levels of P-gp substrates. Case reports from the World Health Organization (WHO) adverse drug reaction database describe increased toxicity in patients taking green tea and certain P-gp substrates (111644).

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

PHENOBARBITAL (Luminal) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, green tea might reduce the effects of phenobarbital and increase the risk for convulsions.  Details Green tea contains caffeine. Animal research suggests that caffeine can decrease the anticonvulsant activity of phenobarbital (23558,23559,23561). 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 Green tea contains caffeine. Phenothiazines 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 Green tea contains caffeine. 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, green tea might reduce the effects of phenytoin and increase the risk for convulsions.  Details Green tea contains caffeine. 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, green tea might increase the levels and clinical effects of pioglitazone.  Details Green tea contains caffeine. 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 Green tea contains caffeine. 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 Green tea contains caffeine. Caffeine and riluzole are both metabolized by cytochrome P450 1A2, and concomitant use might reduce metabolism of one or both agents (11739).

ROSUVASTATIN (Crestor) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, green tea extract might alter the absorption and distribution of rosuvastatin.  Details In animal research, giving green tea extract with rosuvastatin increased plasma levels of rosuvastatin. Rosuvastatin is a substrate of organic anion-transporting polypeptide (OATP)1B1, which is expressed in the liver. The increased plasma levels may have been related to inhibition of OATP1B1 (102717). However, in humans, taking EGCG with rosuvastatin reduced plasma levels of rosuvastatin, suggesting an inhibition of intestinal OATP (102730). It is not clear if drinking green tea alters the absorption of rosuvastatin.

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

THEOPHYLLINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, green tea might increase the levels and adverse effects of theophylline.  Details Green tea contains caffeine. 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, green tea might increase the levels and adverse effects of tiagabine.  Details Green tea contains caffeine. 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 Green tea contains caffeine. 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, green tea might reduce the effects of valproate and increase the risk for convulsions.  Details Green tea contains caffeine. 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, concomitant use might increase the levels and adverse effects of both verapamil and caffeine.  Details Animal research suggests that the green tea constituent EGCG increases the area under the curve (AUC) values for verapamil by up to 111% and its metabolite norverapamil by up to 87%, likely by inhibiting P-glycoprotein (90138). Also, theoretically, concomitant use of verapamil and caffeinated beverages such as green tea might increase plasma caffeine concentrations and the risk of adverse effects, due to the caffeine contained in green tea. Verapamil increases plasma caffeine concentrations by 25% (11741).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, green tea may increase the risk of bleeding if used with warfarin.  Details Conflicting reports exist regarding the potential of green tea to antagonize the effect of warfarin; however, most evidence suggests that drinking green tea in moderation is unlikely to cause a significant interaction. Green tea contains a small amount of vitamin K, approximately 7 mcg per cup (100524). Some case reports have associated the antagonism of warfarin with the vitamin K content of green tea (1460,1461,1463,4211,6048,8028,20868). However, these reports are rare, and very large doses of green tea (about 8-16 cups daily) appear to be needed to cause these effects (1460,1461,1463,8028). Therefore, use of green tea in moderate amounts is unlikely to antagonize the effects of warfarin; however, very large doses should be avoided.

(Read more about GREEN TEA)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, rauwolscine may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Rauwolscine is structurally related to yohimbine. In vitro research shows that yohimbine inhibits platelet aggregation (86773,86806,86835,86853).

CALCIUM CHANNEL BLOCKERS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, rauwolscine may have additive coronary vasodilatory effects if used with calcium channel blockers.  Details In vitro, rauwolscine inhibits calcium influx in aortic smooth muscle cells (103576).

CLONIDINE (Catapres) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, rauwolscine may inhibit the effects of clonidine.  Details In animal research, rauwolscine antagonized the effects of clonidine (103578,103580,103581).

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, rauwolscine might increase levels of drugs metabolized by CYP2D6.  Details Rauwolscine is structurally related to yohimbine. In vitro research shows that yohimbine inhibits CYP2D6 enzyme activity (23117).

SEIZURE THRESHOLD LOWERING DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking rauwolscine with seizure threshold lowering drugs might increase the risk of adverse convulsant effects.  Details In animal research, intraperitoneal rauwolscine lowered the seizure threshold level of the drug metrazol (103574).

STIMULANT DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking rauwolscine with stimulant drugs might increase the risk of adverse stimulant effects.  Details Rauwolscine has demonstrated stimulant effects in animal research (103574).

(Read more about RAUWOLSCINE)

General ...Orally, bitter orange might be unsafe when used in medicinal amounts. Topically and when inhaled as aromatherapy, bitter orange seems to be well tolerated.
Most Common Adverse Effects:
Orally: Hypertension and tachycardia, particularly when used in combination with caffeine and/or other stimulant ingredients.
Topically: Skin irritation.
Serious Adverse Effects (Rare):
Orally: Myocardial infarction, QT prolongation, seizures, stroke, syncope, tachyarrhythmia, and ventricular fibrillation have been reported in patients taking bitter orange in combination with other ingredients. It is unclear if these effects are due to bitter orange, other ingredients, or the combination.

Cardiovascular ...Bitter orange, which contains adrenergic agonists synephrine and octopamine, may cause hypertension and cardiovascular toxicity when taken orally (2040,6969,6979). Studies evaluating the effect of bitter orange on cardiovascular parameters have been mixed. Several studies show that taking bitter orange alone or in combination with caffeine increases blood pressure and heart rate. In one clinical study, bitter orange in combination with caffeine increased systolic and diastolic blood pressure and heart rate in otherwise healthy normotensive adults (13657). In another study, a single dose of bitter orange 900 mg, standardized to 6% synephrine (54 mg), also increased systolic and diastolic blood pressure and heart rate for up to 5 hours in young, healthy adults (13774). Using half that dose of bitter orange and providing half as much synephrine, did not seem to significantly increase blood pressure or QT interval in healthy adults (14311). Increased diastolic, but not systolic, blood pressure or heart rate also occurred in a clinical trial involving a specific supplement containing synephrine 21 mg and caffeine 304 mg (Ripped Fuel Extreme Cut, Twinlab) (35743). Synephrine given intravenously to males increased systolic blood pressure, but lacked an effect on diastolic blood pressure or heart rate (12193).
In clinical research and case reports, tachycardia, tachyarrhythmia, QT prolongation, ischemic stroke, variant angina, and myocardial infarction have occurred with use of bitter orange or synephrine-containing multi-ingredient products (12030,13039,13067,13091,13657,14326,35749,91680). In one case report, a combination product containing bitter orange may have masked bradycardia and hypotension while exacerbating weight loss in a 16 year-old female with an eating disorder taking the product for weight loss (35740). From 1998 to 2004, Health Canada received 16 reports of serious adverse cardiovascular reactions such as tachycardia, cardiac arrest, ventricular fibrillation, blackout, and collapse. In two of these cases, the patient died. In almost all of these cases, bitter orange was combined with another stimulant such as caffeine, ephedrine, or both (14342).
Other research has found no significant effect of bitter orange on blood pressure or heart rate. Several clinical studies have reported that, when taken as a single dose or in divided doses ranging from 20-100 mg for one day, p-synephrine had no significant effect on blood pressure, heart rate, electrocardiogram results or adverse cardiovascular events in healthy adults (35772,91681,91681,95659,101708) Similarly, no difference in blood pressure, heart rate or electrocardiogram results were reported when p-synephrine from bitter orange (Advantra Z/Kinetic; Nutratech/Novel Ingredients Inc.) was taken for 6 weeks in healthy patients (11268). Another clinical study showed no significant effect of bitter orange (Nutratech Inc.), standardized to synephrine 20 mg, on blood pressure or heart rate when taken daily for 8 weeks in healthy males (95656). In other research, changes in blood pressure, heart rate, or QTc interval were lacking when bitter orange was given alone or in combination with caffeine and green tea (14311,35753,35755,35764,35769,35770). In one study of healthy adults, taking a single dose of p-synephrine 103 mg actually reduced mean diastolic blood pressure by 0.4-4 mmHg at 1 and 2 hours after administration when compared with placebo (95659).
A meta-analysis of clinical trials in adults with or without obesity suggests that taking p-synephrine 6-214 mg orally daily does not affect blood pressure or heart rate when used short-term, but modestly increases blood pressure and heart rate when taken for 56-60 days (109950).
The effect of bitter orange on blood pressure, heart rate, and electrocardiogram results in patients with underlying conditions, particularly cardiovascular disease, is unknown and requires further study.

Dermatologic ...Photosensitivity may occur, particularly in fair-skinned people (11909). In a clinical trial, topical application with bitter orange essential oil resulted in irritation (6972).

Endocrine ...Some clinical research shows that taking a specific supplement containing 21 mg of synephrine and 304 mg of caffeine (Ripped Fuel Extreme Cut, Twinlab) increases levels of postprandial glucose (35743). Other preliminary clinical research shows that taking a specific pre-workout supplement (Cellucor C4 Pre-Workout, Nutrabolt) along with a bitter orange extract standardized for synephrine 20 mg (Nutratech Inc.) 30 minutes once before exercise causes a significant 12% increase in glucose (95657); however, there is no difference in blood glucose when compared with placebo when this combination is taken daily for 8 weeks (95656). The effect of bitter orange itself is unclear.

Gastrointestinal ...Bitter orange has been linked to a report of ischemic colitis. In one case, a 52-year-old female developed ischemic colitis after taking a bitter orange-containing supplement (NaturalMax Skinny Fast, Nutraceutical Corporation) for a week. Symptoms resolved within 48 hours after discontinuing the supplement (15186). As this product contains various ingredients, the effect of bitter orange itself is unclear.

Musculoskeletal ...Unsteady gait has been noted in one case report of a patient taking bitter orange (13091). In another case, an otherwise healthy, Black male with sickle cell trait, developed severe rhabdomyolysis following ingestion of a specific weight loss product (Lipo 6, Nutrex Research Inc.), which contained synephrine and caffeine (16054). However, other preliminary clinical research shows that taking a specific pre-workout supplement (Cellucor C4 Pre-Workout, Nutrabolt) along with a bitter orange extract standardized for synephrine 20 mg (Nutratech Inc.), taken 30 minutes once before exercise (95657) or daily for 8 weeks, does not affect creatine kinase or serum creatinine levels when compared with placebo (95656). As these products contain various ingredients, the effect of bitter orange itself is unclear.

Neurologic/CNS ...Dizziness, difficulty in concentrating, memory loss, syncope, seizure, and stroke have been noted in case reports following bitter orange administration (13091,13039). Theoretically, bitter orange may trigger a migraine or cluster headache due to its synephrine and octopamine content (35768). When used as aromatherapy, bitter orange essential oil has also been reported to cause headache in some patients (104187). Sprint athletes taking the bitter orange constituent p-synephrine 3 mg/kg (Synephrine HCL 99%, Nutrition Power) 60 minutes before exercises and sprinting reported more nervousness (mean difference 0.9) when compared with placebo on a Likert scale. Although statistically significant, this difference is not considered clinically significant (95655).

(Read more about BITTER ORANGE)

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, CLA is well tolerated when found in foods. When taken in medicinal amounts, CLA seems to be well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, dyspepsia, flatulence, loose stools, and nausea.
Serious Adverse Effects (Rare) :
Orally: Cases of hepatotoxicity have been reported.

Cardiovascular ...Some preliminary clinical research suggests that the t10,c12 isomer of CLA can decrease high-density lipoprotein (HDL) cholesterol levels (2821). This isomer of CLA, as well as a mixture of CLA isomers, seems to increase plasma triglyceride levels, the ratio of low-density lipoprotein (LDL) cholesterol to HDL cholesterol, and the ratio of total cholesterol to HDL cholesterol (45148,45468), although not all research has identified these effects (107475).
A meta-analysis of 6 randomized, controlled trials shows that administration of CLA in individuals who are overweight or obese significantly increases lipoprotein (a) levels, a value associated with increased risk of cardiovascular disease. Subgroup analyses suggest this increase is more prominent in trials that are longer than 6 months in duration and with CLA doses of at least 3.5 grams daily (107475).

Endocrine ...Orally, CLA has been shown to increase insulin resistance and glucose concentrations, as well as decrease insulin sensitivity in some patients, including obese individuals or patients with type 2 diabetes (2821,13026,45145,45152,45513). Some evidence suggests that this effect is isomer-specific and occurs with only the t10,c12 isomer (2821,13026), while other evidence shows that decreased insulin sensitivity may also occur with the c9,t11 isomer or with a 50:50 mixture of c9,t11 and t10,c12 isomers (45145,45152).

Gastrointestinal ...Orally, the most common adverse effect reported with CLA is gastrointestinal upset including diarrhea, constipation, nausea, loose stools, dyspepsia, bloating, and flatulence (3153,4947,45280,45705,45730,111056). Esophageal irritation was reported in one patient who bit open and swallowed a capsule containing CLA (45577).

Hepatic ...Orally, clinical research shows that CLA 3 grams daily for 12 weeks does not affect liver outcome measures (105809). However, there are at least two case reports of hepatotoxicity. Asthenia, jaundice, and pruritus were reported in a 46-year-old female who consumed CLA for two weeks. Abnormal liver enzyme levels returned to normal following discontinuation of CLA supplementation (45483). Hepatotoxicity, presenting as fulminant hepatitis and characterized by anorexia, nausea, jaundice, choluria, and hepatic encephalopathy requiring liver transplantation has also been reported in a 63-year-old female taking a CLA-containing weight-loss supplement for one month (91589).

Musculoskeletal ...Orally, CLA has been reported to cause back ache in one individual in one clinical trial (45787).

Neurologic/CNS ...Orally, CLA may cause headache or fatigue (3153,45787). In one case report, a 50-year-old female presented with headache and subarachnoid hemorrhage due to reversible cerebral vasoconstriction syndrome (RCVS) after taking a combination product containing green tea, L-carnitine, and CLA for one week. At 28 days after discontinuation of the combination product and surgery, angiography showed complete regression of vascular restrictions (97007). It is unclear if this adverse effect was due to CLA, another ingredient in the product, or a combination of ingredients.

Other ...Orally, CLA has been reported to cause halitosis in one patient in one clinical trial (45839).

(Read more about CONJUGATED LINOLEIC ACID (CLA))

General ...Orally, grains of paradise seem to be well tolerated. No adverse effects have been reported in clinical trials (99890,99892); however, a thorough evaluation of safety outcomes has not been conducted.

(Read more about GRAINS OF PARADISE)

General ...Orally, green coffee appears to be well-tolerated. Although green coffee contains caffeine, it is present in small quantities which are less likely to cause adverse effects. Green coffee contains about 20-50 mg caffeine per cup, compared with about 100 mg caffeine per cup of brewed coffee.

Cardiovascular ...Although acute administration of caffeine, a constituent of green coffee, can cause increased blood pressure, regular consumption does not seem to increase either blood pressure or pulse, even in mildly hypertensive patients (1451,1452,2722,13739). Drinking one or more cups daily of caffeinated coffee, such as green coffee, also doesn't seem to increase the risk of developing hypertension in habitual coffee drinkers (8033,13739).
Chlorogenic acids found in green coffee extracts may adversely affect plasma homocysteine levels. In one randomized controlled trial, 2 grams of chlorogenic acids (the amount found in about 1.5 L of strong coffee) daily for one week resulted in a 12% increase in plasma homocysteine levels (8035). However, in another trial of green coffee extract in a dose equivalent to 140 mg of chlorogenic acids daily for 4 months, there was a slight decrease in plasma homocysteine levels from baseline, but this did not differ significantly from placebo treatment (17970).
The diterpenes cafestol and kahweol found in green coffee beans have been implicated in the hypercholesterolemic effects of unfiltered coffee (19336,53599). However, these compounds are removed from some green coffee extracts. For instance, Svetol (Naturex, South Hackensack, NJ) is reported to contain less than 4 ppm of cafestol and kahweol (88171).

Dermatologic ...Positive skin tests and symptoms of contact allergy have been reported in workers exposed to green coffee bean dust (53568,53653).

Endocrine ...Some evidence shows that caffeine, a constituent of green coffee, is associated with fibrocystic breast disease, breast cancer, and endometriosis in females; however, this is controversial since findings are conflicting (8043). 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 increased consumption of caffeine results in increased insulin resistance (91023).