Vanquish Hardcore by MuscleForce

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Obesity. Preliminary clinical research suggests a specific combination product, containing 1,3-DMAA, caffeine, and other ingredients (OxyELITE Pro, USPLabs), could potentially affect weight or body fat loss. Taking a single 2-capsule dose seems to significantly increase calorie expenditure and markers of lipolysis within 1-2 hours compared to placebo in a small sample of healthy, exercise trained men and women (17906). However, in an 8-week trial, taking this supplement did not significantly reduce weight or increase fat loss compared to placebo (17907). In the single-dose trial, taking the supplement significantly increased blood pressure and heart rate, suggesting the potential for adverse cardiovascular effects (17906). However, in an 8-week study, heart rate was significantly increased, but not blood pressure (17907). More evidence is needed to rate 1,3-DMAA for this use.

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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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INSUFFICIENT RELIABLE EVIDENCE to RATE

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

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EFFECTIVE

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

LIKELY EFFECTIVE

• Mental alertness. Oral caffeine increases mental alertness. However, it might not improve performance or accuracy to the same extent achieved through adequate sleep. Details: Consumption of caffeinated beverages or caffeine supplements seems to prevent a decline in alertness and cognitive capacity when consumed throughout the day (4221,4224,36439,37727,37757,37759,38070,38075,38158,91093)(91075). Caffeine appears to be especially effective in individuals that are not regular users (91074). Taking caffeine 100-600 mg can improve alertness and speed following prolonged sleep deprivation but usually does not affect mental performance or accuracy (10205,37716,37755,37806,37992,38007,38035,38139,91049,91072)(103706,112736). Drinking coffee containing caffeine 100 mg prior to a cognitive performance test improves reaction times in people with recent poor sleep quality, and in those with adequate sleep. However, the increase in vigilance occurring in the sleep-deprived people does not bring their performance up to the level seen with adequate sleep. Also, the number of errors made by sleep-deprived people seems to increase, suggesting that caffeine may have a detrimental effect on inhibitory control (98809). Caffeine also appears to reduce cognitive impairment caused by medications such as chlorpheniramine (91058). Combining caffeine with certain other supplements may improve mental performance. Taking caffeine 80 mg with taurine seems to provide a small improvement in mental performance (9899), although this effect is not observed in sleep deprived subjects (38154). Some clinical research shows that combining caffeine 40-75 mg with glucose 37.5 grams or L-theanine 97-100 mg improves mental performance better than placebo or either substance alone (13732,37762,37903,38116); however, other clinical research shows no additional benefit from combining L-theanine and caffeine (91045).

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about CAFFEINE)

POSSIBLY EFFECTIVE

• Cardiovascular disease (CVD). Dietary cocoa seems to be beneficial for CVD prevention. Oral cocoa extract may reduce the risk of CVD-related death, but it is unclear if it can prevent other CVD-related outcomes like myocardial infarction (MI) or stroke. Details: A large clinical trial in adults without CVD shows that taking a specific cocoa extract daily for around 3.5 years reduces the risk of CVD-related death by 27%, but does not reduce the risk of cardiovascular events, including MI or stroke, or overall mortality when compared with placebo. This specific cocoa extract contained 500 mg of flavanols, including 80 mg of epicatechins (108898). In 2023, the US Food and Drug Administration (FDA) approved a qualified health claim stating that very limited scientific evidence suggests that the cocoa flavanols in high flavanol cocoa powder, for products containing at least 4% naturally conserved cocoa flavanols, may reduce the risk of cardiovascular disease (110017). Observational research in adults without CVD has also found that consuming a higher amount of cocoa is associated with a 10% lower risk of CVD and an up to 50% lower risk of CVD-related mortality when compared with consuming lower amounts of cocoa. Consuming more than 90 grams of cocoa per week did not add further benefit (14288,97192). Additional clinical research shows that taking cocoa flavanols 450 mg twice daily for one month improves cholesterol levels and blood pressure values, resulting in improved Framingham Risk Scores in healthy patients. These scores correspond to a 21% decrease in the 10-year risk for coronary heart disease, a 22% decrease in the risk for CVD, a 31% decrease in the risk for MI, and a 30% decrease in the risk for CVD-related mortality (92273). There is also evidence that consuming cocoa might improve flow-mediated dilatation, a measure of endothelial dysfunction. Meta-analyses of clinical research have found that increased cocoa or chocolate intake significantly improves flow-mediated dilatation. This is seen with intakes of 19-54 grams of cocoa daily, 46-100 grams of dark chocolate daily, or cocoa products containing 16.6-1080 mg of flavonoids daily (17187,42059,42137).
• Hypertension. Oral cocoa seems to be beneficial for modestly decreasing blood pressure in hypertensive patients. It is unclear if dietary cocoa is beneficial for preventing hypertension. Details: Overall, clinical research shows that chocolate or cocoa containing 25-1080 mg daily of flavonoids modestly reduces blood pressure in hypertensive patients (14306,15655,15752,42092,42107,42169,97190,103247). Meta-analyses of clinical research show that consuming commercially available dark chocolate or flavanol-enriched chocolate/cocoa products daily for 2-8 weeks reduces systolic blood pressure (SBP) by around 4 mmHg and diastolic blood pressure (DBP) by around 2 mmHg in patients with hypertension when compared to control products with low levels of flavanols or no flavanols (42169,97190). Additionally, a meta-analysis of clinical trials in middle-aged and elderly patients with or without hypertension shows that consuming cocoa products daily for 4-18 weeks reduces SBP and DBP by around 3 mmHg and 1.5 mmHg, respectively, when compared with control products (103249). Blood pressure lowering seems to occur more readily in hypertensive or pre-hypertensive individuals when compared with normotensive individuals (14306,15655,15752,42092,42107,42169,97190,103247). Consumption of cocoa might also reduce the risk of developing hypertension in normotensive patients. Observational research has found that long-term consumption of moderate amounts of cocoa (2.2 grams to 6.1 grams daily) is associated with a 7% lower risk of hypertension when compared with consumption of less than 0.61 grams daily. However, consumption of amounts greater than 6.1 grams daily does not seem to reduce hypertension risk. Also, this benefit seems to be limited to patients consuming cocoa from plain chocolate, as consumption of cocoa from desserts was linked with a 9% greater risk of hypertension (103248).

POSSIBLY INEFFECTIVE

• Hypercholesterolemia. Oral cocoa does not seem to be beneficial for reducing cholesterol levels in patients with hypercholesterolemia. Details: Some preliminary clinical research in healthy, normocholesterolemic males shows that diets high in stearic acid from cocoa butter result in lower cholesterol levels when compared with diets high in myristic acid from dairy butter. However, a diet high in stearic acid from cocoa butter does not significantly lower cholesterol when compared to baseline in this population (15063). A meta-analysis of 10 clinical studies shows that cocoa or dark chocolate can reduce total cholesterol and low-density lipoprotein (LDL) cholesterol in normocholesterolemic patients (42125). However, some preliminary clinical research in patients with hypercholesterolemia shows that drinking a high-flavanol cocoa beverage daily for 6 weeks does not reduce cholesterol when compared with a low-flavanol cocoa beverage (42013). Also, while some clinical research shows that taking cocoa powder 26 grams with sugar daily for 12 weeks can increase high-density lipoprotein (HDL) cholesterol levels when compared with sugar alone in normocholesterolemic and hypercholesterolemic patients (42026), taking cocoa or dark chocolate 13-41 grams daily does not seem to lower total cholesterol or LDL cholesterol in these patients (42026,42029,42225).
• Stretch marks (striae gravidarum). Topical cocoa butter does not seem to be beneficial for preventing stretch marks during pregnancy. Details: Clinical research shows that topical application with a cream containing cocoa butter 25% to the abdomen daily, starting during the second and third trimesters and continuing until delivery, does not prevent stretch marks when compared with a placebo cream (105261). Other clinical research shows that topical application with a cream containing cocoa butter and vitamin E as tocopheryl acetate to the abdomen, breasts, and thighs, daily, starting during the second trimester and continuing until delivery, does not reduce the prevalence or severity of stretch marks when compared to a cream not containing these ingredients (105262). More research is needed in individuals of all skin types.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral cocoa is beneficial for improving cognitive function in healthy older adults. Details: Some small clinical studies in healthy adults over the age of 60 with or without existing cognitive impairment show that sub-chronic intake of cocoa at doses of 45 mg, 520 mg, or 990 mg once daily for 8 weeks, or as a cocoa drink containing flavanols 609 mg daily for 30 days, modestly improves some measures of cognitive function, including task switching, visual attention, and verbal fluency (42184,92269). However, it does not improve performance on the mini mental state exam (92269). Also, one clinical study in healthy adults aged 60 years and older shows that consuming a dark chocolate bar containing 11 grams of cocoa and drinking 237 mL of an artificially sweetened drink containing 11 grams of cocoa daily for 6 weeks does not improve neuropsychological function when compared with placebo (42050). Additional preliminary clinical research in postmenopausal females aged 50-64 years shows that adding chocolate 10 grams daily, containing 99% cocoa, for 6 months does not improve most measures of cognitive function when compared with not taking cocoa (105259). Reasons for the discrepancies are unclear but may relate to the dose of cocoa, the duration of intake, or the specific cognitive testing procedures conducted.
• Age-related testosterone deficiency. Oral cocoa has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy middle-aged adults shows that taking a combination product containing cocoa seed extract and pomegranate rind (Tesnor, Gencor) daily for 56 days increases serum testosterone levels and hand-grip strength and improves measures of sexual function and psychological well-being when compared with placebo (111527). It is unclear if these effects are due to cocoa, pomegranate, or the combination.
• Aging skin. It is unclear if oral cocoa is beneficial for aging skin. Details: Preliminary clinical research in adults with aging skin shows taking a specific product (GliSODin Skin Nutrients Advanced Anti-Aging Formula, Isocell North America Inc.) 780 mg three times daily, containing cocoa extract, as well as superoxide dismutase, krill oil, sea buckthorn, hyaluronic acid, and other nutrients, in combination with daily use of tazarotene cream 0.1%, for 90 days improves fine wrinkling, photodamage, and skin elasticity when compared with tazarotene cream and placebo (91778). Additional preliminary clinical research in patients with photoaged skin shows that drinking a cocoa drink containing 320 mg of flavanols daily for 24 weeks improves wrinkle depth and skin elasticity, but not skin hydration, when compared with placebo (92274).
• Asthma. Although there has been interest in using oral cocoa for asthma, there is insufficient reliable information about the clinical effects of cocoa for this condition.
• Athletic performance. Although there has been interest in using oral cocoa for improving athletic performance, there is insufficient reliable information about the clinical effects of cocoa for this use.
• Atrial fibrillation. It is unclear if dietary cocoa is beneficial for preventing atrial fibrillation. Details: Most population research has found that chocolate consumption is not associated with a reduced risk of atrial fibrillation (97188,97189).
• Chronic fatigue syndrome (CFS). It is unclear if oral cocoa is beneficial for CFS. Details: In patients with CFS, preliminary clinical research shows that consuming 45 grams of a polyphenol-rich chocolate in three divided doses daily for 8 weeks can reduce fatigue by 35%, anxiety by 37%, and depression by 45%, and can increase overall function by 30%, when compared with pretreatment (42116).
• Cirrhosis. It is unclear if oral cocoa is beneficial for cirrhosis. Details: Clinical research shows that consuming a liquid test meal (Ensure Plus) in addition to dark chocolate (Lindt Excellence 85% Cocoa, Lindt & Sprüngli) 0.55 grams/kg can reduce the postprandial increase in hepatic venous pressure gradient in patients with cirrhosis when compared with the test drink alone (42164).
• Cognitive function. Research on the use of oral cocoa for improving cognitive function in healthy adults is conflicting. Details: A large clinical trial in older adults shows that taking cocoa extract containing 500 mg of flavanols daily for 3 years does not improve measures of cognitive function including global cognition, episodic memory, and executive function when compared with placebo, even when taken with a multivitamin-mineral product (Centrum Silver) (111524). Also, in middle-aged participants, clinical research shows that taking 20 grams of a dark chocolate drink mix containing 250 mg or 500 mg of polyphenols as a single dose does not seem to improve measures of cognitive function (92272). In contrast, clinical research in healthy younger individuals shows that consuming a single dose of cocoa flavanols 520-994 mg as a specific powder (Cocoapro) improves some, but not all, measures of cognitive function when examined in a situation of sustained mental effort (42093). Additionally, consuming a single dose of cocoa flavanols 900 mg as a specific powder (Acticoa) seems to improve reaction time during cognitive testing when compared with placebo in healthy adults and patients with type 1 diabetes (103251). However, acute dosing with cocoa flavanols 374-747 mg as specific powders (Acticoa) or cocoa extract capsules (Naturex) does not seem to improve measures of cognitive function, visual working memory, or ability to focus during testing in young people (99984,99985,109448). Reasons for the discrepancies are unclear but may relate to the dose of cocoa, the duration of intake, the level of stress during cognitive testing, or the specific cognitive testing procedures conducted.
• Cognitive impairment. Oral cocoa flavanols have only been evaluated in combination with other ingredients; their effect when used alone is unclear. Details: A large clinical study in adults at least 55 years of age with subjective or mild cognitive impairment shows that consuming dark chocolate containing 500 mg cocoa flavanols and taking fish oil containing DHA 1.1 grams and EPA 0.4 grams daily for 12 months does not improve cognitive function scores when compared with placebo (111453).
• Constipation. Oral cocoa husk has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children with chronic constipation shows that taking 2-4 sachets containing cocoa husk 8-16 grams and beta-fructosans 2-4 grams daily for 4 weeks can reduce hard stools by 45% and reduce transit time by 36 hours when compared with a placebo (42016).
• Diabetes. Several small clinical studies suggest that oral cocoa may cause small but clinically insignificant improvements in glycemic control in patients with diabetes. However, cocoa does not appear to be beneficial for the prevention of diabetes. Details: While some individual studies show conflicting results (97252,99982), two similar meta-analyses of 8-9 small clinical trials in patients with diabetes show that taking cocoa 1-54 grams daily for up to 52 weeks reduces fasting blood glucose by around 7-9 mg/dL and low-density lipoprotein (LDL) cholesterol by around 10-15 mg/dL, but does not improve glycated hemoglobin (HbA1c), insulin levels, blood pressure, total cholesterol, or high-density lipoprotein (HDL) cholesterol, when compared with control (109447,109449). This slight improvement in fasting blood glucose, along with a lack of effect on HbA1c, suggests that cocoa is unlikely to lead to clinically meaningful improvements in glycemic control. Population research has found that eating up to 60 grams of chocolate per week is associated with a lower risk of developing diabetes. Higher consumption was not found to affect diabetes risk (97192). However, secondary analysis of a large clinical study in adults aged 74 on average shows that taking an extract containing cocoa flavanols 500 mg daily, with or without a multivitamin, for about 3.5 years does not reduce the risk of developing self-reported type 2 diabetes when compared with placebo. Subgroup analysis based on body mass index, level of physical activity, or multivitamin consumption did not change results (111619).
• Exercise-induced muscle damage. It is unclear if oral cocoa flavanols are beneficial for preventing exercise-induced muscle damage. Details: Preliminary clinical research shows that taking a single dose of cocoa flavanols (Chococru Extraordinary Flavanol Cocoa) 830 mg or 1245 mg within 5 minutes of a strenuous exercise protocol does not reduce exercise-induced muscle damage over 72 hours when compared with a control providing no cocoa flavanols (105260).
• Fatigue. It is unclear if oral cocoa is beneficial for fatigue. Details: A moderate-size clinical study in otherwise healthy females aged 40-60 years with fatigue shows that consuming a beverage containing cocoa flavanols 240 mg daily for 8 weeks does not improve self-reported fatigue scores when compared with placebo (111620).
• Heart failure. It is unclear if dietary cocoa is beneficial for heart failure prevention. Details: Population research has found that consuming up to 250 grams of chocolate weekly is associated with reduced risk of heart failure. However, consuming 300 grams weekly or more does not appear to affect the risk of heart failure (97187,97191).
• HIV/AIDS-related dyslipidemia. It is unclear if oral cocoa is beneficial for HIV/AIDS-related dyslipidemia. Details: Preliminary clinical research in patients with HIV shows that consuming dark chocolate 65 grams containing cocoa 36 grams for 15 days does not affect low-density lipoprotein (LDL) cholesterol or total cholesterol levels when compared with a white chocolate placebo. However, it slightly increases levels of high-density lipoprotein (HDL) cholesterol (96472).
• Impaired glucose tolerance (prediabetes). It is unclear if oral cocoa is beneficial in patients with prediabetes. Details: A small clinical study in premenopausal adults with overweight or obesity and mild insulin resistance shows that drinking a cocoa drink high in flavanols twice daily for 4 weeks does not improve measures of insulin resistance or insulin-mediated glucose uptake when compared with a low-flavanol cocoa drink (111532).
• Influenza. Although there has been interest in using oral cocoa for influenza, there is insufficient reliable information about the clinical effects of cocoa for this condition.
• Insect repellent. It is unclear if topical cocoa oil is beneficial as an insect repellent. Details: Preliminary clinical research shows that topical application of cocoa oil, 1 mL on each leg and 0.5 mL on each forearm, reduces bites from black flies (Simulium damnosum) by 99% (41954).
• Isolated systolic hypertension. It is unclear if oral cocoa is beneficial for isolated systolic hypertension. Details: Preliminary clinical research shows that consuming 100 grams daily of cocoa polyphenol-rich dark chocolate might modestly reduce systolic and diastolic blood pressure in elderly patients with isolated systolic hypertension (13166).
• Menopausal symptoms. It is unclear if oral cocoa is beneficial for menopausal symptoms. Details: In postmenopausal individuals aged 50-64 years, preliminary clinical research shows that adding chocolate 10 grams daily, containing cocoa 99%, for 6 months reduces body fat mass by approximately 0.6 kg and body fat percentage by 0.8%, and modestly improves some measures of quality of life, when compared with no treatment (105255,105258). However, there was no effect on all measures of quality of life, general menopausal symptoms, weight, body mass index, or most measures of cognitive function (105255,105258,105259).
• Multiple sclerosis (MS). Although there has been interest in using oral cocoa for MS, there is insufficient reliable information about the clinical effects of cocoa for this condition.
• Muscle strength. Oral cocoa seed extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy males shows that taking a combination product containing cocoa seed extract and pomegranate rind extract 400 mg daily for 8 weeks increases testosterone levels, hand grip strength, and upper arm circumference when compared with placebo (108485).
• Nipple fissures. It is unclear if topical cocoa butter is beneficial for the treatment or prevention of nipple fissures. Details: A small clinical study in breastfeeding adults shows that applying topical cocoa butter to the nipple and areola after each breastfeeding session for 10 days immediately postpartum reduces nipple pain, rashes, and cracks when compared with the topical application of the mother's breastmilk (111525). The validity of this study is limited by a lack of blinding and a high dropout rate.
• Obesity. It is unclear if oral cocoa is beneficial for obesity. Details: Preliminary clinical research in overweight or obese premenopausal females shows that following a reduced-calorie diet in addition to consuming two squares of dark chocolate and drinking 8 ounces of a sugar-free cocoa beverage daily for 18 weeks does not increase weight loss when compared with the reduced-calorie diet plus a non-chocolate snack (42130,99983).
• Parkinson disease. It is unclear if oral cocoa is beneficial for Parkinson disease. Details: Preliminary clinical research shows that consuming a single dose of dark chocolate 200 grams containing approximately 80% cocoa does not improve motor function in patients with Parkinson disease when compared with a white chocolate control, although there seems to be some improvements after one hour when compared with baseline (42156).
• Peripheral arterial disease (PAD). It is unclear if oral cocoa is beneficial for PAD. Details: A small clinical study in patients with PAD shows that drinking a flavanol-rich cocoa beverage 15 grams daily for 6 months increases 6-minute walking distance by up to 43 meters when compared with placebo (103250). Cocoa has also been studied in adults with diabetes at risk for developing PAD, with conflicting results. A small clinical study in adults with and without diabetes shows that taking a single dose of cocoa flavanols 790 mg does not improve peripheral microvascular or macrovascular parameters compared with placebo (111529). However, another small clinical study in healthy adults and those with diabetes at risk for PAD shows that taking cocoa flavanols (CocoaVia, Mars Inc) 1350 mg improves endothelial function in the brachial and femoral arteries after 2 hours when compared with placebo, suggesting that cocoa flavanols might reduce the risk of developing PAD in both populations studied (111528). The validity of this study is limited by the small sample size and short study duration.
• Stroke. It is unclear if dietary cocoa is beneficial for stroke prevention. Details: Population research has found that the highest dietary intake of chocolate is associated with a 16% reduced risk of stroke when compared with the lowest intake (97192). More evidence is needed to rate cocoa for these uses.

(Read more about COCOA)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Diabetes. Although there has been interest in using oral diiodothyronine for diabetes, there is insufficient reliable information about the clinical effects of diiodothyronine for this purpose.
• Hyperlipidemia. Although there has been interest in using oral diiodothyronine for hyperlipidemia, there is insufficient reliable information about the clinical effects of diiodothyronine for this purpose.
• Muscle strength. Although there has been interest in using oral diiodothyronine to improve muscle strength, there is insufficient reliable information about the clinical effects diiodothyronine for this purpose.
• Obesity. Although there has been interest in using oral diiodothyronine for weight loss, there is insufficient reliable information about the clinical effects diiodothyronine for this purpose. More evidence is needed to rate diiodothyronine for these uses.

(Read more about DIIODOTHYRONINE)

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

(Read more about GRAINS OF PARADISE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Dry eye. Preliminary clinical research in 14 patients with dry eye syndrome shows that applying 1-2 drops of 15% N,N-DMPEA (AF2975, Angelini Pharmaceuticals, Inc.) into the eye four times daily for 21 days improves tear composition when compared with placebo (95470). More evidence is needed to rate N,N-DMPEA for this use.

(Read more about N,N-DIMETHYLPHENETHYLAMINE (N,N-DMPEA))

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Athletic performance. One small clinical study shows that taking octopamine 150 mg 60 minutes before exercise does not improve endurance or reduce perceived exertion in healthy, active young men when compared with placebo (100089). More evidence is needed to rate octopamine for this use.

(Read more about OCTOPAMINE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Athletic performance. Although there has been interest in using oral phenethylamine for athletic performance, there is insufficient reliable information about the clinical effects of phenethylamine for this purpose.
• Depression. It is unclear if oral phenethylamine is beneficial in patients with depression. Details: A small retrospective review of adults with recurrent major depressive episodes shows that taking phenethylamine 10-60 mg orally daily in addition to selegiline 5 mg orally twice daily for 4 weeks relieves depression in 60% of patients. Of the responding patients, additional treatment with phenethylamine and selegiline for up to 50 weeks appeared to maintain depression relief in 86% of these patients (24338). The validity of this study is limited by its retrospective nature and the lack of a comparator group.
• Obesity. Although there has been interest in using oral phenethylamine for obesity, there is insufficient reliable information about the clinical effects of phenethylamine for this purpose. More evidence is needed to rate phenethylamine for these uses.

(Read more about PHENETHYLAMINE (PEA))

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.

(Read more about RAUWOLSCINE)

LIKELY UNSAFE ...when used orally. 1,3-DMAA is a drug originally used as a stimulant nasal decongestant. There is concern that it increases the risk of serious adverse cardiovascular events, similar to other stimulants such as synephrine in bitter orange and ephedrine alkaloids from ephedra. There are several case reports linking 1,3-DMAA to serious adverse events including lactic acidosis, hemorrhagic stroke, heat stroke, and death (17599,17660,17662,17663,17904,94361,94369,94374). Although some supplement manufacturers claim that 1,3-DMAA is a natural compound found in geranium oil, this has not been verified by laboratory analysis. Some laboratories have not been able to detect 1,3-DMAA in geranium oil (94370,94372). There is concern that some supplement manufacturers may be artificially spiking their supplements with this synthetic drug (17661,17662). The New Zealand government restricted sales of supplements containing 1,3-DMAA to prevent the sale to people under 18 years of age due to concerns about safety (17599). The FDA has declared products containing 1,3-DMAA to be illegal and potential health risks (94383). Avoid using.

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

(Read more about 1,3-DMAA)

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.

(Read more about BITTER ORANGE)

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

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

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

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

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

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

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

(Read more about BLACK PEPPER)

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 and appropriately (13161,14306,14307,14308,15655,15752,17187,92271,92274,103247)(103250,108898). However, cocoa naturally contains caffeine, and caffeine may be unsafe when used orally in doses of more than 400 mg daily (11733,98806). While most cocoa products contain only small amounts of caffeine (about 2-35 mg per serving) (2708,3900), one cup of unsweetened, dry cocoa powder can contain up to 198 mg of caffeine (100515). To be on the safe side, cocoa should be used in amounts that provide less than 400 mg of caffeine daily. Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine naturally found in ingredients such as cocoa does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product. Cocoa and dark chocolate products worldwide also contain heavy metals such as lead and cadmium. In the US, one ounce (approximately 28 grams) of most commercially available dark chocolate products tested contained levels of lead and/or cadmium above the maximum allowable dose level for California, with cadmium levels generally increasing with the percentage of cocoa (109847,109848,109849). Advise patients to consume cocoa in moderation. ...when used topically. Cocoa butter is used extensively as a base for ointments and suppositories and is generally considered safe (11).

CHILDREN: POSSIBLY UNSAFE
when dark chocolate is used orally. Cocoa and dark chocolate products worldwide contain heavy metals such as lead and cadmium. In the US, one ounce (approximately 28 grams) of most commercially available dark chocolate products tested contained levels of lead and/or cadmium above the maximum allowable dose level for California, with cadmium levels generally increasing with the percentage of cocoa (109847,109848,109849). Children are at increased risk of adverse effects from intake of lead and/or cadmium. There is insufficient reliable information available about the safety of other chocolate-based products that typically contain smaller quantities of cocoa.

PREGNANCY: POSSIBLY SAFE
when used orally in moderate amounts. However, due to the caffeine content of cocoa preparations, intake should be closely monitored during pregnancy to ensure moderate consumption. Fetal blood concentrations of caffeine approximate maternal concentrations (4260). Some research has 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). While many cocoa products contain only small amounts of caffeine (about 2-35 mg per serving) (2708,3900), unsweetened, dry cocoa powder can contain up to 198 mg of caffeine per cup (100515). According to a review by Health Canada, and a subsequent large meta-analysis conducted in the US, doses of up to 300 mg daily can be consumed during pregnancy without an increased risk of spontaneous abortion, still birth, preterm birth, fetal growth retardation, or congenital malformations (11733,98806). To be on the safe side, cocoa should be used in amounts that provide less than 300 mg of caffeine daily. 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 cocoa, 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: POSSIBLY UNSAFE
when used orally in large amounts. Caffeine found in cocoa 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). Additionally, high intake of caffeine during pregnancy have been associated with premature delivery, low birth weight, and loss of the fetus (6). While many cocoa products contain only small amounts of caffeine (about 2-35 mg per serving) (2708,3900), unsweetened, dry cocoa powder can contain up to 198 mg of caffeine per cup (100515). To be on the safe side, cocoa should be used in amounts that provide less than 300 mg of caffeine daily (2708). 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 cocoa, 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. Cocoa and dark chocolate products worldwide also contain heavy metals such as lead and cadmium. In the US, one ounce (approximately 28 grams) of most commercially available dark chocolate products tested contained levels of lead and/or cadmium above the maximum allowable dose level for California, with cadmium levels generally increasing with the percentage of cocoa (109847,109848,109849). Large doses or excessive intake of cocoa should be avoided during pregnancy.

LACTATION: POSSIBLY SAFE
when used in moderate amounts or in amounts commonly found in foods. Due to the caffeine content of cocoa preparations, intake should be closely monitored while breastfeeding. During lactation, breast milk concentrations of caffeine are thought to be approximately 50% of serum concentrations. Moderate consumption of cocoa would likely result in very small amounts of caffeine exposure to a nursing infant (6). 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 cocoa, 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.

LACTATION: POSSIBLY UNSAFE
when used orally in large amounts. Consumption of excess chocolate (16 oz per day) may cause irritability and increased bowel activity in the infant (6026). Cocoa and dark chocolate products worldwide also contain heavy metals such as lead and cadmium. In the US, one ounce (approximately 28 grams) of most commercially available dark chocolate products tested contained levels of lead and/or cadmium above the maximum allowable dose level for California, with cadmium levels generally increasing with the percentage of cocoa (109847,109848,109849). Large doses or excessive intake of cocoa should be avoided during lactation.

(Read more about COCOA)

There is insufficient reliable information available about the safety of diiodothyronine.

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

(Read more about DIIODOTHYRONINE)

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)

LIKELY SAFE ...when used in small amounts for flavoring food (95469).

POSSIBLY SAFE ...when used ophthalmically. N,N-DMPEA 15% ophthalmic solution has been used with apparent safety for 21 days (95470).

POSSIBLY UNSAFE ...when used orally in medicinal amounts. There is insufficient reliable evidence regarding the safety of oral N,N-DMPEA in humans. However, one case of hemorrhagic stroke associated with the use of a multi-ingredient supplement (Jacked Power, MM Sports) containing N,N-DMPEA has been reported. While further analysis showed that this supplement actually contained beta-methylphenylethylamine (BMPEA) and not N,N-DMPEA, patients should avoid taking products which include N,N-DMPEA on the label due to the overall lack of safety data and potential risk of unlisted ingredients (89219,95472).

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

(Read more about N,N-DIMETHYLPHENETHYLAMINE (N,N-DMPEA))

POSSIBLY UNSAFE ...when used orally. Octopamine is chemically similar to synephrine, a stimulant that might cause severe adverse effects in some patients. Health Canada states that, based on pharmacology alone, octopamine can likely be used safely at doses of up to 50 mg daily (91684). However, a clinical evaluation of safety outcomes has not been conducted.

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

(Read more about OCTOPAMINE)

POSSIBLY UNSAFE ...when used orally. Preliminary, low-quality clinical research suggests that phenethylamine can be used with apparent safely with medical supervision in doses up to 60 mg daily for up to 50 weeks (24338). However, there are concerns about the use of phenethylamine in dietary supplements. Phenethylamine has stimulant effects similar to amphetamines (29931,29934). A case report has also linked a phenethylamine-containing combination product to tachycardia, anxiety, and agitation (24343).

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

(Read more about PHENETHYLAMINE (PEA))

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)

(Read more about 1,3-DMAA)

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).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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ADENOSINE (Adenocard) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, caffeine might decrease the vasodilatory effects of adenosine and interfere with its use prior to stress testing.  Details Some evidence shows that caffeine is a competitive inhibitor of adenosine and can reduce the vasodilatory effects of adenosine in humans (38172). However, other research shows that caffeine does not seem to affect supplemental adenosine because high interstitial levels of adenosine overcome the antagonistic effects of caffeine (11771). It is recommended that methylxanthines and methylxanthine-containing products be stopped 24 hours prior to pharmacological stress tests (11770). However, methylxanthines appear more likely to interfere with dipyridamole (Persantine) than adenosine-induced stress testing (11771).

ALCOHOL (Ethanol) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase levels and adverse effects of caffeine.  Details Alcohol reduces caffeine metabolism. Concomitant use of alcohol can increase caffeine serum concentrations and the risk of caffeine adverse effects (6370).

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, caffeine may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Caffeine is reported to have antiplatelet activity. Theoretically, it might increase the risk of bleeding when used concomitantly with these agents (8028,8029); however, this interaction has not been reported in humans.

ANTIDIABETES DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, taking caffeine with antidiabetes drugs might interfere with blood glucose control.  Details Data are conflicting. Reports claim that caffeine might increase or decrease blood sugar (6024,8646).

CARBAMAZEPINE (Tegretol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, caffeine might reduce the effects of carbamazepine and increase the risk for convulsions.  Details Animal research suggests that taking caffeine can lower the anticonvulsant effects of carbamazepine and can induce seizures when taken in doses above 400 mg/kg (23559,23561). Human research has shown that taking caffeine 300 mg in three divided doses along with carbamazepine 200 mg reduces the bioavailability of carbamazepine by 32% and prolongs the plasma half-life of carbamazepine 2-fold in healthy individuals (23562).

CIMETIDINE (Tagamet) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = B Theoretically, cimetidine might increase the levels and adverse effects of caffeine.  Details Cimetidine decreases the rate of caffeine clearance by 31% to 42% (11736).

CLOZAPINE (Clozaril) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Caffeine might increase the levels and adverse effects of clozapine and acutely exacerbate psychotic symptoms.  Details Caffeine might increase the effects and toxicity of clozapine. Caffeine doses of 400-1000 mg per day inhibit clozapine metabolism (5051). Clozapine is metabolized by cytochrome P450 1A2 (CYP1A2). Although researchers speculate that caffeine might inhibit CYP1A2, there is no reliable evidence that caffeine affects CYP1A2. There is also speculation that genetic factors might make some patients more sensitive to an interaction between clozapine and caffeine (13741). In one case report, severe, life-threatening clozapine toxicity and multiorgan system failure occurred in a patient with schizophrenia stabilized on clozapine who consumed caffeine 600 mg daily (108817).

CONTRACEPTIVE DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, contraceptive drugs might increase the levels and adverse effects of caffeine.  Details Oral contraceptives decrease the rate of caffeine clearance by 40-65% (2714,11737).

CYTOCHROME P450 1A2 (CYP1A2) INHIBITORS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the levels and adverse effects of caffeine.  Details Caffeine is metabolized by CYP1A2. Theoretically, drugs that inhibit CYP1A2 may decrease the rate of caffeine clearance and increase caffeine levels (5051,11741).

DIPYRIDAMOLE (Persantine) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, caffeine might decrease the vasodilatory effects of dipyridamole and interfere with its use prior to stress testing.  Details Caffeine inhibits dipyridamole-induced vasodilation (11770,11772). It is recommended that methylxanthines and methylxanthine-containing products be stopped 24 hours prior to pharmacological stress tests (11770). Methylxanthines appear more likely to interfere with dipyridamole (Persantine) than adenosine-induced stress testing (11771).

DISULFIRAM (Antabuse) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, disulfiram use might increase the levels and adverse effects of caffeine.  Details Disulfiram decreases the rate of caffeine clearance (11840).

DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, using caffeine with diuretic drugs might increase the risk of hypokalemia.  Details Caffeine, especially in excessive amounts, can reduce potassium levels due to stimulation of the sodium-potassium pump (23579,37905,37953,38003,38034). Diuretics can also cause lower potassium levels.

EPHEDRINE Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use might increase the risk for stimulant adverse effects.  Details Use of ephedrine with caffeine can increase the risk of stimulatory adverse effects. There is evidence that using ephedrine with caffeine might increase the risk of serious life-threatening or debilitating adverse effects such as hypertension, myocardial infarction, stroke, seizures, and death (1275,6486,10307).

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, estrogens might increase the levels and adverse effects of caffeine.  Details Estrogen inhibits caffeine metabolism (2714,23570).

ETHOSUXIMIDE (Zarontin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, caffeine might reduce the effects of ethosuximide and increase the risk for convulsions.  Details Animal research suggests that caffeine 92.4 mg/kg can decrease the anticonvulsant activity of ethosuximide (23560). However, this effect has not been reported in humans.

FELBAMATE (Felbatol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, caffeine might reduce the effects of felbamate and increase the risk for convulsions.  Details Animal research suggests that a high dose of caffeine 161.7 mg/kg can decreases the anticonvulsant activity of felbamate (23563). However, this effect has not been reported in humans.

FLUCONAZOLE (Diflucan) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, fluconazole might increase the levels and adverse effects of caffeine.  Details Fluconazole decreases caffeine clearance by approximately 25% (11022).

FLUTAMIDE (Eulexin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, caffeine might increase the levels and adverse effects of flutamide.  Details In vitro evidence suggests that caffeine can inhibit the metabolism of flutamide (23553). However, this effect has not been reported in humans.

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

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, abrupt caffeine withdrawal might increase the levels and adverse effects of lithium.  Details Caffeine has diuretic activity. When abruptly discontinued, it might alter the clearance of lithium (609). There are two case reports of lithium tremor that worsened upon abrupt coffee withdrawal (610).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(Read more about CAFFEINE)

ACE INHIBITORS (ACEIs) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking cocoa with ACEIs might increase the risk of adverse effects.  Details Human research shows that dark chocolate can inhibit ACE (42112). Additionally, prolonged angioedema in an elderly patient on an ACE inhibitor was precipitated with intake of diabetic chocolate (42049).

ADENOSINE (Adenocard) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, cocoa might decrease the vasodilatory effects of adenosine and interfere with its use prior to stress testing.  Details Cocoa contains 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. It is recommended that methylxanthines and methylxanthine-containing products be stopped 24 hours prior to pharmacological stress tests. However, methylxanthines appear more likely to interfere with dipyridamole than adenosine-induced stress testing (11771).

ALCOHOL (Ethanol) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use might increase levels and adverse effects of caffeine.  Details Cocoa contains caffeine. 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, cocoa may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Clinical research shows that intake of cocoa can inhibit platelet adhesion, aggregation, and activity (6085,17076,41928,41948,41957,41958,41995,42014,42070,42145)(111526) and increase aspirin-induced bleeding time (23800). For patients on dual antiplatelet therapy, cocoa may enhance the inhibitory effect of clopidogrel, but not aspirin, on platelet aggregation (111526).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking cocoa with antihypertensive drugs might increase the risk of hypotension.  Details Clinical research shows that cocoa can modestly decrease blood pressure in hypertensive and normotensive patients (13166,14306,15655,15752,17187,42059,42092,42107,42137,42143)(42169,103249,109446).

BETA-ADRENERGIC AGONISTS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Theoretically, large amounts of cocoa might increase the cardiac inotropic effects of beta-agonists.  Details Cocoa contains caffeine. Theoretically, large amounts of caffeine might increase cardiac inotropic effects of beta-agonists (15). A case of atrial fibrillation associated with consumption of large quantities of chocolate in a patient with chronic albuterol inhalation abuse has also been reported (42075).

CIMETIDINE (Tagamet) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might increase the effects and adverse effects of caffeine in cocoa.  Details Cocoa contains caffeine. Cimetidine decreases caffeine clearance by 30% to 50% (15,506).

CONTRACEPTIVE DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might increase the effects and adverse effects of caffeine found in cocoa.  Details Cocoa contains caffeine. Oral contraceptives decrease the rate of caffeine clearance by 40% to 65% (2714,11737).

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 Cocoa 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 cocoa and increase caffeine levels.

DIPYRIDAMOLE (Persantine) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, cocoa might decrease the vasodilatory effects of dipyridamole and interfere with its use prior to stress testing.  Details Cocoa contains caffeine. Caffeine may 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 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 Cocoa contains caffeine. In human research, 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 cocoa with diuretic drugs might increase the risk of hypokalemia.  Details Cocoa 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 = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the risk for stimulant adverse effects.  Details Cocoa 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 (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 Cocoa contains 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 Cocoa 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, cocoa might increase the levels and adverse effects of flutamide.  Details Cocoa contains caffeine. In vitro evidence suggests that caffeine can inhibit the metabolism of flutamide (23553).

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 Cocoa contains caffeine. Fluvoxamine reduces caffeine metabolism (6370).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, abrupt cocoa withdrawal might increase the levels and adverse effects of lithium.  Details Cocoa contains caffeine. There are two case reports of lithium tremor that worsened upon abrupt coffee withdrawal (609,610).

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 Cocoa contains caffeine. Methoxsalen can reduce caffeine metabolism (23572).

METMORPHIN (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 Cocoa contains caffeine. Animal research suggests that metformin can reduce caffeine metabolism (23571).

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 Cocoa contains caffeine. Mexiletine can decrease caffeine elimination by 50% (1260,11741). Concomitant use might increase the effects and adverse effects of caffeine in cocoa.

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 Cocoa contains caffeine. 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 Cocoa 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).

PENTOBARBITAL (Nembutal) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, cocoa might decrease the effects of pentobarbital.  Details Cocoa contains caffeine. 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, cocoa might reduce the effects of phenobarbital and increase the risk for convulsions.  Details Cocoa 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 Cocoa 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 Cocoa 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, cocoa might reduce the effects of phenytoin and increase the risk for convulsions.  Details Cocoa 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.

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 Cocoa contains caffeine. Quinolones (also referred to as fluoroquinolones) decrease caffeine clearance (606,607,608).

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 Cocoa contains caffeine. Caffeine and riluzole are both metabolized by cytochrome P450 1A2, 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 Cocoa contains caffeine. Concomitant use might increase the risk of stimulant 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 Cocoa contains caffeine. Terbinafine decreases the rate of caffeine clearance (11740).

THEOPHYLLINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, cocoa might increase the levels and adverse effects of theophylline.  Details Cocoa contains caffeine. Large amounts of caffeine might inhibit theophylline metabolism (11741). Caffeine decreases theophylline clearance 23% to 29% (506).

TIAGABINE (Gabitril) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, cocoa tea might increase the levels and adverse effects of tiagabine.  Details Cocoa 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 Cocoa 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, cocoa might reduce the effects of valproate and increase the risk for convulsions.  Details Cocoa 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, verapamil might increase the levels and adverse effects of caffeine.  Details Cocoa contains caffeine. Verapamil increases plasma caffeine concentrations by 25% (11741).

(Read more about COCOA)

(Read more about DIIODOTHYRONINE)

(Read more about GRAINS OF PARADISE)

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D In vitro research shows that N,N-DMPEA strongly inhibits cytochrome P450 2D6 (CYP2D6) (91878). Theoretically, concomitant use with drugs metabolized by CYP2D6 might increase the risk for adverse effects from these drugs.  Details Some drugs metabolized by CYP2D6 include amitriptyline (Elavil), clozapine (Clozaril), codeine, desipramine (Norpramin), donepezil (Aricept), fentanyl (Duragesic), flecainide (Tambocor), fluoxetine (Prozac), meperidine (Demerol), methadone (Dolophine), metoprolol (Lopressor, Toprol XL), olanzapine (Zyprexa), ondansetron (Zofran), tramadol (Ultram), trazodone (Desyrel), and others.

(Read more about N,N-DIMETHYLPHENETHYLAMINE (N,N-DMPEA))

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B In humans, octopamine 450-600 mg daily increases blood pressure in hypotensive patients (100089). However, evidence from animal research suggests that octopamine can lower blood pressure (11995). Theoretically, concomitant use of octopamine and antihypertensive drugs might potentiate and/or reduce the activity of antihypertensive drugs.  Details Some antihypertensive drugs include captopril (Capoten), enalapril (Vasotec), losartan (Cozaar), valsartan (Diovan), diltiazem (Cardizem), Amlodipine (Norvasc), hydrochlorothiazide (HydroDiuril), furosemide (Lasix), and many others.

STIMULANT DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Octopamine is thought to have stimulant effects (94386). Theoretically, taking octopamine with other stimulant drugs might increase the risk of hypertension and adverse cardiovascular effects.  Details Some stimulant drugs include amphetamine, caffeine, diethylpropion (Tenuate), methylphenidate, phentermine (Ionamin), pseudoephedrine (Sudafed, others), and many others.

(Read more about OCTOPAMINE)

MONOAMINE OXIDASE INHIBITORS (MAOIs) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking phenethylamine concomitantly with MAOIs may increase adverse effects.  Details In humans, phenethylamine is oxidized by MAO-B to form the inactive metabolite phenylacetic acid (29929,29930). Animal research shows that administering an MAOI prior to phenethylamine increases the amphetamine-like effects of phenethylamine (24360). However, low-quality clinical research has used phenethylamine with selegiline, an MAOI, with apparent safety (24338).

SEROTONERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, combining serotonergic drugs with phenethylamine might increase the risk of serotonergic adverse effects.  Details Animal research shows that phenethylamine increases levels of serotonin, norepinephrine, and dopamine (24340,24344,24354). Theoretically, combining serotonergic drugs with phenethylamine might increase the risk of additive serotonergic adverse effects, including serotonin syndrome and cerebral vasoconstrictive disorders (8056). However, low-quality clinical research has used phenethylamine with selegiline, a monoamine oxidase inhibitor (MAOI), with apparent safety (24338).

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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).

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General ...Orally, taking 1,3-DMAA combination products (OxyELITE Pro, AmphetaLean, or Jack3d, USPlabs) has been reported to cause cardiac arrest, atrial fibrillation, chest pressure, angina, tachycardia, palpitations, hypertension, hypotension, myocardial infarction, and acute coronary syndrome (17660,91680,94361,94362,94365,94369,94371,94377). Increased heart rate and blood pressure have also been reported. Other reported adverse effects associated with the use of 1,3-DMAA-containing products have included life-threatening lactic acidosis (17660), nausea, vomiting, diarrhea, and abdominal pain (17663,17907,17908,94365,94371,94377), urinary changes (17663,94365,94371,94377), liver injury (94367,94368,94369), anaphylaxis (94365), muscle symptoms such as spasm or weakness (94377), neurological symptoms including tremors, insomnia, sweating, tiredness, confusion, headache, and chills (17907,17663), hemorrhagic stroke (17663,90318), pupil dilation or tinnitus (94365,94371), psychiatric symptoms such as anxiety, agitation, paranoia, and aggression (17660,17907,94365,94371,94377), or rapid breathing (17660,94371). The dose of 1,3-DMAA at which such adverse effects occur is not clear (94368).
Death has occurred in some cases following organ failure and cardiac arrest (17904,94361,94369,94374).
Topically, rubbing an eye while mixing a drink with a 1,3-DMAA-containing combination product (Jack3d) has caused pupil dilation (94368).

Cardiovascular ...Due to the stimulant effects of 1,3-DMAA, there is concern that it might increase the risk of adverse cardiovascular events similar to synephrine from bitter orange or ephedrine from ephedra. Cardiovascular outcomes have rarely been assessed in patients taking 1,3-DMAA alone. Most adverse effects are linked to 1,3-DMAA-containing combination products. Palpitations and tachycardia are some of the most common side effects reported for adults and children taking 1,3-DMAA-containing combination products (17660,91680,94365,94371). Other less common adverse effects have included chest pressure, angina, atrial fibrillation, hypertension, hypotension, myocardial infarction, and acute coronary syndrome (17660,91680,94362,94365,94371,94377).
There is inconsistent data about the effects of 1,3-DMAA on heart rate and blood pressure (94368). For example, some research suggests that taking specific 1,3-DMAA-containing combination products (OxyELITE Pro or Jack3d, USPlabs) significantly increases systolic blood pressure and increases heart rate within 1-2 hours of taking a dose. These increases appear to be dose dependent (17906,17907,17908). However, in an 8-week study, heart rate was significantly increased, but blood pressure was not (17907). Other research shows that neither acute nor chronic intake of 1,3-DMAA increases heart rate or blood pressure (17908,94364,94368,94376). Overall, it seems that oral intake of a single dose of a 1,3-DMAA-containing product is more likely to increase systolic blood pressure. Resting blood pressure is less likely to remain increased following chronic use (94368,94379). Higher doses are more likely to increase heart rate and blood pressure. Although most sports supplements contain 25-65 mg/dose, some contain as much as 285 mg/dose (94377).
In case reports of healthy young adults taking 1,3-DMAA-containing combination products prior to exercise, cardiac arrest causing death has occurred (94361,94369).

Endocrine ...In one report, a patient who took a specific combination product containing 1,3-DMAA (Jack3d by USP Labs) prior to intense exercise experienced life-threatening lactic acidosis (17660).

Gastrointestinal ...Orally, taking 1,3-DMAA-containing combination products has been reported to cause nausea (17907,17908,94365,94371,94377), vomiting (17663,94365,94371,94377), diarrhea (94365), vomiting blood (94371), and abdominal pain (94371).

Genitourinary ...Urinary hesitancy (94365), urinary retention (94371), and uncontrolled urination (94377), have been reported following ingestion of 1,3-DMAA-containing combination products.

Hepatic ...Acute liver injury, in some cases requiring a liver transplant, has been reported following oral intake of 1,3-DMAA-containing products (94367,94368,94369).

Immunologic ...An anaphylactic reaction has been reported following oral intake of 1,3-DMAA-containing products (94365).

Musculoskeletal ...Orally, dimethylamine-containing products have caused muscle spasm (94365), muscle weakness (94377), and leg pains (94377).

Neurologic/CNS ...Orally, taking specific 1,3-DMAA-containing combination products (OxyELITE Pro or Jack3d, USPlabs) has been reported to cause feelings of jitters, sleeplessness, shakiness, chills, sweating, fatigue, tingling, and lack of focus in clinical trials (17907). Other adverse effects reported for products containing 1,3-DMAA have included headache, dizziness, tremor, numbness, flushing, seizure, blacking out, visual disturbances, confusion, and lethargy (17660,17908,94365,94368,94371,94377). In a case report, a 26 year old male reported with a hemorrhagic stroke linked to taking the supplement Jack3d, which contains 1,3-DMAA, schizandrol A, caffeine, beta-alanine, creatine, and L-arginine alpha-ketoglutarate (90318). In another report, a patient experienced a hemorrhagic stroke after taking two tablets of a product containing 1,3-DMAA 278 mg each along with caffeine 150 mg and a can of beer (17663).

Ocular/Otic ...Orally, dimethylamine-containing products have caused tinnitus (94365) and pupil dilation (94371). Pupil dilation also occurred after rubbing an eye while mixing a drink with the specific product Jack3d, containing 1,3-DMAA (94368).

Psychiatric ...Orally, taking 1,3-DMAA-containing combination products has been reported to cause feelings of anxiety (17907,94365), suicidal behavior (94365), agitation or irritability (94365,94371,94377), paranoia (94377), depression (94377), panic (94377), and aggression or combativeness (17660,94365).

Pulmonary/Respiratory ...Orally, combination products containing 1,3-DMAA have caused rapid breathing and hyperventilation (17660,94371).

Other ...There are at least two reports of death in US Army soldiers who took 1,3-DMAA supplements and suffered heat stroke and related complications following physical fitness training (17904).

(Read more about 1,3-DMAA)

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).

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

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

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

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

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

(Read more about BLACK PEPPER)

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

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

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 and topically, cocoa is generally well tolerated.
Most Common Adverse Effects:
Orally: Borborygmi, constipation, diuresis, gastrointestinal discomfort, headaches, and nausea.
Serious Adverse Effects (Rare):
Orally: Tachycardia.

Cardiovascular ...Some cases of increased heart rate have been reported with oral cocoa use (13161,42132).

Dermatologic ...In some cases, when taken orally, cocoa can cause allergic skin reactions (13161). Topically, cocoa butter has occasionally caused a rash. In animals, it has been shown to block pores and cause acne; however, this has not been found in humans (11).

Gastrointestinal ...In human trials, chocolate consumption was associated with a higher incidence of flatulence, irritable bowel syndrome, upset stomach, gastric upset, borborygmi (a gurgling noise made by fluid or gas in the intestines), bloating, nausea, vomiting, and constipation or obstipation (41986,42221,41921,1374,42220,1373,42099,42097,42156,42123,18229,42169,42111). Chocolate consumption has been implicated as a provoking factor in gastroesophageal reflux disease (GERD) (41974,42005,41946,1374). Unpalatability has been reported (42079,42169). Consumption of chocolate and other sweet foods may lead to increased dental caries (42129,42030).

Genitourinary ...In some cases, when taken orally, cocoa can cause increased urination (13161).

Neurologic/CNS ...In some cases, when taken orally, cocoa can cause shakiness and might trigger migraine and other headaches (13161,42169,92271).

Other ...Due to the high sugar and caloric content of chocolate, there is concern about weight gain in people who consume large amounts of chocolate (17187).

(Read more about COCOA)

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

(Read more about DIIODOTHYRONINE)

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 ...Ophthalmically, N,N-DMPEA seems to be well tolerated. No adverse effects were reported in one clinical trial evaluating ophthalmic use of N,N-DMPEA for 21 days (95470). It is unknown whether N,N-DMPEA causes adverse effects when taken orally in amounts found in supplements.

(Read more about N,N-DIMETHYLPHENETHYLAMINE (N,N-DMPEA))

General ...Octopamine is chemically similar to synephrine, a stimulant that might cause severe adverse effects in some patients. Due to theoretical concerns for stimulant-related adverse effects, Health Canada has set the maximum daily dose of octopamine at 50 mg (91684). However, clinical evidence on the safety of octopamine at any dose is lacking. In one case report, chronic use of a sports supplement containing octopamine and other ingredients resulted in thrombus and myocardial infarction (100091).

Cardiovascular ...Octopamine is commonly used as a stimulant. Due to its chemical similarities to synephrine, a stimulant with the potential to cause severe cardiovascular effects, Health Canada has set the maximum daily dose of octopamine at 50 mg (91684). However, clinical evidence on the safety of octopamine at any dose is lacking.
In a previously healthy, 39-year-old man, chronic use of a multi-ingredient sports supplement was associated with the development of a thrombus, angina, and acute myocardial infarction. The product claimed to contain synephrine 40 mg, caffeine 400 mg, and unspecified amounts of octopamine and tyramine, in addition to various other products such as St. John's Wort. It is not clear if these effects were due to octopamine, the other ingredients, the patient's concomitant dehydration, or a combination of these factors (100091).

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General ...There is currently a limited amount of information available on the adverse effects of phenethylamine. A thorough evaluation of safety outcomes has not been conducted.

Cardiovascular ...A case of tachycardia has been reported for an individual who consumed a weight loss product containing phenethylamine 200-300 mg, as well as caffeine 500-750 mg, bitter orange 400-600 mg, willow bark 150-225 mg, cayenne pepper 80-120 mg, 1,3-dimethyloamyloamine 70-105 mg, gooseberry extract 40-60 mg, bergamot orange 40-60 mg, and black pepper 10-15 mg, daily for 2 months (24343). It is not clear if these adverse effects were related to phenethylamine.

Neurologic/CNS ...A case of anxiety and agitation has been reported for an individual who consumed a weight loss product containing phenethylamine 200-300 mg, caffeine 500-750 mg, bitter orange 400-600 mg, willow bark 150-225 mg, cayenne pepper 80-120 mg, 1,3-dimethyloamyloamine 70-105 mg, gooseberry extract 40-60 mg, bergamot orange 40-60 mg, and black pepper 10-15 mg, daily for 2 months (24343). It is not clear if these adverse effects were related to phenethylamine or other ingredients.

(Read more about PHENETHYLAMINE (PEA))

General ...Orally, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.
Serious Adverse Effects (Rare):
Orally: A related chemical, yohimbine, has been reported to cause serious adverse effects, such as loss of consciousness, paralysis, seizures, and vertigo.

Dermatologic ...Since rauwolscine is structurally related to yohimbine, rauwolscine might theoretically cause similar adverse effects. Yohimbine may cause rash, erythrodermic skin eruption, and exanthema (3312,3971,86878,86896).

Gastrointestinal ...Since rauwolscine is structurally related to yohimbine, rauwolscine might theoretically cause similar adverse effects. Nausea, vomiting, increased salivation, diarrhea, and gastrointestinal distress may occur with yohimbine use (3970,17465,86780,86786,86804,86827,86896).

Genitourinary ...Since rauwolscine is structurally related to yohimbine, rauwolscine might theoretically cause similar adverse effects. Orally, yohimbine may cause dartos contraction or decreased libido in some patients (86786,86882).

Immunologic ...Since rauwolscine is structurally related to yohimbine, rauwolscine might theoretically cause similar adverse effects. There is one report of a hypersensitivity reaction including fever, chills, malaise, itchy and scaly skin, progressive renal failure, and lupus-like syndrome associated with ingestion of a one-day dose of yohimbine (6169).

Neurologic/CNS ...Since rauwolscine is structurally related to yohimbine, rauwolscine might theoretically cause similar adverse effects. Orally, yohimbine has been associated with reports of tremulousness, head twitching, seizures, loss of consciousness, enhanced brain norepinephrine release, decreased energy, dizziness, vertigo, headache, feeling cold, flushing, diaphoresis, and paralysis (11,18,3312,3971,17465,86786,86801,86804,86827,86896).

Psychiatric ...Since rauwolscine is structurally related to yohimbine, rauwolscine might theoretically cause similar adverse effects. Orally, yohimbine may cause anxiety (17465) and impulsivity (86784,86810).

Pulmonary/Respiratory ...Since rauwolscine is structurally related to yohimbine, rauwolscine might theoretically cause similar adverse effects. Orally, yohimbine may cause bronchospasm, tachypnea, cough, sinusitis, and rhinorrhea (17465,86825,86850,94112).

Renal ...Since rauwolscine is structurally related to yohimbine, rauwolscine might theoretically cause similar adverse effects. A case of acute renal failure related to yohimbine-induced systemic lupus erythematosus has been reported (6169).

(Read more about RAUWOLSCINE)