Thermo Java (sugar free) by Omnitrition International, Inc.

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.

(Read more about BITTER ORANGE)

EFFECTIVE

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

LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about CAFFEINE)

EFFECTIVE

• Dyspepsia. Oral calcium carbonate is approved by the US Food and Drug Administration (FDA) as an antacid. Details: Taking calcium carbonate orally as an antacid is effective for treating dyspepsia (1843). Calcium carbonate has FDA approval as an antacid.
• Hyperkalemia. Intravenous calcium gluconate is approved by the US Food and Drug Administration (FDA) for preventing hyperkalemia-induced cardiac abnormalities. Details: Administering calcium gluconate intravenously can reverse electrocardiographic changes and arrhythmias induced by hyperkalemia (12946). Intravenous calcium gluconate is FDA-approved for preventing hyperkalemia-induced cardiac abnormalities.
• Hypocalcemia. Oral calcium treats and prevents hypocalcemia. Intravenous calcium is used to treat severe hypocalcemia. Details: Taking calcium orally is effective for treating and preventing hypocalcemia. Intravenous calcium gluconate, acetate, gluceptate, or chloride is effective for severe hypocalcemia or hypocalcemic tetany (12928).
• Kidney failure. Oral calcium carbonate or calcium acetate is used as a phosphate binder during kidney failure. Details: Taking calcium carbonate or calcium acetate orally is effective as a phosphate binder. Calcium acetate (PhosLo) appears to control hyperphosphatemia better than sevelamer (Renagel) (12943,12944,38990). Calcium citrate is not recommended for this purpose because it increases aluminum absorption and does not bind phosphate as efficiently as calcium acetate or calcium carbonate (21631). Some clinical research also shows that taking calcium orally reduces blood pressure in patients with kidney failure (975).

LIKELY EFFECTIVE

• Corticosteroid-induced osteoporosis. Oral calcium in combination with vitamin D prevents bone density loss that occurs during long-term treatment with corticosteroids. Details: Taking calcium in combination with vitamin D as adjunctive therapy seems to be effective for reducing bone mineral density loss in people using corticosteroids long-term (982,1046,1830,1831,1832,4462,4463,4464,4465,4466)(4467,12945,38493). One specific product used in clinical research is Oscal (Marion Merrel Dow Inc.), which contains elemental calcium 500 mg per tablet plus vitamin D 125 IU per tablet (982). Another product used is Oscal 250 + D (SmithKline Beecham Healthcare), which contains elemental calcium 250 mg and vitamin D 125 IU per tablet (1046).
• Hyperparathyroidism. Oral calcium reduces parathyroid hormone levels in patients with secondary hyperparathyroidism due to kidney failure. Details: Taking calcium orally reduces parathyroid hormone levels in patients with kidney failure and secondary hyperparathyroidism (1827,1828,1829,39174,39425). In elderly women, the combination of calcium and vitamin D reverses secondary hyperparathyroidism and reduces hip fracture risk (8818). Also, population research suggests increased calcium intake from the diet and supplements reduces the risk of primary hyperparathyroidism in women. Supplemental intakes of at least 500 mg/day and dietary intakes of approximately 1100 mg/day are considered to be protective (91353).
• Osteoporosis. Adequate calcium intake, from the diet and/or supplements, is recommended for the prevention and treatment of osteoporosis. Details: The Bone Health and Osteoporosis Foundation (BHOF) recommends ensuring adequate calcium intake in line with the recommended dietary allowance (RDA) by age, along with adequate vitamin D intake, for the prevention and treatment of osteoporosis in adults over 50 years of age. Supplementation can be used to augment dietary intake when adequate dietary intake is not feasible (109425). In the US and Canada, foods containing at least 200 mg calcium with less phosphorous content than calcium can be labelled with a health claim regarding the relationship between adequate calcium intake and a reduced risk for osteoporosis (11940,102148). However, calcium supplementation is not recommended specifically for the primary prevention of osteoporosis. The US Preventive Task Force (USPSTF) states that the current evidence is insufficient to assess the balance of benefits and harms of vitamin D and calcium supplementation, alone or in combination, for the primary prevention of fractures in community dwelling adults without osteoporosis (95695). Also, calcium supplements do not seem to be effective for preventing loss of bone mineral density (BMD) during lactation (988), in patients who have had bone marrow transplantation (1817), or in patients who have had renal transplantation (4823,38736,38871). Maximal bone growth occurs in the teenage years, and then BMD in females remains relatively constant until age 30-40. After age 40, bone loss typically occurs at rates of 0.5% to 1% per year. In males, this occurs several decades later. Bone loss is more pronounced if dietary calcium intake is below the RDA, which is the case for many Americans (2571,2578). One meta-analysis of randomized controlled trials in healthy children 7-14 years old shows that fortifying food with calcium 250-1000 mg daily for up to 24 months modestly improves femoral neck BMD, but not hip or spine BMD. However, the included trials did not supplement vitamin D (107232). During the 5 years immediately after menopause, calcium supplementation has very little effect on bone loss (2569,2570,2575,2576). The rapid loss of estrogen causes a high bone resorption rate, which increases serum calcium levels and therefore decreases intestinal absorption of calcium (2570). After this period, the typical rate of bone loss is 2% per year (2572,2576). Taking calcium 1000-1600 mg daily as carbonate, citrate, lactate gluconate, or citrate malate salt decreases this rate by 0.25% to 1% annually (977,979,981,2569,2571,2572,2575,2576,2578,6850)(38978,38980,39064). The greatest reductions (1% or more) are seen in the first 1-2 years of supplementation when bone remodeling foci can be filled (2569,2576). After this period, the differences in rate of loss between supplemented and non-supplemented females are closer to 0.25% per year (2569,2577). A meta-analysis of clinical evidence suggests that there is no additional benefit after 4 years (38980). Small clinical studies have found that continuous calcium supplementation at an average daily dose of 1050 mg, started after menopause and continued for 1.5-4 years, may reduce fracture rates by 26% when compared with no calcium supplementation. The largest of these studies was conducted in nursing home residents who also received daily vitamin D; the benefits of calcium, specifically, are unclear (39386). Some research also suggests that calcium and vitamin D improves primary prevention of osteoporotic fractures in some older individuals with osteoporosis, particularly the elderly and those who are no longer community dwelling (12930,38875,38849,39026,109471). However, not all research is positive. One large clinical trial in elderly adults with a low-trauma fracture show that taking calcium 1000 mg daily with or without vitamin D 800 IU daily for 2-7 years does not reduce the risk of a second fracture when compared with placebo (13073). Another clinical study shows that taking calcium 1000 mg daily plus vitamin D 800 IU daily does not prevent a second fracture in elderly patients, or prevent a first fracture in elderly patients with other risk factors such as low body weight (less than 58 kg, 127.6 pounds), smoking, family history of hip fracture, or fair or poor self-reported health (12929). Also, some exploratory research suggests that supplements may need to be continued indefinitely; in adults over 68 years of age, any effects of 2 years of calcium supplements on BMD appear to be lost within 2 years after discontinuing supplements (6853). Calcium has additive effects when used with other agents such as vitamin D, estrogens, or calcitonin. Whereas calcium alone generally reduces or prevents loss of BMD, combination with other agents can produce small increases in BMD ranging from 0.3% to 3.3% depending on the combination and dosages used (978,980,1836,2570,2571,2572,2576). However, one meta-analysis in healthy adults shows that fortifying foods with calcium 250-1000 mg daily, in conjunction with vitamin D supplementation, for up to 24 months does not improve BMD when compared with control (107232). The full potential of osteoporosis treatments cannot be realized without adequate calcium intake (2569,2570,2571,2572). Advise patients taking agents such as estrogens, calcitonin, bisphosphonates, or raloxifene (Evista) to ensure that their daily calcium intake meets the RDA. Use supplements if necessary. The usefulness of calcium in preventing osteoporosis in males is not as well-studied. Some observational research has found that calcium 870 mg daily is not associated with changes in BMD and bone loss in males (97201). However, clinical evidence suggests that taking calcium 1000 mg daily for 2 years might improve trabecular or cortical bone mass by 2% to 4% (980,8827,8873). Dietary supplementation with calcium and vitamin D seems to moderately reduce bone loss measured in the femoral neck, spine, and total body, and seems to reduce the incidence of nonvertebral fractures in older patients with osteopenia or low BMD (980).
• Premenstrual syndrome (PMS). Adequate calcium intake seems to prevent symptoms of PMS. Details: There seems to be a link between low dietary calcium intake and symptoms of PMS (2004,6847,39007). Taking calcium 1000-1336 mg daily seems to significantly reduce depressed mood, water retention, and pain, especially if daily calcium intake is inadequate (1822,1823,1824,2004,95821). Calcium carbonate 1200 mg daily seems to decrease PMS symptom scores by about 18% when compared with placebo (1822). Increasing dietary calcium intake is also associated with a decreased risk of developing PMS. Consuming an average of 1283 mg of calcium per day from foods is associated with about a 30% lower risk of developing PMS compared with consuming an average of 529 mg daily (13094); however, taking calcium supplements does not appear to be associated with the risk of developing PMS.

POSSIBLY EFFECTIVE

• Colorectal cancer. Oral calcium seems to be beneficial for preventing colorectal cancer, especially in those with adequate vitamin D levels and normal body mass index (BMI). Details: Population studies have found that increased intake of dietary or supplemental calcium is associated with a reduced risk of colorectal cancer and colorectal adenomas (1047,8820,12120,38951,98898,98899). Clinical trials and meta-analyses of clinical research also show that taking calcium supplements 1.2-2 grams daily for up to 4 years can reduce the risk of colorectal adenoma recurrence by up to 29% (970,12118,12950,15267,34596,38718,39042,95817). However, not all research has been positive. Some meta-analyses of clinical research or observational studies suggest that taking calcium does not reduce the risk of familial adenomatous polyposis or colorectal cancer (34596,39042,39349). Other contradictory research suggests that postmenopausal females who take calcium 1000 mg daily plus vitamin D 400 IU daily do not have a reduced risk of developing colorectal cancer (14290); however, this finding may not be reliable due to the high baseline intake of calcium in study participants. The reason for these conflicting findings is not entirely clear. Vitamin D might be an important factor. People with lower than average vitamin D levels do not seem to get any benefit from calcium supplements (12118). Also, one meta-analysis of previous trials suggests that taking calcium 1200 mg daily reduces the risk of colorectal adenomas in people with a normal BMI, but not in those who are overweight or obese (99715). Despite this conflicting evidence, the US Food and Drug Administration (FDA) approved a qualified health claim in 2005 stating that calcium supplements may reduce the risk of colorectal cancer and colorectal adenomas. However, the FDA has determined that there is little scientific evidence to support this claim (102366).
• Fetal bone mineralization. If calcium intakes are low during pregnancy, oral calcium seems to be beneficial for increasing fetal bone density. Details: With low dietary calcium intake (less than 562 mg elemental calcium daily) during pregnancy, calcium supplementation increases fetal bone mineralization and density. However, calcium supplementation does not offer any additional benefit if calcium intakes are adequate (3263,3264).
• Hypertension. Oral calcium seems to reduce blood pressure by a small amount in adults with or without hypertension. However, it is unclear if this reduction is clinically significant. Details: Many clinical trials and observational studies, including a meta-analysis of 18 high-quality clinical trials, show that intake of calcium supplements or dietary calcium modestly reduces systolic blood pressure in patients with or without hypertension, usually around 1-2 mmHg. Calcium seems to be more effective for certain subpopulations of patients, such as those who are salt-sensitive or have low baseline dietary calcium intake (945,972,974,976,984,1818,1819,1820,1821,6852)(13138,14406,38803,39063,39094,39221,113920,113925). However, a large-scale clinical trial in postmenopausal females shows that taking vitamin D (cholecalciferol) 400 IU daily in combination with elemental calcium 1000 mg daily does not lower blood pressure or reduce the risk of developing hypertension (16714). Additionally, a meta-analysis of 8 clinical trials shows that taking calcium in combination with vitamin D for up to 7 years has no effect on blood pressure (98861). The validity of this finding is limited by the poor methodological quality of the included studies. Some observational research suggests that calcium can reduce the risk for hypertension. Population research in females aged 45 years and older suggests that higher intake of calcium from both diet and supplemental sources is linked to a lower risk of developing hypertension when compared to lower calcium intake (14265). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim stating that calcium supplements may reduce the risk of hypertension. However, the FDA has concluded that this claim is based on supporting, rather than conclusive, evidence (102367). Research evaluating the effect of calcium supplementation during pregnancy on the child's blood pressure has yielded conflicting findings. A systematic review of 2 clinical studies and 3 observational studies found that calcium intake during pregnancy is associated with a 1-2 mmHg reduction in the systolic blood pressure of the offspring between the ages of 1-7 years (38852). However, a separate meta-analysis of 3 clinical studies shows that calcium intake during pregnancy does not reduce systolic or diastolic blood pressure in the offspring (113923).
• Osteomalacia. Oral calcium seems to reverse osteomalacia caused by very low calcium intakes. Details: Osteomalacia is commonly caused by vitamin D deficiency; however, very low calcium intake can also lead to osteomalacia in children and adults. Calcium supplementation can reverse osteomalacia caused by calcium deficiency. Along with appropriate vitamin D supplementation, individuals at risk of osteomalacia need sufficient calcium intake (94819).
• Pre-eclampsia. Oral calcium seems to reduce the risk of pre-eclampsia, especially in high-risk individuals and those with low baseline dietary calcium intake. Details: Although there is some conflicting evidence (971,38756), most clinical research shows that taking calcium orally 1-2 grams daily reduces the risk of pre-eclampsia (973,1833,8828,39043,39319,39426,97348,113919). A large clinical trial of 11,000 pregnant individuals in India and Tanzania shows that supplementation with 500 mg daily is similarly effective to 1500 mg daily (113908). Multiple meta-analyses which include 16-30 clinical studies have found that varying doses of calcium supplementation reduce the relative risk of pre-eclampsia by 46% to 51% when compared with placebo (97348,113909,113919). One of these meta-analyses found that for every 19 females treated with calcium, one episode of pre-eclampsia would be avoided (97348). Additionally, one of these meta-analyses found that calcium reduces the relative risk of pre-eclampsia by 51%, regardless of whether it is taken at a dose above or below 1000 mg daily (113919). Some research suggests that calcium supplementation may have a greater effect in individuals at high risk of pre-eclampsia or with low baseline dietary calcium intake, and when taken at greater than or equal to 20 weeks of gestation (15029,38497,97348,99714,113919). However, another meta-analysis of 30 clinical studies found a similar benefit of calcium in both high- and low-risk individuals (113919). A separate meta-analysis of 6 clinical studies conducted in China evaluated the benefits of calcium carbonate 500-600 mg daily taken in conjunction with aspirin 50-75 mg daily during pregnancy. This combination was associated with an 80% lower relative risk of pre-eclampsia and an 83% lower relative risk of pre-eclampsia with gestational hypertension when compared with routine care (113913). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim regarding the use of calcium supplements to reduce the risk of pregnancy-induced hypertension and pre-eclampsia. However, due to the limited and conflicting research available at that time, the FDA stated that this outcome was highly unlikely (102366). Since then, large, high-quality clinical research has supported this finding. In fact, in 2016 the World Health Organization (WHO) released a recommendation to prescribe oral calcium 1.5-2 grams daily during pregnancies at high risk of pre-eclampsia if dietary calcium intakes are low (97347).
• Pregnancy-induced hypertension. Oral calcium may reduce the risk of pregnancy-induced hypertension. Details: A meta-analysis of 17 clinical studies shows that calcium supplementation during pregnancy may reduce the relative risk of pregnancy-induced hypertension by 30% when compared with control (113909). A separate meta-analysis of 6 clinical studies conducted in China, which evaluated the benefits of calcium carbonate 500-600 mg daily taken in conjunction with aspirin 50-75 mg daily during pregnancy, shows that this combination reduces the relative risk of pregnancy-induced hypertension by 85% when compared with routine care (113913).
• Rickets. Oral calcium seems to reverse rickets caused by very low calcium intakes. Details: Rickets is commonly caused be vitamin D deficiency; however, very low calcium intake can also lead to rickets. Calcium supplementation can reverse rickets caused by calcium deficiency (94819). A small clinical study in children with nutritional rickets shows that taking calcium 500-2000 mg daily for 24 weeks improves radiographically measured rickets caused by calcium deficiency. Rickets seems to improve more rapidly with calcium 1000 mg compared to calcium 500 mg. However, increasing the calcium dose to 2000 mg daily is not more beneficial than calcium 1000 mg daily (98904).
• Tooth retention. Oral calcium with vitamin D seems to help with tooth retention in the elderly population. Details: A clinical trial in the elderly population shows that taking calcium citrate malate 500 mg daily along with vitamin D3 (cholecalciferol) 700 IU daily orally for 3 years reduces the risk of tooth loss by about 52% when compared with placebo (8816).

POSSIBLY INEFFECTIVE

• Breast cancer. Oral calcium, via supplementation or as part of the diet, does not seem to be beneficial for breast cancer prevention. Details: Although some studies disagree (15631,39041,95811,107237,113917), most population research suggests that increased calcium intake is not associated with overall breast cancer risk (15631,16715,98895,107236,107237,113917). However, one meta-analysis of observational studies shows that although higher total calcium intake is not associated with breast cancer risk, higher dietary calcium intake, specifically, may be associated with a slightly reduced risk (113917). Also, some analyses suggest that calcium intake may be associated with the risk for certain breast cancer sub-types. Some subgroup analyses suggest that calcium intake may reduce the risk of breast cancer in postmenopausal, but not pre-menopausal, adults (15631,107237) and that dietary calcium intake may reduce estrogen receptor(ER)-negative breast cancer, but not ER-positive breast cancer (107236). However, most research has not evaluated the effects of calcium supplementation or intake on breast cancer subtypes. The best evidence to date, from a large scale clinical trial (Women's Health Initiative), shows that taking vitamin D (cholecalciferol) 400 IU daily plus calcium 1000 mg daily for 7 years after menopause does not reduce the risk of developing invasive breast cancer at the end of the study and 5 years after the end of the intervention (16715,98895).
• Fractures. Although oral calcium prevents fractures in osteoporosis, most evidence shows that calcium does NOT prevent factures in people who do not have osteoporosis. See Osteoporosis discussion for more information on the use of calcium for this purpose. Details: Robust meta-analyses of mostly large, high-quality clinical studies show that calcium supplementation 500-1600 mg daily for 0.5-7 years with or without vitamin D does not reduce total fractures, hip fractures, vertebral fractures, or non-vertebral fractures in older adults without osteoporosis (95822,112486). A large-scale study in postmenopausal females aged 50-79 years who were enrolled in the Women's Health Initiative (WHI) suggests that calcium 1000 mg plus vitamin D 400 IU daily for 7 years only modestly improves bone mineral density (BMD) and does not significantly reduce fracture risk. This lack of effect may have been due to low adherence to the treatment regimen. In those who were 80% adherent, the combination of calcium plus vitamin D reduced the risk of hip fracture by about 29% (14282). Also, some clinical research shows that taking calcium carbonate 1000 mg and vitamin D 400 IU for 5 years does not attenuate loss of height after menopause when compared with placebo (95810). Additional meta-analyses of clinical and observational evidence suggest that calcium supplementation is not associated with a reduced risk of vertebral or nonvertebral fractures, such as hip fractures (38589,38888,98895). Some other research has suggested that calcium in combination with vitamin D reduces fracture risk in older patients without osteoporosis (980,1836,8818,12930,12933,12952,38849,102145,107235); however, this research is confounded by a number of variables, including the presence of hormonal therapy and differing levels of fracture risk at baseline (1836,8818,95822). Conflicting findings on this topic might also be due to genetic differences in patient populations. A population analysis of the WHI study found that, in older females with the lowest genetic susceptibility to low BMD, taking calcium with vitamin D is associated with a reduction in fracture risk. However, in females with a higher genetic susceptibility to low BMD, there is no association between supplementation and fracture risk. This might be because individuals with a lower susceptibility to low BMD are also more responsive to calcium and vitamin D supplementation (97357). As of April 2018, the U.S. Preventative Services Task Force (USPSTF) concludes that there is insufficient evidence to determine whether supplementing with vitamin D >400 IU daily along with calcium >1000 mg daily is safe and effective for preventing fractures in community dwelling adults without vitamin D deficiency, osteoporosis, or a history of fracture. USPSTF recommends against supplementing with calcium 1000 mg daily or less along with vitamin D 400 IU daily or less for preventing primary fractures in community-dwelling postmenopausal females (95695).
• Obesity. Oral calcium does not seem to improve weight loss in adults or children with overweight or obesity. Details: Observational research has found that adults and children with low calcium intake are more likely to gain weight, have a higher body mass index (BMI), and be overweight or obese when compared to people with high calcium intake (12124,12125,12126,12127,14265). Additional observational research has found that increasing calcium intake is associated with weight loss in females; the results in males have been conflicting (12127,15602,15603). Despite these findings from observational research and a few small clinical studies (12128,15397,14438,98905,113918), most clinical research has found that increased calcium intake does not increase weight loss (12052,13138,15396,15399,38985,39004,97356). A meta-analysis of 20 clinical studies shows that daily dietary and supplemental calcium intake that meets the dietary reference intake (DRI) of 1000 mg or more daily does not increase weight loss in overweight individuals or patients with obesity when compared with intake below the DRI (95813). An older meta-analysis of 13 clinical trials also shows that increased dietary and supplemental calcium intake does not increase weight loss (15605).
• Overall mortality. Oral calcium does not seem to reduce overall mortality. Details: While some population research has found that calcium taken in combination with vitamin D in older females is associated with a lower risk of death (97353), most evidence shows that calcium, with or without vitamin D, has no effect on all-cause mortality (93533,97308,113584).

INEFFECTIVE

• Cardiovascular disease (CVD). Oral calcium does not reduce the risk of developing CVD and may actually increase risk in some patients. Details: Clinical research shows that calcium does not decrease CVD risk. Several separate meta-analyses of clinical and population research involving over 50,000 patients show that taking calcium 600-1200 mg daily for up to 7 years does not reduce the risk of CVD-related outcomes, including stroke and myocardial infarction, cardiovascular death, or overall mortality (39018,91350,92994,93533,97308,98902,107231,107233). No association was found between total dietary or supplemental calcium intake with or without vitamin D and the risk of CVD or mortality (91350,93533,97308). In fact, some population and clinical research has found that when calcium is used alone or with vitamin D, there is an INCREASED risk of CVD and coronary heart disease (38077,107233). However, other clinical research disagrees (93533). One meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years increases the risk of CVD and coronary heart disease by 1.1-1.2 times when compared with control. However, the majority of the included research evaluated postmenopausal females and it is unclear if this finding is applicable to other populations (107233).
• Chemotherapy-induced peripheral neuropathy. Intravenous calcium does not prevent nerve pain in patients given oxaliplatin. Oral calcium has not been evaluated for this purpose. Details: While pooled analyses of cohort studies and randomized controlled trials suggest that calcium and magnesium infusion decreases the incidence of oxaliplatin-induced neurotoxicity, a meta-analysis of only randomized controlled trials shows that the infusion has no effect in preventing neurotoxicity (90028,90029,90031). Additionally, clinical trials show that administering calcium gluconate 1 gram with magnesium sulfate 1 gram intravenously immediately before, or before and after, the administration of a single oxaliplatin cycle (90005), or over the entire 6-cycle course of oxaliplatin, does not improve symptoms of neurotoxicity when compared with placebo (96474).
• Myocardial infarction (MI). Oral calcium does not prevent MI. When taken in the absence of vitamin D, oral calcium may increase the risk of MI. Details: Population research has found that increased dietary intake of calcium is associated with a decreased risk of MI (91350). However, a 2010 meta-analysis of clinical research shows that taking calcium at a dose of at least 500 mg daily is associated with an approximate 30% INCREASE in the risk of MI in patients over the age of 40. According to this analysis, one additional case of MI will occur for every 69 patients that take calcium for 5 years (17482). A more recent meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years increases the risk of MI by 1.2 times when compared with control. However, the majority of the included research studied postmenopausal females and it is unclear if this finding is applicable to other populations (107233) In contrast, other meta-analyses of clinical research have shown that taking calcium for up to 7 years is NOT associated with an increased risk of MI, including a meta-analysis that only included postmenopausal females (93533,107231). Reasons for these discrepancies are not entirely clear. It may relate to whether calcium is taken as monotherapy or in combination with vitamin D. When taken with vitamin D, which is commonly recommended, calcium supplementation does not appear to be associated with an increased risk of MI in postmenopausal females (93533). Also, the association between calcium supplementation and MI risk may be influenced by the amount of calcium consumed as part of the diet. Supplementation with calcium may be associated with an increased risk of MI in people with dietary calcium intake above 805 mg daily, but not in those with dietary calcium intake below 805 mg daily (17482)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol use disorder. It is unclear if oral calcium is beneficial for alcohol use disorder. Details: Preliminary clinical research shows that taking calcium carbonate 800 mg and vitamin D 200 IU orally daily for 14 days modestly reduces alcohol craving scores and withdrawal scores when compared with placebo in adults with alcohol dependence that are undergoing withdrawal. Taking calcium carbonate did not reduce the need for diazepam; however, the study may have been inadequately powered to detect a difference between groups (107234).
• Atherosclerosis. It is unclear if oral calcium is beneficial for atherosclerosis. Details: A population study has found that taking calcium 1.2 grams daily for 3 years has no effect on carotid intima thickness or carotid atherosclerosis incidence. A total calcium intake (dietary and supplemental) of at least 1794 mg daily in older females may be associated with a decreased risk of carotid atherosclerosis when compared with a total calcium intake below 1010 mg daily (97351).
• Autism spectrum disorder. It is unclear if oral calcium during pregnancy is beneficial for reducing the odds of autism spectrum disorder in the offspring. Details: A small observational study found that calcium supplementation during pregnancy is associated with a 52% reduced odds of an autism spectrum disorder in the offspring (98900).
• Brain tumor. It is unclear if dietary calcium intake is associated with risk of brain tumor. Details: A meta-analysis of 4 case-control studies has found that higher dietary calcium intake is associated with a lower odds of brain tumor when compared with lower dietary intake (113922). The validity of this finding is limited by the exploratory nature of the included studies, which analyzed all dietary ingredients for any potential associations.
• Cancer. Oral calcium alone does not seem to prevent cancer. It is unclear if oral calcium with vitamin D is beneficial for preventing cancer. Details: Taking calcium alone does not seem to significantly reduce the risk of cancer (12118,15629). The role of calcium in cancer prevention when taken along with vitamin D is controversial, as conflicting results exist. One clinical trial shows that healthy postmenopausal females who take supplemental calcium 1400-1500 mg daily plus vitamin D3 (cholecalciferol) 1100 IU daily have a 60% lower relative risk for developing cancer of any type. Approximately 25 postmenopausal females would need to take this combination for 4 years to prevent one occurrence of cancer (15629). However, a more recent clinical study shows that healthy postmenopausal females who take supplemental calcium 1500 mg daily plus vitamin D3 (cholecalciferol) 2000 IU daily do not have a reduced risk of cancer at 4 years (93943). Reasons for the disparate results are not entirely clear. The discrepancies do not appear to be related to baseline vitamin D levels or different study populations. It is possible that, given the 10-year time lapse between the two publications, the discrepancies result from differences in cancer detection capability. Also, since cancer risk was a secondary outcome measure in the earlier study and a primary outcome measure in the more recent study, it is possible that the discrepancies result from differences in statistical methodologies. The effect of vitamin D and calcium on cancer risk in males and younger patients is not known. There is also interest in using calcium for reducing the risk of hematological malignancies. An analysis of the Women's Health Initiative study shows that taking calcium 1000 mg daily in combination with vitamin D3 400 IU for up to 10 years is associated with a 20% reduction in the risk of hematologic malignancies when compared with placebo. However, no effect on hematologic malignancy related mortality was seen (97354).
• Depression. It is unclear if oral calcium is beneficial for depression prevention. Details: Population research has found no association between a higher dietary intake of calcium and the risk of depression when compared with a lower dietary intake of calcium (96480).
• Diabetes. It is unclear if dietary calcium intake is associated with type 2 diabetes risk. Details: Some population research has found that a higher intake of calcium from the diet or supplements, alone or in combination with vitamin D, is associated with a lower risk of developing type 2 diabetes when compared with lower calcium intake (14265,16713,96473,113929). One meta-analysis of cohort and cross-sectional studies found that the highest level of dietary calcium intake is associated with an 18% relative reduction in risk of type 2 diabetes when compared with the lowest level of intake. A dose-response analysis suggests that each 300, 600, and 1000 mg per day increase in dietary calcium intake is associated with a 7%, 14%, and 23% reduced risk of type 2 diabetes, respectively (113929). However, population research is often limited by confounding variables. For example, one analysis suggests that any beneficial effect might be influenced by concomitant magnesium intake (96473,113929), while another suggests that any benefit from increased intake may be more pronounced in females, adults aged 50 years or older, and Asian populations (113929). Furthermore, other population research has found that serum calcium levels higher than 9.6 mg/dL are associated with greater risk of developing diabetes in Chinese adults with osteoporosis (95815).
• Dyslipidemia. It is unclear if oral calcium is beneficial for dyslipidemia. Details: One clinical study in adults with mild to moderate hypercholesterolemia shows that adding calcium carbonate 400 mg three times daily to a low-fat diet (American Heart Association Step 1) for 6 weeks reduces low-density lipoprotein (LDL) cholesterol levels by 4% and increases high-density lipoprotein (HDL) cholesterol levels by 4% when compared with the low-fat diet and placebo (2557). In contrast, a clinical study in females with dyslipidemia shows that taking calcium 800 mg daily for 2 years INCREASES total cholesterol levels and carotid intima-media thickness in postmenopausal, but not premenopausal, females when compared with placebo (97350). Calcium supplementation has also been evaluated in combination with vitamin D. A meta-analysis of randomized controlled trials including adults with normolipidemia and dyslipidemia shows that taking calcium 500-2000 mg daily and vitamin D 200-7142 IU daily modestly improves HDL cholesterol and triglyceride levels, but not LDL cholesterol levels, when compared with placebo. Subgroup analyses suggest that calcium and vitamin D supplementation is most beneficial in patients with dyslipidemia at baseline (107227). The relationship between dietary calcium intake and serum lipid levels has also been evaluated in observational research. A meta-analysis of 7-11 observational studies found that dietary calcium intake is not associated with total cholesterol levels, although small differences in individual lipid parameters were identified. Additionally, a meta-analysis of 4-9 observational studies suggests that calcium intake is not associated with the risk of developing hypertriglyceridemia, hypercholesterolemia, or low HDL. A subgroup analysis found that higher calcium intake may be associated with lower triglyceride levels in Asian populations (113927). Overall, these findings are limited by significant heterogeneity and the cross-sectional nature of the included studies.
• Dysmenorrhea. It is unclear if oral calcium is beneficial for reducing pain associated with dysmenorrhea. Details: Clinical research shows that taking calcium carbonate 1000 mg with vitamin D 5000 IU daily for three menstrual cycles does not reduce pain when compared with placebo in patients with primary dysmenorrhea (95821). However, calcium carbonate 1000 mg taken alone seems to reduce pain when compared with placebo.
• Endometrial cancer. It is unclear if oral calcium is beneficial for endometrial cancer prevention. Details: A meta-analysis of population research suggests that calcium supplements may reduce the risk of endometrial cancer, but dietary calcium does not seem to have any effect (38893).
• Exercise-induced muscle damage. It is unclear if oral calcium is beneficial for reducing exercise-induced muscle damage. Details: A very small clinical study in resistance-trained adults shows that taking calcium carbonate 500 mg 4 times daily for 3 weeks does not attenuate exercise-induced muscle damage from bench presses when compared with placebo (113933). This study may have been inadequately powered to detect a difference between groups.
• Fall prevention. It is unclear if oral calcium with vitamin D is beneficial for preventing falls. Details: Research suggests that calcium in combination with vitamin D, but not calcium alone, might prevent falls by decreasing body sway and normalizing systolic blood pressure (6362,11939,39038). Some experts think the combination of calcium and vitamin D may be important (11916). Preliminary clinical research in adults residing in a health care facility shows that taking vitamin D supplements while increasing dietary calcium and protein for 2 years reduces falls by 11% when compared with standard diets. Intervention diets were supplemented with milk, yogurt, and cheese to provide calcium 1142 mg and protein 69 grams daily (107235). There might also be different effects in females compared to males. In one study, females aged 65 years or older who took vitamin D 700 IU plus calcium citrate 500 mg daily over a 3-year period had a 46% lower risk of falling. However, this combination did not decrease falls in males (14291).
• Fluorosis. Oral calcium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking calcium orally, in combination with ascorbic acid (vitamin C) and vitamin D, seems to be effective for reducing excessive fluoride levels in children and improving symptoms of fluorosis in children aged 6-12 years (990).
• Heart failure. It is unclear if oral calcium in combination with vitamin D is beneficial for preventing heart failure. Details: Based on a secondary analysis of a large-scale clinical trial (Women's Health Initiative), taking calcium 1000 mg with vitamin D 400 IU daily does not reduce the risk of heart failure in the overall population or in individuals at high risk. However, in a subgroup of postmenopausal females without risk factors for heart failure, calcium and vitamin D supplementation might reduce the risk of developing heart failure by about 37% (97307).
• Lead toxicity. It is unclear if oral calcium is beneficial for reducing blood levels of lead. Details: Lead is mobilized along with calcium from bone during pregnancy and lactation, resulting in increased serum concentrations of lead. One clinical study suggests that calcium supplementation does not significantly decrease these elevated lead concentrations (1586). However, another clinical study suggests that taking calcium reduces blood lead levels by 11% when compared with placebo, with greatest effects observed in those with high baseline levels of lead (38957).
• Lyme disease. Although there is interest in using oral calcium for Lyme disease, there is insufficient reliable information about the clinical effects of calcium for this condition.
• Metabolic syndrome. It is unclear if oral calcium alone or with vitamin D is beneficial for metabolic syndrome prevention. Details: Population research has found that a higher intake of calcium from diet and supplements alone, or in combination with vitamin D, is associated with a lower risk of developing metabolic syndrome when compared with lower calcium intake (14265,16713).
• Nephrotic syndrome. It is unclear if oral calcium with vitamin D is beneficial for preventing nephrotic syndrome. Details: Clinical research shows that taking calcium 500-1000 mg daily for 3 months in combination with vitamin D3 60,000 IU daily or weekly for 4 weeks has no effect on bone mineral density or the risk of relapse in children with steroid-sensitive nephrotic syndrome (97355).
• Nonmelanoma skin cancer. It is unclear if oral calcium is beneficial for preventing keratinocyte carcinomas. Details: In middle aged and older adults recently diagnosed with a colorectal adenoma, clinical research shows that taking calcium 1200 mg daily as calcium carbonate for 3-5 years does not reduce the incidence of keratinocyte cancer when compared with placebo over a median of 8 years. A sub-group analysis shows that taking calcium alone or with vitamin D3 1000 IU daily reduced the risk of invasive cutaneous squamous cell carcinoma by a moderate amount, but had no effect on the risk of basal cell carcinoma (104622).
• Oral mucositis. When used in combination with fluoride treatments, a calcium phosphate mouth rinse seems to prevent and reduce mucositis-related pain in patients undergoing hematopoietic stem cell transplantation (HSCT). Details: A small clinical study in patients undergoing HSCT shows that using a particular mouth rinse (Caphosol, EUSA Pharma) containing calcium phosphate, in combination with fluoride treatments, reduces days of mucositis, the duration of pain, and the dose and days of morphine used when compared with placebo and fluoride treatment (38611).
• Ovarian cancer. It is unclear if oral calcium is beneficial for ovarian cancer prevention. Details: An older meta-analysis of 12 cohort studies found that dietary calcium intake is not associated with a reduced risk of ovarian cancer (38792). However, a more recent pooled analysis of 15 cohort and case-control studies has found that the highest intake of dietary or dairy calcium is associated with a 20% lower risk of ovarian cancer when compared to the lowest intake (97349).
• Postpartum depression. It is unclear if oral calcium is beneficial for reducing postpartum depression risk. Details: Preliminary clinical research shows that taking calcium 2 grams daily beginning at 11-21 weeks gestation reduces depression at 12 weeks postpartum when compared with placebo. However, no benefit is seen at 6 weeks postpartum (39447).
• Pregnancy-related leg cramps. It is unclear if oral calcium is beneficial for preventing leg cramps during pregnancy. Details: A small clinical study shows that taking calcium 1 gram twice daily (as a mixture of salts) for 2 weeks can reduce pregnancy-related leg cramps during the second half of pregnancy when compared with no treatment (2567).
• Prematurity. It is unclear if supplemental calcium is beneficial for the growth and development of preterm infants. Details: A small clinical study in preterm infants consuming human milk shows that supplementation with calcium 45 mg/kg daily and phosphorus 25 mg/kg daily does not affect infant weight, length, head circumference, or risk of osteopenia after 6 weeks when compared with human milk alone (113924). However, the duration and size of this study may have been too limited to detect any difference between groups.
• Preterm labor. It is unclear if oral calcium reduces the risk of preterm labor. Details: A meta-analysis of 10 clinical studies shows that taking calcium supplements during pregnancy does not reduce the risk of preterm labor when compared with placebo (113909). A separate meta-analysis of 7 clinical studies conducted in China, which evaluated the benefits of calcium carbonate 500-600 mg daily taken in conjunction with aspirin 50-75 mg daily during pregnancy, shows that this combination reduces the relative risk of preterm labor by 74% when compared with routine care (113913).
• Prostate cancer. It is unclear if oral calcium is beneficial for prostate cancer prevention. Details: Some clinical research shows that taking calcium 1200 mg daily might decrease the risk of developing prostate cancer (14133). However, some epidemiological research suggests that consuming very high doses of calcium, over 2000 mg daily, might actually increase the risk of developing prostate cancer (14134). Some epidemiological research also suggests that doses greater than 1500 mg daily increase the risk of poorly differentiated, clinically advanced, and fatal prostate cancer (14132). Consumption of dairy products has also been weakly linked to a modest increase in risk of prostate cancer (98894). However, contradictory research suggests that there is no association between dietary intake of calcium and overall risk of prostate cancer (14131,14132,104630).
• Stroke. It is unclear if oral calcium is beneficial for stroke prevention. Details: Some population research has found that increasing dietary calcium intake is associated with a decreased risk of ischemic stroke (4822,38678). However, other population research has found that increasing dietary calcium intake is not associated with a decreased risk of stroke (91350). One meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years does not affect the risk of stroke when compared with control. However, the majority of the included research evaluated postmenopausal females, and it is unclear if this finding is applicable to other populations (107233).
• Vertigo. Oral calcium with vitamin D might reduce positional vertigo; the effect of calcium when used alone is unclear. Details: A large clinical study in adults with recurrent benign paroxysmal positional vertigo shows that taking calcium 500 mg and vitamin D 400 IU twice daily for one year reduces annual recurrence of vertigo by 27% when compared with no treatment. The number needed to treat to prevent vertigo was 3.7 (103681). It is unclear if this benefit is due to vitamin D, calcium, or the combination. More evidence is needed to rate calcium for these uses.

(Read more about CALCIUM)

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 distensae). Topical cocoa butter does not seem to be beneficial for preventing stretch marks. 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

• Athletic performance. It is unclear if oral garcinia is beneficial for improving athletic performance. Details: Two very small, exploratory studies in untrained females and in elite athletes show that taking hydroxycitric acid (HCA), the active ingredient of garcinia, 250 mg daily for 5 days increases time to exhaustion and lowers the respiratory exchange ratio when compared with taking placebo (19151,26858).
• Hyperlipidemia. It is unclear if oral garcinia is beneficial in patients with hyperlipidemia. Details: A small open-label study of adults with obesity shows that taking garcinia 600 mg twice daily for 3 months may reduce total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides when compared to baseline (111243). The validity of these findings is limited by a lack of a comparator group and blinding.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral garcinia is beneficial in patients with NAFLD. Details: A small clinical study in females with obesity and NAFLD shows that taking a specific product containing garcinia bark leaf extract (HCA Garcinia Vita Plus, Vitamin House) 312.5 mg daily for 8 weeks in combination with a calorie-restricted diet improves body weight, body mass index (BMI), triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol when compared to baseline. However, liver enzyme levels increased slightly (111240). While a calorie-restricted control group was included, a lack of appropriate statistical comparison limits the validity of any between-group findings. Thus, it is unclear if these results are due to garcinia, the calorie-restricted diet, or the combination.
• Obesity. Despite contradictory evidence, oral garcinia seems to produce a very modest weight reduction in some people who are obese or overweight. Details: A meta-analysis of 8 small clinical trials shows that taking garcinia for 8-12 weeks seems to reduce weight by about 1.3 kg and body mass index (BMI) by about 1 kg/m2 when compared with control (104432). This analysis is limited by prominent heterogeneity in the included studies and a lack of sensitivity analyses. Most studies included in the analyses used garcinia 1000-4667 mg (standardized to 50% or 60% hydroxycitric acid) in divided doses daily as non-branded extracts or as specific branded supplements (Super CitriMax, InterHealth Nutraceuticals; Citrin, Sabinsa Corporation) (728,19152,19153,88158,104432). It is unclear which dose, if any, may be most beneficial. More recently, a small, open-label trial in adults with obesity shows that taking garcinia 600 mg twice daily for 3 months reduces body weight and BMI by 1.7 kg and 0.7 kg/m^2 when compared to baseline (111243). The validity of these findings is limited by a lack of a comparator group and blinding. Limited research has also studied garcinia in combination with glucomannan for 6 months, with evidence of moderate benefit for weight loss (96536). More evidence is needed to rate garcinia for these uses.

(Read more about GARCINIA)

EFFECTIVE

• Anemia of chronic disease. Oral and intravenous (IV) iron in combination with erythropoiesis-stimulating agents (ESAs) are effective for treating anemia of chronic disease. Details: Iron supplementation with ESAs is effective for treating anemia associated with chronic kidney disease (CKD) or chemotherapy. During therapy with ESAs, iron levels should be monitored and supplementation provided as needed to ensure that the response is not limited by lack of iron for erythropoiesis (1087,1091,20110,20111,110192). Research shows that IV iron appears to be more effective than oral supplements for this purpose (20112,20113). In patients with CKD, IV iron at total doses from 2232 mg over 6 months to 1020 mg over one week increases hemoglobin levels more than oral doses of 4-6 mg/kg daily or 325 mg daily for up to 6 months (20112). Some research has evaluated the effect of IV or oral iron in patients not treated with ESAs. In patients with cancer or CKD, oral iron supplements have been shown to improve iron status (110184,110192). However, overall benefits of iron alone remain unclear in treated or untreated patients with cancer and more research is needed to rule out an increase in mortality and to determine any effect on blood transfusion requirements (110192). Preliminary clinical research shows that children aged 6 months to 10 years with HIV and anemia who take elemental iron 3 mg/kg daily along with a multivitamin for 3 months have a 41% lower chance of having persistent anemia at 3 months when compared with multivitamins alone (95432).
• Iron deficiency anemia. Oral and intravenous (IV) iron are effective for treating or preventing iron deficiency anemia. The benefits of iron supplementation in people with iron deficiency without anemia are unclear. Details: Oral iron supplements, mainly as ferrous sulfate, are effective for treating and preventing iron deficiency anemia in adults, children, and infants (1089,7135,17495,17496,17497,103806,20114,20115,91183,96621)(104680,104681,112601). Other forms are also effective, including sodium iron ethylenediaminetetra-acetate (NaFeEDTA), iron(III)-hydroxide polymaltose complex (IPC), iron protein succinylate, iron bisglycinate, and lactoferrin with iron (20117,20118,110189). Treatment with iron supplements should increase hemoglobin levels by 1 gram/dL every 2-3 weeks. However, even after hemoglobin has normalized, it may take up to 4 months for iron stores to be replenished (17497). Historically, treatment of iron deficiency anemia with oral iron supplements has typically consisted of a daily dosing regimen, often taken in divided doses to reduce adverse effects. In more recent years, however, intermittent iron supplementation (1-3 doses/week) has become preferred for some patients, particularly those with mild anemia, due to better absorption and a possible reduction in side effects compared to daily dosing. One small clinical study shows that taking ferrous sulfate 60 mg on alternate days in single doses improves iron absorption when compared to once daily dosing (96630). Another small clinical study in females with iron-deficiency anemia shows that fractional iron absorption is 40% to 50% higher with alternate-day dosing compared with daily dosing. Furthermore, total iron absorption was shown to be similar for alternate day dosing of elemental iron 200 mg compared with daily dosing of 100 mg, but the incidence of gastrointestinal adverse effects may be lower for the alternate day dosing regimen (101514). A meta-analysis of 25 clinical trials, including 10,996 menstruating females with or without pre-existing iron deficiency and/or anemia, shows that intermittent iron reduces the risk of anemia and increases hemoglobin and serum ferritin when compared with placebo or no intervention. This meta-analysis did not identify differences in the risk of anemia, hemoglobin, or serum ferritin between intermittent and daily iron supplementation. However, it did show that females receiving intermittent dosing had a 59% reduction in the risk for adverse effects. The validity of these findings is limited by significant heterogeneity in the enrolled populations and selected dosing strategies, including frequency of intermittent dosing, total weekly dose, and duration of follow-up. In addition, the subgroup analyses performed by baseline anemia, hemoglobin, and serum ferritin, as well as duration of follow-up, showed differing overall conclusions when comparing intermittent and daily iron supplementation. While intermittent dosing appears to be beneficial when compared with daily dosing for some patients with iron deficiency anemia, intermittent dosing may be less effective than daily iron supplementation in some patients (103806). For patients with severe anemia, twice daily dosing may be preferred to alternate day dosing due to faster response. A small clinical study in patients with iron deficiency anemia shows that taking ferrous sulfate 200 mg twice daily is more effective at increasing hemoglobin levels by 3 weeks when compared with ferrous sulfate 400 mg taken on alternate days in single doses (102864). Intermittent iron supplementation has also been investigated in children. A meta-analysis of clinical research in children and adolescents with or without pre-existing iron deficiency and/or anemia shows that taking iron supplements 1-2 times weekly is similarly effective as 3-7 times weekly for decreasing iron deficiency and iron deficiency anemia. However, ferritin and hemoglobin levels increased to a greater extent with 3-7 times weekly supplementation (112601). Blood transfusion may be required for some patients with severe iron deficiency anemia who have symptoms such as dyspnea and fatigue (17497). Intravenous iron should be considered in patients who cannot tolerate oral iron or in patients with chronic bleeding or intestinal malabsorption (17497). Guidance from the American Gastroenterological Association and the British Society of Gastroenterology recommends treatment with iron while awaiting investigations to rule out gastrointestinal issues in adults in the absence of an alternative explanation. Ferrous sulfate, fumarate, or gluconate daily are recommended. If adverse effects occur, intake can be reduced to once every other day, or alternative oral or parenteral sources of iron can be used. Parenteral sources should be used if oral sources are contraindicated or ineffective. Treatment should be monitored and continued after hemoglobin levels have normalized (110193,115890). Iron supplementation may also be beneficial in patients with iron deficiency without anemia, which can cause fatigue and reduced well-being, although guidelines are lacking. A meta-analysis of randomized controlled trials in adults with iron deficiency but not anemia shows that supplemental iron improves iron stores and hemoglobin levels. In addition, iron moderately reduces self-reported fatigue, but not physical capacity, when compared with placebo. Oral ferrous sulfate was used in most studies included in the analysis; however, IV or intramuscular iron were also used (104684). Intravenous iron has also been evaluated for the prevention of postoperative anemia. A meta-analysis of several, moderate-quality clinical studies in adults undergoing cardiac surgery, including patients with or without anemia, shows that various types of IV iron (e.g. ferric carboxymaltose, iron sucrose) reduce the risk of red blood cell transfusions by approximately 23%, and improve hemoglobin and iron levels by postoperative day 4, when compared with placebo and oral iron therapy (115898). The validity of these results is limited by heterogeneous methods across clinical studies including patient population, iron formulation, and use of erythropoietin.
• Pregnancy-related iron deficiency. Oral and intravenous (IV) iron are effective for managing pregnancy-related iron deficiency. Details: Clinical research shows that taking iron orally at an average daily dose of 15-225 mg of elemental iron increases maternal hemoglobin levels by up to 1 gram/dL when compared with placebo and reduces the risk of maternal anemia by 50% to 100% (20122,20123,20124,110180,110188,115895). Some clinicians may recommend alternating days of iron administration to reduce gastrointestinal adverse effects. A pooled analysis shows that taking iron supplements, with or without folic acid, on alternating days during pregnancy maintains adequate iron intake and reduces gastrointestinal adverse effects when compared with taking iron daily (96625). Another meta-analysis shows that daily supplementation of iron with folic acid increases hemoglobin levels by 0.24 g/dL when compared with intermittent supplementation, given as 1, 2, or 3 doses weekly. However, clinical significance of this slight increase is unlikely, and no difference in rates of anemia are noted between dosing strategies (115896). Various forms of oral iron seem to be equally effective for raising hemoglobin levels (110185,110188,115895). However, in patients with anemia during pregnancy, meta-analyses of several, moderate-quality clinical studies show that IV iron (e.g. iron sucrose) is more effective than oral iron (e.g. ferrous sulfate) for improving hemoglobin levels and reducing the risk for anemia (110185,115897).

POSSIBLY EFFECTIVE

• Breath-holding attacks. Oral iron seems to be effective for reducing the frequency of breath-holding attacks in children with iron deficiency. Details: The incidence of breath-holding attacks is increased in children with iron deficiency or iron deficiency anemia. Most research shows that oral supplementation with ferrous sulfate 3-6 mg/kg daily for 4-16 weeks reduces the frequency of breath-holding attacks in children aged 1-72 months (20128,104682,104683). The best evidence comes from a meta-analysis of one randomized controlled trial and 11 observational single arm studies (104682). In this analysis, approximately 84% of children experienced at least a 50% decreased frequency of breath-holding attacks (104682). Some preliminary clinical research also shows that administering intramuscular iron reduces the frequency of breath-holding attacks and increases remission in children with iron deficiency anemia (20128).
• Cognitive function. Oral iron seems to be effective for improving cognitive function in children and adolescents with iron deficiency. Details: Taking iron orally seems to improve cognitive function in iron-deficient children and adolescents (20121,112600). For example, ferrous sulfate 650 mg twice daily for 8 weeks improved verbal learning and memory in non-anemic iron-deficient adolescent females (1095). Ferrous sulfate 50 mg twice weekly for 16 weeks appeared to improve attention measures in adolescent females with possible anemia (91186). Iron also appears to reverse developmental and learning deficits caused by iron-deficiency in anemic infants (1104). Some clinical research is focused on children and adolescents from low- and middle-income countries. In children aged 5-19 years with or without iron-deficiency anemia, a meta-analysis of clinical research shows that iron supplementation for 3-8 months dose-dependently improves measured intelligence by a modest amount. However, there was no effect on other measures of cognition, including attention or memory (110181). Another meta-analysis of clinical research in school age children shows that taking iron for 2-12 months modestly improves intelligence, attention, and memory, but not educational achievement, when compared with placebo or no intervention. However, sub-analyses show that any benefits are limited to children with anemia (112600). Most studies included in the analyses evaluated daily iron supplementation, with a few studies assessing iron taken 4-6 times weekly (110181,112600). In contrast, a large clinical trial in schoolchildren in Ethiopia shows that taking iron supplements, providing 42 mg of elemental iron, once weekly for 11 months does not improve working memory, nonverbal intelligence, planning, or problem-solving, and may even worsen one measure of attention and concentration when compared with placebo (113904). These discrepant findings may be related to differences in frequency of dosing (daily vs. weekly) and baseline demographics; only 20% and 4% of children in this study had iron deficiency and iron deficiency anemia, respectively.
• Heart failure. Intravenous (IV) iron seems to be effective for improving certain outcomes in patients with heart failure and iron deficiency. It is unclear if oral iron is effective. Details: Iron deficiency is common in patients with heart failure (17499,112597,112598,112599). A number of large clinical trials and meta-analyses of clinical research in patients with heart failure show that administering IV iron, as ferric carboxymaltose, iron dextran, iron isomaltoside, or iron sucrose, for at least 12 weeks modestly improves quality of life, increases exercise capacity, and reduces hospitalizations when compared with placebo or standard care. However, there was no effect on all-cause mortality or cardiovascular mortality (17498,91179,110176,110187,112597,112598,112599,113900,113901). Based on these results, guidelines from the American Heart Association and European Society of Cardiology support the use of IV iron in patients with heart failure with reduced ejection fraction and iron deficiency to improve symptoms and quality of life. Additionally, IV iron supplementation in these patients is associated with a reduced risk of heart failure hospitalization (115935,115936). Limited research has investigated the effect of oral iron in this population. A small meta-analysis of clinical research shows with low certainty that taking iron orally has beneficial effects on serum ferritin and left ventricular ejection fraction (110178). Most research shows that taking oral iron does not improve hemoglobin levels, quality of life, or exercise capacity when compared with placebo (100970,110178). However, one small clinical trial shows that taking oral iron modestly improves iron status and overall symptoms and increases the 6-minute walking distance by about 46 meters, compared with a reduction of only 14 meters in those taking placebo (110183). Some doses used in individual clinical studies have included iron polysaccharide 150 mg twice daily for 16 weeks and ferrous sulfate 200 mg three times daily for 12 weeks (100970,110183).
• Restless legs syndrome (RLS). Oral and intravenous (IV) iron seem to be beneficial for RLS. The American Academy of Neurology recommends a combination of oral ferrous sulfate and vitamin C or IV ferric carboxymaltose for patients with RLS. Details: RLS is commonly associated with iron deficiency anemia. Some clinical research shows that taking iron in the form of ferrous sulfate 325 mg twice daily for 12 weeks reduces RLS symptoms comparably to pramipexole. Symptoms such as leg discomfort, need to move, and sleep disturbances improved considerably in about half of the patients taking either treatment (91181). Additional clinical research shows that taking ferrous sulfate 325 mg twice daily along with vitamin C 100 mg twice daily for 12 weeks reduces symptoms of RLS when compared with vitamin C alone in patients with RLS and low-normal serum ferritin levels (94189). Based on these results, clinical practice guidelines by the American Academy of Neurology report that taking this combination of oral ferrous sulfate and vitamin C is likely to improve symptoms in patients with RLS and low-normal serum ferritin (93587). Intravenous iron may also reduce symptoms of RLS. Clinical practice guidelines by the American Academy of Neurology report that two doses of IV ferric carboxymaltose 500 mg given 5 days apart are likely to improve symptoms and quality of life within 28 days in patients with moderate to severe RLS, regardless of serum ferritin levels. Iron sucrose, given IV, has also been evaluated in patients with RLS, but there is currently insufficient available evidence to support or refute the use of this form of iron for treating RLS (93587). Additionally, IV and oral iron have been compared in the management of RLS. A clinical study in adults with RLS and iron deficiency anemia shows that administering IV ferumoxytol 1020 mg for 2 doses, 2-7 days apart, reduces self-reported symptom severity and frequency comparably to taking oral ferrous sulfate 650 mg daily for 6 weeks (115894). The validity of these results is limited by methodological concerns, including lack of a placebo control group and failure to obtain all follow-up data.

POSSIBLY INEFFECTIVE

• Athletic performance. Oral iron does not seem to improve athletic performance. Details: A meta-analysis of clinical research in adults of childbearing age shows that iron supplementation improves some exercise performance measures, such as maximal oxygen uptake capacity, but not others, such as time until exhaustion and energy consumption, when compared with control (91184). Another meta-analysis of clinical research in patients with iron deficiency without anemia shows that iron supplementation improves subjective measures of fatigue, but does not improve exercise time to exhaustion or other measures of physical capacity (104684). A small clinical study in healthy children shows that taking iron supplements or consuming food providing iron 30-200 mg daily for 1-2 months improves running performance when compared with placebo. This was demonstrated by reductions of heart rate of 6.6 to 8 beats per minute during the running exercise. One preliminary study included in this analysis also showed that iron supplementation improved treadmill endurance time (20140).
• Child growth. Oral iron does not seem to be beneficial for child growth. Details: Meta-analyses of mainly preliminary clinical research show that oral iron supplementation, at doses averaging 2-80 mg or 1-10 mg/kg elemental iron daily for up to 52 weeks, does not increase growth rate in children (20131,20132,20133,95434).
• Preterm labor. Oral iron does not seem to prevent preterm labor and may actually increase the risk in malaria-endemic regions. Details: A meta-analysis of results from five clinical studies shows that maternal intake of iron as ferrous sulfate 20-60 mg daily for 14-26 weeks starting in the second trimester of pregnancy does not affect the length of gestation or increase birthweight of the infant (95434). In females from a malaria-endemic area who have never been pregnant before, another clinical study shows that taking ferrous gluconate 60 mg and folic acid 2.8 mg weekly, starting before conception and continuing to the first antenatal visit, may more than double the risk of preterm birth, defined as a delivery under 37 weeks gestation, when compared with folic acid alone (100969). Some research suggests that the adverse outcome in this latter study may be explained by a rise in hepcidin levels in pregnant patients with malaria. Hepcidin is a hormone that regulates iron absorption and distribution, and malaria can upregulate hepcidin. High levels of hepcidin can decrease iron absorption, stimulate inflammatory processes, and cause progesterone withdrawal, leading to preterm labor (102863).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• ACE inhibitor-induced cough. It is unclear if oral iron is beneficial in patients with this condition. Details: A small clinical trial shows that taking ferrous sulfate 256 mg daily reduces or eliminates cough induced by ACE inhibitors such as captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestril), and others, when compared with placebo (7307).
• Androgenic alopecia. Oral iron has only been evaluated in combination with other ingredients, its effect when used alone is unclear. Details: A moderate-sized clinical study in adults with androgenic alopecia or telogen effluvium shows that taking one tablet daily of a specific product (GFM Oral, Cantabria Labs), providing an unknown dose of iron in combination with selenium, taurine, cysteine, methionine, and hydrolyzed collagen, along with conventional therapy, consisting primarily of finasteride or minoxidil, for 12 weeks improves hair loss when compared with conventional therapy alone (111636). It is unclear if this effect is due to iron, other ingredients, or the combination.
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral iron is beneficial in children with ADHD. Details: A meta-analysis of three small, lower quality clinical studies in children and adolescents with ADHD and iron deficiency shows that taking ferrous fumarate 200-400 mg, dependent upon body weight, or ferrous sulfate 80 mg daily for 3 months does not improve hyperactivity and inattention when compared with placebo. However, the results of individual clinical studies are inconsistent (115893). The validity of these results is limited by high heterogeneity across clinical studies, including patient baseline characteristics, use of investigator-, parent-, and teacher-rated ADHD scales, and concomitant use of ADHD medication therapy (e.g. stimulants).
• Child development. It is unclear if oral iron is beneficial for improving development in non-anemic children. Details: Some observational research has found that iron deficiency in infancy is associated with poor verbal performance and social skills in childhood (102862). It is unknown whether iron supplementation can ameliorate these developmental issues. In non-anemic infants and children, clinical research shows that iron does not improve cognitive performance; the evidence for the benefits of iron on psychomotor development is conflicting (20129,20130,91315,96616,96626,115891).
• Esophageal cancer. It is unclear if oral iron is beneficial for esophageal cancer prevention. Details: Population research has found that taking iron supplements is associated with a 32% lower risk of esophageal adenocarcinoma when compared to never taking iron supplements. However, use of iron supplements is not associated with a lower risk of esophageal squamous cell carcinoma (95435).
• Fatigue. It is unclear if oral iron is beneficial in patients with fatigue due to iron deficiency without anemia. Details: A meta-analysis of mainly preliminary clinical research in adults with iron deficiency without anemia shows that iron reduces self-reported fatigue moderately more than placebo (104684). A specific ferrous sulfate supplement (Tardyferon; Pierre Fabre Médicament) providing 80 mg of elemental iron daily for 4-12 weeks was used in two studies included in this analysis (11406,91188).
• Inflammatory bowel disease (IBD). In patients with active IBD, intravenous iron may be more beneficial than oral iron due to impaired absorption. However, it may also increase the risk of infection in these patients. Details: Since the absorption of oral iron may be impaired in patients with active symptoms of IBD, guidelines from the British Society of Gastroenterology suggest that treatment with parenteral iron may be needed in patients with IBD who have moderate to severe iron-deficiency anemia (110193). However, a meta-analysis of clinical research in this population shows that administering IV iron, usually as iron sucrose or ferric carboxymaltose, increases the risk of infection by 73% when compared with oral iron or no iron (110186).
• Postoperative recovery. It is unclear if intravenous (IV) iron is beneficial for recovery following cardiac surgery. Details: A meta-analysis of low- to moderate-quality clinical research in patients with preoperative iron-deficiency anemia shows that treatment with IV iron before cardiac surgery does not improve the rate of transfusions or the length of stay in the intensive care unit or hospital when compared with control groups, including placebo, oral iron, or no treatment. Also, a meta-analysis of clinical research shows that IV iron does not reduce postoperative mortality rates (110182).
• Postpartum depression. Although there has been interest in using iron for postpartum depression, there is insufficient reliable information about the clinical effects of iron for this condition.
• Prematurity. Enteral iron seems to be beneficial for some measures of development in preterm infants. Details: A meta-analysis of clinical research in preterm or low birthweight infants fed human milk shows that enteral iron supplementation increases linear growth and reduces the risk of anemia when compared with control groups receiving no iron supplementation. However, there was no effect on serum ferritin, weight, head circumference, cognitive development, risk of infection, or risk of necrotising enterocolitis (110177). Additional clinical research in infants born at 24-28 weeks' gestation shows that a higher average enteral iron dose by 60 days of age is positively associated with cognitive performance at 2 years of corrected age. However, this association was not present for iron doses received at 90 days of age (110190). More evidence is needed to rate iron for these uses.

(Read more about IRON)

EFFECTIVE

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

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about TYROSINE)

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, 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 or intravenously and appropriately. Calcium is safe when used in appropriate doses (7555,12928,12946,95817). However, excessive doses should be avoided. The Institute of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: Age 0-6 months, 1000 mg; 6-12 months, 1500 mg; 1-8 years, 2500 mg; 9-18 years, 3000 mg; 19-50 years, 2500 mg; 51+ years, 2000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stone, hypercalciuria, hypercalcemia, and milk-alkali syndrome. There has also been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these studies, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Other clinical studies suggest that, when combined with vitamin D supplementation, calcium supplementation is not associated with an increased risk of CVD, CHD, or MI (93533,107231). Other analyses report conflicting results and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Advise patients not to consume more than the recommended daily intake of 1000-1200 mg per day, to consider total calcium intake from both dietary and supplemental sources (17484), and to combine calcium supplementation with vitamin D supplementation (93533).

POSSIBLY UNSAFE ...when used orally in excessive doses. The National Academy of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: 19-50 years, 2500 mg; 51 years and older, 2000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stones, hypercalciuria, hypercalcemia, and milk-alkali syndrome. There has also been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these studies, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Other clinical studies suggest that, when combined with vitamin D supplementation, calcium supplementation is not associated with an increased risk of CVD, CHD, or MI (93533,107231). Other analyses report conflicting results and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Advise patients to not consume more than the recommended daily intake of 1000-1200 mg per day, to consider total calcium intake from both dietary and supplemental sources (17484), and to combine calcium supplementation with vitamin D supplementation (93533).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Calcium is safe when used in appropriate doses (17506).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses. The Institute of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: 0-6 months, 1000 mg; 6-12 months, 1500 mg; 1-8 years, 2500 mg; 9-18 years, 3000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stones, hypercalciuria, hypercalcemia, and milk-alkali syndrome.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately (945,1586,3263,3264,17506). The World Health Organization (WHO) recommends prescribing oral calcium supplementation 1.5-2 grams daily during pregnancy to those with low dietary calcium intake to prevent pre-eclampsia (97347).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses. The Institute of Medicine sets the same daily tolerable upper intake level (UL) for calcium according to age independent of pregnancy status: 9-18 years, 3000 mg; 19-50 years, 2500 mg (17506). Doses over these amounts might increase the risk of neonatal hypocalcemia-induced seizures possibly caused by transient neonatal hypoparathyroidism in the setting of excessive calcium supplementation during pregnancy, especially during the third trimester. Neonatal hypocalcemia is a risk factor for neonatal seizures (97345).

(Read more about CALCIUM)

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 garcinia extract when used orally. However, there is some concern about liver toxicity. There are numerous case reports of elevated liver enzymes and symptoms of liver toxicity in patients who have taken garcinia alone or in combination with other ingredients for as little as one week. In at least two reports, hepatotoxicity occurred in patients who were taking garcinia alone. Most other reports occurred in patients taking multi-ingredient products (13037,53511,93380,93381,93384,93385,93392,93393,93394,96535)(102544,102545,111241).

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

(Read more about GARCINIA)

LIKELY SAFE ...when used orally and appropriately. For people age 14 and older with adequate iron stores, iron supplements are safe when used in doses below the tolerable upper intake level (UL) of 45 mg per day of elemental iron. The UL is not meant to apply to those who receive iron under medical supervision (7135,96621). To treat iron deficiency, most people can safely take up to 300 mg elemental iron per day (15). ...when used intravenously and appropriately. Ferric carboxymaltose 200 mg and iron sucrose 200 mg have been given intravenously for up to 10 doses with no reported serious adverse effects (91179). A meta-analysis of clinical studies of hemodialysis patients shows that administering high-dose intravenous (IV) iron does not increase the risk of hospitalization, infection, cardiovascular events, or death when compared with low-dose IV iron, oral iron, or no iron treatment (102861). A more recent meta-analysis of clinical studies of all patient populations shows that administering IV iron does not increase the risk of hospital length of stay or mortality, although the risk of infection is increased by 16% when compared with oral iron or no iron (110186). Another meta-analysis of 3 large clinical trials in patients with heart failure shows that IV ferric carboxymaltose at a dose of around 1500 mg every 6 months for a year does not increase the incidence of adverse effects when compared with placebo (113901). Despite these findings, there are rare reports of hypophosphatemia and/or osteomalacia (112603,112608,112609,112610,113905).

LIKELY UNSAFE ...when used orally in excessive doses. Doses of 30 mg/kg are associated with acute toxicity. Long-term use of high doses of iron can cause hemosiderosis and multiple organ damage. The estimated lethal dose of iron is 180-300 mg/kg; however, doses as low as 60 mg/kg have also been lethal (15).

CHILDREN: LIKELY SAFE
when used orally and appropriately (7135,91183,112601).

CHILDREN: LIKELY UNSAFE
when used orally in excessive amounts. Tell patients who are not iron-deficient not to use doses above the tolerable upper intake level (UL) of 40 mg per day of elemental iron for infants and children aged 0-13 years and 45 mg per day for children aged 14-18 years. Higher doses frequently cause gastrointestinal side effects such as constipation and nausea (7135,20097). Iron is the most common cause of pediatric poisoning deaths. Doses as low as 60 mg/kg can be fatal (15).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Iron is safe during pregnancy and breast-feeding in patients with adequate iron stores when used in doses below the tolerable upper intake level (UL) of 45 mg daily of elemental iron (7135,96625,110180).

PREGNANCY AND LACTATION: LIKELY UNSAFE
when used orally in high doses. Tell patients who are not iron deficient to avoid exceeding the tolerable upper intake level (UL) of 45 mg daily of elemental iron. Higher doses frequently cause gastrointestinal side effects such as nausea and vomiting (7135) and might increase the risk of preterm labor (100969). High hemoglobin concentrations at the time of delivery are associated with adverse pregnancy outcomes (7135,20109).

(Read more about IRON)

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

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

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

(Read more about TYROSINE)

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

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

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

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, bitter orange might increase levels of drug metabolized by CYP2D6.  Details In vitro research shows that octopamine, a constituent of bitter orange, weakly inhibits CYP2D6 enzymes (91878). This effect has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Bitter orange might increase levels of drugs metabolized by CYP3A4.  Details Small clinical studies suggest that single or multiple doses of freshly squeezed bitter orange juice 200-240 mL can inhibit CYP3A4 metabolism of drugs (7029,11362,93470), causing increased drug levels and potentially increasing the risk of adverse effects. However, the extent of the effect of bitter orange on CYP3A4-mediated drug interactions is unknown. Some evidence suggests that bitter orange selectively inhibits intestinal CYP3A4, but not hepatic CYP3A4. Its effect on P-glycoprotein, which strongly overlaps with CYP3A4 interactions, is unclear (7029,11269,11270,11362). One small clinical study shows that drinking 8 ounces of freshly squeezed bitter orange juice has no effect on cyclosporine, which seems to be more dependent on hepatic CYP3A4 and P-glycoprotein than intestinal CYP3A4 (11270).

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

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

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

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

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

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

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

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

(Read more about BITTER ORANGE)

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

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

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

ANTIDIABETES DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, taking caffeine with antidiabetes drugs might interfere with blood glucose control.  Details Data are conflicting. Reports claim that caffeine might increase or decrease blood sugar (6024,8646,114662).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(Read more about CAFFEINE)

ALUMINUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Calcium citrate might increase aluminum absorption and toxicity. Other types of calcium do not increase aluminum absorption.  Details Calcium citrate can increase the absorption of aluminum when taken with aluminum hydroxide. The increase in aluminum levels may become toxic, particularly in individuals with kidney disease (21631). However, the effect of calcium citrate on aluminum absorption is due to the citrate anion rather than calcium cation. Calcium acetate does not appear to increase aluminum absorption (93006).

BISPHOSPHONATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Calcium reduces the absorption of bisphosphonates.  Details Advise patients to take bisphosphonates at least 30 minutes before calcium, but preferably at a different time of day. Calcium supplements decrease absorption of bisphosphonates (12937).

CALCIPOTRIENE (Dovonex) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Taking calcipotriene with calcium might increase the risk for hypercalcemia.  Details Calcipotriene is a vitamin D analog used topically for psoriasis. It can be absorbed in sufficient amounts to cause systemic effects, including hypercalcemia (12938). Theoretically, combining calcipotriene with calcium supplements might increase the risk of hypercalcemia.

CALCIUM CHANNEL BLOCKERS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Intravenous calcium may decrease the effects of calcium channel blockers; oral calcium is unlikely to have this effect.  Details Intravenous calcium is used to decrease the effects of calcium channel blockers in the management of overdose. Intravenous calcium gluconate has been used before intravenous verapamil (Isoptin) to prevent or reduce the hypotensive effects without affecting the antiarrhythmic effects (6124). But there is no evidence that dietary or supplemental calcium when taken orally interacts with calcium channel blockers (12939,12947).

CEFTRIAXONE (Rocephin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Co-administration of intravenous calcium and ceftriaxone can result in precipitation of a ceftriaxone-calcium salt in the lungs and kidneys.  Details Avoid administering intravenous calcium in any form, such as parenteral nutrition or Lactated Ringers, within 48 hours of intravenous ceftriaxone. Case reports in neonates show that administering intravenous ceftriaxone and calcium can result in precipitation of a ceftriaxone-calcium salt in the lungs and kidneys. In several cases, neonates have died as a result of this interaction (15794,21632). So far there are no reports in adults; however, there is still concern that this interaction might occur in adults.

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Using intravenous calcium with digoxin might increase the risk of fatal cardiac arrhythmias.  Details Hypercalcemia increases the risk of fatal cardiac arrhythmias with digoxin (12940). However, one retrospective analysis of clinical data suggests that intravenous calcium does not increase the risk of dysrhythmias or mortality in patients receiving digoxin (38960).

DILTIAZEM (Cardizem, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, calcium may reduce the therapeutic effects of diltiazem.  Details Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically, calcium might increase this risk of hypercalcemia and reduce the effectiveness of diltiazem.

DOLUTEGRAVIR (Tivicay) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce levels of dolutegravir.  Details Advise patients to take dolutegravir either 2 hours before or 6 hours after taking calcium supplements. Pharmacokinetic research suggests that taking calcium carbonate 1200 mg concomitantly with dolutegravir 50 mg reduces plasma levels of dolutegravir by almost 40%. Calcium appears to decrease levels of dolutegravir through chelation (93578).

ELVITEGRAVIR (Vitekta) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce levels of elvitegravir.  Details Advise patients to take elvitegravir either 2 hours before or 2 hours after taking calcium supplements. Pharmacokinetic research suggests that taking calcium along with elvitegravir can reduce blood levels of elvitegravir through chelation (94166).

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce the absorption and effectiveness of levothyroxine.  Details Advise patients to take levothyroxine and calcium supplements at least 4 hours apart. Calcium reduces levothyroxine absorption, probably by forming insoluble complexes (5082). Calcium carbonate supplements reduce effectiveness of levothyroxine in patients with hypothyroidism (5081,5082,6137).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of calcium and lithium may increase this risk of hypercalcemia.  Details Clinical research suggests that long-term use of lithium may cause hypercalcemia in 10% to 60% of patients (38953). Theoretically, concomitant use of lithium and calcium supplements may further increase this risk.

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce the absorption of quinolone antibiotics.  Details Advise patients to take oral quinolones at least 2 hours before or 4-6 hours after calcium supplements or calcium-fortified foods. Taking calcium at the same time as oral quinolones can reduce quinolone absorption. Calcium binds to quinolones in the gut (4412,10339,21638,38570).

RALTEGRAVIR (Isentress) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Calcium may reduce levels of raltegravir.  Details Pharmacokinetic research shows that taking a single dose of calcium carbonate 3000 mg along with raltegravir 400 mg twice daily modestly decreases the mean area under the curve of raltegravir, but the decrease does not necessitate a dose adjustment of raltegravir (94164). However, a case of elevated HIV-1 RNA levels and documented resistance to raltegravir has been reported for a patient taking calcium carbonate 1 gram three times daily plus vitamin D3 (cholecalciferol) 400 IU three times daily in combination with raltegravir 400 mg twice daily for 11 months. It is thought that calcium reduced raltegravir levels by chelation, leading to treatment failure (94165).

SOTALOL (Betapace) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Calcium seems to reduce the absorption of sotalol.  Details Advise patients to separate doses by at least 2 hours before or 4-6 hours after calcium. Calcium appears to reduce the absorption of sotalol, probably by forming insoluble complexes (10018).

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Calcium seems to reduce the absorption of tetracycline antibiotics.  Details Advise patients to take oral tetracyclines at least 2 hours before, or 4-6 hours after calcium supplements. Taking calcium at the same time as oral tetracyclines can reduce tetracycline absorption. Calcium binds to tetracyclines in the gut (1843).

THIAZIDE DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Taking calcium along with thiazides might increase the risk of hypercalcemia and renal failure.  Details Thiazides reduce calcium excretion by the kidneys (1902). Using thiazides along with moderately large amounts of calcium carbonate increases the risk of milk-alkali syndrome (hypercalcemia, metabolic alkalosis, renal failure). Patients may need to have their serum calcium levels and/or parathyroid function monitored regularly.

VERAPAMIL (Calan, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, calcium may reduce the therapeutic effects of verapamil.  Details Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically, use of calcium supplements may increase this risk of hypercalcemia and reduce the effectiveness of verapamil.

(Read more about CALCIUM)

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)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, hydroxycitric acid (HCA), the main active ingredient in garcinia, might increase the risk of bleeding when used with antiplatelet or anticoagulant drugs.  Details HCA inhibits platelet aggregation in vitro. The inhibitory effect seems to be greater in platelets extracted from diabetic subjects than non-diabetic subjects (26862).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, hydroxycitric acid (HCA), the main active ingredient in garcinia, might have additive effects with antidiabetes drugs and increase the risk of hypoglycemia.  Details HCA reduces fasting and postprandial blood glucose levels in animal models, theoretically by delaying glucose absorption (26863,26867,26868). This effect has not been reported in humans.

HEPATOTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use with other potentially hepatotoxic drugs might increase the risk of developing liver damage.  Details There have been reports of acute hepatitis with elevated liver enzymes associated with garcinia, when taken alone or in combination with other ingredients (13037,53511,93380,93381,93384,93392,93393,93394,102544,102545). Case reports collected from the Drug Induced Liver Injury Network suggest this risk may be greater in people who carry the HLA B*35:01 allele (108401).

SEROTONERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, combining garcinia with other serotonergic drugs might increase the risk of serotonergic side effects, including serotonin syndrome.  Details In one report, a patient experienced serotonin syndrome after taking garcinia extract (60% hydroxycitric acid) 1000 mg daily in combination with escitalopram 20 mg, which had been taken for a year. The patient was switched to sertraline 50 mg daily and again experienced serotonin syndrome (23545).

(Read more about GARCINIA)

BISPHOSPHONATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Iron reduces the absorption of bisphosphonates.  Details Advise patients that doses of bisphosphonates should be separated by at least two hours from doses of all other medications, including supplements such as iron. Divalent cations, including iron, can decrease absorption of bisphosphonates by forming insoluble complexes in the gastrointestinal tract (15).

CHLORAMPHENICOL Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, taking chloramphenicol with iron might reduce the response to iron therapy in iron deficiency anemia.  Details Chloramphenicol interferes with erythrocyte maturation (15,3046). However, since chloramphenicol isn't usually taken for prolonged periods, this isn't likely to be clinically significant.

DENOSUMAB (Prolia, others) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Administration of intravenous iron within one month of denosumab administration might increase the risk of severe hypophosphatemia and hypocalcemia.  Details A case of severe hypocalcemia (albumin corrected calcium 6.88 mg/dL, ionized calcium 3.68 mg/dL) and hypophosphatemia (<0.5 mg/dL) with respiratory acidosis, QT interval prolongation, and nonsustained ventricular tachycardia was reported in a 76-year-old male who had received an iron polymaltose infusion within 2 weeks of a subcutaneous injection of denosumab. Serum parathyroid hormone was also elevated (348 pg/mL). Subsequent iron infusions with iron polymaltose and ferric carboxymaltose were followed by transient hypophosphatemia, but without hypocalcemia. Additionally, a literature review describes 6 additional cases of hypophosphatemia and hypocalcemia in patients 52-92 years of age who had been administered intravenous iron as either ferric carboxymaltose or iron polymaltose and subcutaneous denosumab within 1-4 weeks of each other (113905).

DOLUTEGRAVIR (Tivicay) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Iron might decrease dolutegravir levels by reducing its absorption.  Details Advise patients to take dolutegravir at least 2 hours before or 6 hours after taking iron. Pharmacokinetic research shows that iron can decrease the absorption of dolutegravir from the gastrointestinal tract through chelation (93578). When taken under fasting conditions, a single dose of ferrous fumarate 324 mg orally along with dolutegravir 50 mg reduces overall exposure to dolutegravir by 54% (94190).

INTEGRASE INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking iron along with integrase inhibitors might decrease the levels and clinical effects of these drugs.  Details Iron is a divalent cation. There is concern that iron may decrease the absorption of integrase inhibitors from the gastrointestinal tract through chelation (93578). One pharmacokinetic study shows that iron can decrease blood levels of the specific integrase inhibitor dolutegravir through chelation (94190). Also, other pharmacokinetic research shows that other divalent cations such as calcium can decrease the absorption and levels of some integrase inhibitors through chelation (93578,93579).

LEVODOPA Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Iron might decrease levodopa levels by reducing its absorption.  Details Advise patients to separate doses of levodopa and iron as much as possible. There is some evidence in healthy people that iron forms chelates with levodopa, reducing the amount of levodopa absorbed by around 50% (9567). The clinical significance of this hasn't been determined.

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Iron might decrease levothyroxine levels by reducing its absorption.  Details Advise patients to separate levothyroxine and iron doses by at least 2 hours. Iron can decrease the absorption and efficacy of levothyroxine by forming insoluble complexes in the gastrointestinal tract (9568).

METHYLDOPA (Aldomet) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Iron might decrease methyldopa levels by reducing its absorption.  Details Advise patients to separate methyldopa and iron doses by at least 2 hours. Iron can decrease the absorption of methyldopa from the gastrointestinal tract through chelation, resulting in increases in blood pressure (7900,20151).

MYCOPHENOLATE MOFETIL (CellCept) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, iron might decrease mycophenolate mofetil levels by reducing its absorption.  Details Advise patients to take iron 4-6 hours before, or 2 hours after, mycophenolate mofetil. It has been suggested that a decrease of absorption is possible, probably by forming nonabsorbable chelates. However, mycophenolate pharmacokinetics are not affected by iron supplementation in available clinical research (3046,20152,20153,20154,20155).

PENICILLAMINE (Cuprimine, Depen) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Iron might decrease penicillamine levels by reducing its absorption.  Details Advise patients to separate penicillamine and iron doses by at least 2 hours. Oral iron supplements can reduce absorption of penicillamine by 30% to 70%, probably due to chelate formation. In people with Wilson's disease, this interaction has led to reduced efficacy of penicillamine (3046,3072,20156).

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Iron might decrease levels of quinolone antibiotics by reducing their absorption.  Details Advise patients to separate quinolone antibiotics and iron doses by at least 2 hours. Iron decreases the absorption of quinolones due to formation of insoluble complexes in the gastrointestinal tract (15,3072).

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Iron might decrease levels of tetracycline antibiotics by reducing their absorption.  Details Advise patients to take iron at least 2 hours before or 4 hours after tetracycline antibiotics. Concomitant use can decrease absorption of tetracycline antibiotics from the gastrointestinal tract by 50% to 90% (15).

(Read more about IRON)

LEVODOPA Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, tyrosine might decrease the effectiveness of levodopa.  Details Tyrosine and levodopa compete for absorption in the proximal duodenum by the large neutral amino acid (LNAA) transport system (2719). Advise patients to separate doses of tyrosine and levodopa by at least 2 hours.

THYROID HORMONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, tyrosine might have additive effects with thyroid hormone medications.  Details Tyrosine is a precursor to thyroxine and might increase levels of thyroid hormones (7212).

(Read more about TYROSINE)

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

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

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

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

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

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

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

(Read more about BITTER ORANGE)

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

Cardiovascular ...Caffeine can temporarily increase blood pressure. Usually, blood pressure increases 30 minutes after ingestion, peaks in 1-2 hours, and remains elevated for over 4 hours (36539,37732,37989,38000,38300).
Although acute administration of caffeine can cause increased blood pressure, regular consumption does not seem to increase either blood pressure or pulse, even in mildly hypertensive patients (1451,1452,2722,38335). However, the form of caffeine may play a role in blood pressure increase after a more sustained caffeine use. In a pooled analysis of clinical trials, coffee intake was not associated with an increase in blood pressure, while ingesting caffeine 410 mg daily for at least 7 days modestly increased blood pressure by an average of 4.16/2.41 mmHg (37657). Another meta-analysis of clinical research shows that taking caffeine increases systolic and diastolic blood pressure by approximately 2 mmHg when compared with control. Preliminary subgroup analyses suggest that caffeine may increase blood pressure more in males or at doses over 400 mg (112738).
When used prior to intensive exercise, caffeine can increase systolic blood pressure by 7-8 mmHg (38308). The blood pressure-raising effects of caffeine are greater during stress (36479,38334) and after caffeine-abstinence of at least 24 hours (38241).
Epidemiological research suggests there is no association of caffeine consumption with incidence of hypertension (38190). Habitual coffee consumption also doesn't seem to be related to hypertension, but habitual consumption of sugared or diet cola is associated with development of hypertension (13739).
Epidemiological research has found that regular caffeine intake of up to 400 mg daily is not associated with increased incidence of atrial fibrillation (38018,38076,91028,91034,97451,97453,103708), atherosclerosis (38033), cardiac ectopy (91127), stroke (37804), ventricular arrhythmia (95948,97453), and cardiovascular disease in general (37805,98806). One clinical trial shows that in adults with diagnosed heart failure, consumption of 500 mg of coffee does not result in an increased risk for arrhythmia during exercise (95950). However, caffeine intake may pose a greater cardiovascular risk to subjects that are not regular users of caffeine. For example, in one population study, caffeinated coffee consumption was associated with an increased risk of ischemic stroke in subjects that don't regularly drink coffee (38102). In a population study in Japanese subjects, caffeine-containing medication use was modestly associated with hemorrhagic stroke in adults that do not consume caffeine regularly (91059).
The most common side effect of caffeine in neonates receiving caffeine for apnea is tachycardia (98807,114658).

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

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

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

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

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

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

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

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

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

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

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

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

(Read more about CAFFEINE)

General ...Orally and intravenously, calcium is well-tolerated when used appropriately.
Most Common Adverse Effects:
Orally: Belching, constipation, diarrhea, flatulence, and stomach upset.
Serious Adverse Effects (Rare):
Orally: Case reports have raised concerns about calciphylaxis and kidney stones.

Cardiovascular ...There has been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these results, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Many of these trials also only included postmenopausal females. Other analyses report conflicting results, and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Reasons for these discrepancies are not entirely clear. It may relate to whether calcium is taken as monotherapy or in combination with vitamin D. When taken with vitamin D, which is commonly recommended, calcium supplementation does not appear to be associated with an increased risk of CVD, CHD, or MI (93533,107231). Also, the association between calcium supplementation and CVD, CHD, or MI risk may be influenced by the amount of calcium consumed as part of the diet. Supplementation with calcium may be associated with an increased risk of MI in people with dietary calcium intake above 805 mg daily, but not in those with dietary calcium intake below 805 mg daily (17482). To minimize the possible risk of CVD, CHD, or MI, advise patients not to consume more than the recommended daily intake of 1000-1200 mg and to consider total calcium intake from both dietary and supplemental sources (17484). While dietary intake of calcium is preferred over supplemental intake, advise patients who require calcium supplements to take calcium along with vitamin D, as this combination does not appear to be associated with an increased risk of MI (93533).
Rarely, calcium intake can increase the risk of calciphylaxis, which usually occurs in patients with kidney failure. Calciphylaxis is the deposition of calcium phosphate in arterioles, which causes skin ulcers and skin necrosis. In a case report, a 64-year-old female with a history of neck fracture, sepsis, and ischemic colitis presented with painful leg ulcers due to calciphylaxis. She discontinued calcium and vitamin D supplementation and was treated with sodium thiosulfate and supportive care (95816).

Gastrointestinal ...Orally, calcium can cause belching, flatulence, nausea, gastrointestinal discomfort, and diarrhea (1824,1843,12950,38803). Although constipation is frequently cited as an adverse effect of calcium, there is no scientific substantiation of this side effect (1824,1843,1844,1845,12950,38978). Calcium carbonate has been reported to cause acid rebound, but this is controversial (12935,12936).

Oncologic ...There is some concern that very high doses of calcium might increase the risk of prostate cancer. Some epidemiological evidence suggests that consuming over 2000 mg/day of dietary calcium might increase the risk for prostate cancer (4825,12949). Additional research suggests that calcium intake over 1500 mg/day might increase the risk of advanced prostate cancer and prostate cancer mortality (14132). Consumption of dairy products has also been weakly linked to a small increase in prostate cancer risk (98894). However, contradictory research suggests no association between dietary intake of calcium and overall prostate cancer risk (14131,14132,104630). More evidence is needed to determine the effect of calcium, if any, on prostate cancer risk.

Renal ...Kidney stones have been reported in individuals taking calcium carbonate 1500 mg daily in combination with vitamin D 2000 IU daily for 4 years (93943).

(Read more about CALCIUM)

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 ...Orally, garcinia and its constituent, hydroxycitric acid (HCA), seem to be generally well tolerated in clinical research.
Most Common Adverse Effects:
Orally: Diarrhea, gastrointestinal discomfort, headache, and nausea.
Serious Adverse Effects (Rare):
Orally: Garcinia has been linked with cases of hepatotoxicity and liver failure. There have also been rare cases of mania and pancreatitis.

Cardiovascular ...There is a case report of a 48-year-old female who developed acute necrotizing eosinophilic myocarditis (ANEM) after using a garcinia supplement orally for 2. 5 weeks. On admission to hospital, she was hypotensive and had an elevated serum troponin level, progressing to fulminant heart failure, acute kidney failure, and sustained ventricular arrhythmias. She recovered after treatment with extra-corporeal membrane oxygenation (ECMO) and high-dose corticosteroids (88160). Although the patient had no prior medical history and was not taking any medications, this cannot conclusively be attributed to garcinia.
When taken orally, a specific formulation of the multi-ingredient product Hydroxycut (Iovate Health Sciences Inc.), which was available until 2009, has been associated with malignant hypertension and hypertensive retinopathy. Hydroxycut contains caffeine, garcinia, gymnema, green tea, glucomannan, guarana extract, and willow bark. The suspected causal agent is caffeine, which is dosed at 600 mg daily if Hydroxycut is taken as recommended; however, the responsibility of the other ingredients cannot be ruled out (16527).

Endocrine ...In one case report, a 56-year-old female with pre-existing diabetes, hepatitis C, and hypertension developed diabetic ketoacidosis (DKA) and pancreatitis after taking an unknown amount of garcinia and African mango for one month. Upon admission, she presented with altered mental status, elevated serum glucose and lipase, and high anion gap metabolic acidosis. After 3 days of intensive supportive care, the DKA and pancreatitis resolved. The suspected probable causal agent was garcinia; however, African mango cannot be ruled out (97341). There have been at least 3 other cases of acute pancreatitis associated with use of garcinia (unknown dose) for 2 weeks and up to 7 months in adults ages 36-82 years (105056,105058,105071).

Gastrointestinal ...Orally, garcinia and its active constituent hydroxycitric acid (HCA) have caused mild and infrequent nausea, diarrhea, and other gastrointestinal symptoms (728,11977,19153,88158,88159).

Hepatic ...Orally, garcinia and its constituent hydroxycitric acid (HCA) might cause liver toxicity. Several cases of acute liver toxicity have been reported in patients taking garcinia supplements (93392,93393,93394,95573,102544,102545,104431,111241). Reported doses of garcinia extract range from 480-1800 mg daily, providing up to 900 mg HCA daily (93392,93394,95573,102544,104431). However, not all experts agree that HCA plays a causal role in the hepatotoxicity associated with garcinia supplements; some suggest other mechanisms may be in play, such as immune-mediated processes (95576,108401). In most cases, patients presented with a hepatocellular pattern of toxicity and symptoms of abdominal pain, coagulopathy, jaundice, and elevated transaminases after taking garcinia for several weeks to several months (93393,93394,95573,102544,102545,104431,108401,111241). In most of these cases, there was no evidence of other natural causes of liver disease, such as viral hepatitis. Some of these patients used acetaminophen at recommended doses for limited durations, suggesting that a potential synergistic effect may occur when multiple hepatotoxic agents are used concomitantly.
The Drug-Induced Liver Injury Network has identified 22 cases (11 moderate; 7 severe) of liver injury from garcinia, with 5 cases occurring with garcinia alone, 16 cases occurring in combination with green tea, and 1 case occurring in combination with ashwagandha. Clinical presentations of liver injury related to garcinia closely resemble green tea-related liver injury. Most patients (82%) presented with a hepatocellular pattern of enzyme elevations. The median age of these case reports was 35 years, 41% identified as Hispanic, and most patients were overweight but not obese. In case reports involving garcinia alone, the carrier frequency on HLAB*35:01 was 60%, which is higher than the carrier frequency found in reports of liver injury due to other supplements (19%) and in population controls (11%). Within 3 months of injury onset, 1 patient required liver transplantation and 1 patient died from liver injury (108401).
There have been at least four cases of liver failure requiring transplantation associated with garcinia supplements (93392,95573,98425,104431). In one case related specifically to garcinia, a 52-year-old female had been taking a combination product (USA Nutra Labs) providing garcinia 1000 mg daily, standardized to 60% HCA. The supplement also provided calcium 50 mg, chromium 200 mcg, and potassium 50 mg. Symptoms started within a few weeks of initiation of the product (93392). In another case, a 34-year-old Hispanic male experienced acute liver failure requiring transplant after taking a specific garcinia product (Garcinia Cambogia 5:1 Extract, Swanson Vitamins) 160 mg three times daily before meals for 5 months (95573). In other reports, one 26-year-old male and one female presented to the emergency room with liver failure after 2-7 months of taking a supplement containing garcinia and green tea, with or without whey protein, Veldt raisin, and coffea arabica (98425,104431).
There have also been numerous cases of acute liver toxicity associated with combination products containing garcinia, such as Hydroxycut (Iovate Health Sciences Inc) (13037,53511,93380,93381,93384,93385,96535,98425,104431). Available until 2009, Hydroxycut contained garcinia, green tea, chromium, caffeine, calcium, potassium, and gymnema. A currently available garcinia-containing combination product called Seryburn Day Triple has also been associated with supplement-induced liver injury. (13037,93380,93381,95570,95572,95575,111241). In most of these cases, patients had elevated levels of liver enzymes without evidence of chronic liver disease. Patients usually developed symptoms within 1-12 weeks of taking the product. The clinical pattern of liver damage was often hepatocellular. Most cases reported altered liver enzyme values including ALT, AST, bilirubin, alkaline phosphatase, and international normalized ratio. In most cases, symptoms resolved with near normalization of enzyme levels once the garcinia-containing combination product was discontinued (13037,53511,93380,93381,93384,95567,95572,95575,111241).
However, there is one report of transplant related to Hydroxycut use (93381). As the suspected causal agents, garcinia and green tea were removed from the product during reformulation in 2009 (13037,53511,93380,93381,93384). Hepatotoxicity has been reported in at least one new formulation of Hydroxycut not containing garcinia (93394). Consequently, some experts believe that there is not enough information to attribute hepatotoxicity from this product to garcinia or HCA (95576). Also, in some cases, causality of hepatotoxicity was less clear because patients were taking many other supplements and drugs (95570).There is also a report of fatal liver failure in an obese female taking montelukast while also taking two dietary supplements containing multiple ingredients, including garcinia, gymnema, chromium, bitter orange, and many others. The authors speculated that the combination of montelukast with one or more ingredients in these dietary supplements may have resulted in liver failure (93385).

Musculoskeletal ...Orally, garcinia-containing products have been associated with rhabdomyolysis. There is a case report of a patient who developed rhabdomyolysis 3 hours after ingestion of an herbal product containing ephedra, guarana, chitosan, gymnema, garcinia, and chromium (19154). Since there were multiple ingredients, the effect cannot be conclusively attributed to garcinia. Another case of rhabdomyolysis has been reported for a patient taking an undetermined formulation of Hydroxycut at a dose of 4 caplets daily, naproxen sodium 220 mg as needed for pain, dextroamphetamine daily for 5 days, and hydrocodone-acetaminophen and cyclobenzaprine for pain. Two weeks later, after stopping Hydroxycut and receiving supportive care, the rhabdomyolysis resolved. Hydroxycut was determined to be possibly associated with the rhabdomyolysis (95566). Since Hydroxycut contains multiple ingredients and garcinia content was possible but not confirmed, a causal relationship with garcinia could not be determined.

Neurologic/CNS ...Orally, garcinia and its active constituent hydroxycitric acid (HCA) may cause headache and dizziness (11977). A 35-year-old female reported ocular complications, headache, dizziness, and nausea after taking garcinia extract, providing more than 500 mg of HCA, three times daily for one week. The patient's neurologic symptoms resolved one day after discontinuing the garcinia extract (102546). It is unclear if these neurologic adverse effects were separate from or related to the patient's visual disturbances.

Ocular/Otic ...In one case, a 35-year-old female presented with ocular pain in both eyes, decreased vision in the left eye, headache, dizziness, and nausea after taking garcinia extract orally for one week. Ophthalmologic testing was consistent with adverse ocular effects, showing myopic shift with anterior chamber shallowing and swelling of retinal nerve fiber and macula. The patient reported taking a garcinia product containing hydroxycitric acid 500 mg three times daily, which was more than double the recommended dose per the product label. Symptoms resolved upon discontinuation of the garcinia extract and treatment with oral and topical steroids (102546).

Psychiatric ...Orally, garcinia supplements have been linked to several cases of mania. Typically, symptoms develop 1-8 weeks after starting garcinia. In a report of three patients, symptoms included reduced need for sleep, increased activities and spending, delusions of grandiosity, pressured speech, and agitation. Two of the patients were previously diagnosed with bipolar disorder, and use of garcinia was believed to precipitate episodes during stable phases of the disease. The third patient had no history of bipolar disorder, and use of garcinia was thought to possibly have unmasked previously undiagnosed primary bipolar disorder. In all three cases, recovery included discontinuation of garcinia (95568). In a separate case report, a 23-year-old male taking a specific combination product containing garcinia (Hydroxycut) 1-2 capsules daily for 1 month presented to the emergency room with mania. The patient had no history of bipolar disorder. Although the patient was started on risperidone and clonazepam, symptoms resolved following discontinuation of the supplement. Treatment was discontinued within 4 days of initiation, and the patient remained asymptomatic (95574). A 22-year-old female with no history of bipolar disorder developed mania and psychosis, presenting 10 days after starting Garcinia Cambogia Plus (Apex Vitality Health) 500-1500 mg daily, and Cleanse and Detox (Apex Vitality Health). The latter supplement contains raspberry ketones, licorice root, pumpkin seed, buckthorn root, Cascara sagrada, Irvingia gabonensis, rhubarb, pectin, Lactobacillus acidophilus, and aloe. Symptoms improved upon stopping the supplements and starting lithium and quetiapine (99421).

(Read more about GARCINIA)

General ...Orally or intravenously, iron is generally well tolerated when used appropriately.
Most Common Adverse Effects:
Orally: Abdominal pain, constipation, diarrhea, gastrointestinal irritation, nausea, and vomiting.
Serious Adverse Effects (Rare):
Orally: Case reports have raised concerns about oral or gastric ulcerations.
Intravenously: Case reports have raised concerns about hypophosphatemia and osteomalacia.

Cardiovascular ...There is debate regarding the association between coronary heart disease (CHD) or myocardial infarction (MI) and high iron intake or high body iron stores. Some observational studies have reported that high body iron stores are associated with increased risk of MI and CHD (1492,9542,9544,9545,15175). Some observational studies reported that only high heme iron intake from dietary sources such as red meat are associated with increased risk of MI and CHD (1492,9546,15174,15205,15206,91180). However, the majority of research has found no association between serum iron levels and cardiovascular disease (1097,1099,9543,9547,9548,9549,9550,56469,56683).
There is one case of Kounis syndrome, also referred to as allergic angina or allergic myocardial infarction, in a 39-year-old female patient without previous coronary artery disease given intravenous ferric carboxymaltose. The patient experienced anaphylactic symptoms, including headache, abdominal pain, and breathing difficulties, 3 minutes after starting the infusion. She was further diagnosed with non-ST-elevation myocardial infarction (112607).
There is also a case of a 56-year-old female, negative for HFE mutation homozygosity, diagnosed with acquired iron overload cardiomyopathy after starting ferrous sulfate 325 mg twice daily 3 years prior for iron deficiency secondary to alcoholic cirrhosis with esophageal varices and encephalopathy. The patient had no follow-up care over the 3 years and denied any blood transfusions over that time (113906).

Dermatologic ...Cutaneous hemosiderosis, or skin staining, has been reported following intravenous (IV) iron infusion in various case reports. Most of these cases are due to extravasation following iron infusion (112605,112611). In one case, extravasation has occurred following iron derisomaltose infusion in a 41-year-old female with chronic kidney disease (112605). Rarely, diffuse cutaneous hermosiderosis has occurred. In one case, a 31-year-old female with excessive sweating developed cutaneous hemosiderosis in the armpits following an (IV) iron polymaltose infusion (112611).

Endocrine ...Population research in females shows that higher ferritin levels are associated with an approximately 1. 5-fold higher odds of developing gestational diabetes. Increased dietary intake of heme-iron, but not non-heme iron, is also associated with an increased risk for gestational diabetes. The effects of iron supplementation could not be determined from the evaluated research (96618). However, in a sub-analysis of a large clinical trial in pregnant adults, daily supplementation with iron 100 mg from 14 weeks gestation until delivery did not affect the frequency or severity of glucose intolerance or gestational weight gain (96619).
Intravenous (IV) iron may trigger hypophosphatemia in some patients (113905). A meta-analysis of clinical studies in adults with iron deficiency anemia shows that IV ferric carboxymaltose is associated with a higher risk of hypophosphatemia when compared with other IV formulations (i.e. iron dextran, iron isomaltoside, iron sucrose, and ferumoxytol) (115899). Severe hypophosphatemia requiring IV phosphate has also occurred following IV ferric carboxymaltose (112608,112610).
Additionally, cases of osteomalacia related to hypophosphatemia subsequent to parenteral iron administration have been rarely reported (112603,112609).

Gastrointestinal ...Orally, iron can cause dry mouth, gastrointestinal irritation, heartburn, abdominal pain, constipation, diarrhea, nausea, or vomiting (96621,102864,104680,104684,110179,110185,110188,110189,110192,115894). These adverse effects are uncommon at doses below the tolerable upper intake level (UL) of 45 mg per day of elemental iron in adults with normal iron stores (7135). Higher doses can be taken safely in adults with iron deficiency, but gastrointestinal side effects may occur (1095,20118,20119,56698,102864). Taking iron supplements with food seems to reduce gastrointestinal side effects (7135). However, food can also significantly reduce iron absorption. Iron should be taken on an empty stomach, unless it cannot be tolerated.
There are several formulations of iron products such as ferrous sulfate, ferrous gluconate, ferrous fumarate, and others. Manufacturers of some formulations, such as polysaccharide-iron complex products (Niferex-150, etc), claim to be better tolerated than other formulations; however, there is no reliable evidence to support this claim. Gastrointestinal tolerability relates mostly to the elemental iron dose rather than the formulation (17500).
Enteric-coated or controlled-release iron formulations might reduce nausea for some patients, however, these products also have lower absorption rates (17500).
Liquid oral preparations can blacken and stain teeth (20118).
Iron can also cause oral ulcerations and ulcerations of the gastric mucosa (56684,91182,96622,110179). In one case report, an 87-year-old female with Alzheimer disease experienced a mucosal ulceration, possibly due to holding a crushed ferrous sulfate 80 mg tablet in the mouth for too long prior to swallowing (91182). The ulceration was resolved after discontinuing iron supplementation. In another case report, a 76-year old male suffered gastric mucosal injury after taking a ferrous sulfate tablet daily for 4 years (56684). In a third case report, a 14-year-old female developed gastritis involving symptoms of upper digestive hemorrhage, nausea, melena, and stomach pain. The hemorrhage was attributed to supplementation with ferrous sulfate 2 hours after meals for the prior 2 weeks (96622). In one case report, a 43-year old female developed atrophic gastritis with non-bleeding ulcerations five days after starting oral ferrous sulfate 325 mg twice daily (110179).
Intravenously, iron can cause gastrointestinal symptoms such as nausea and diarrhea(104684,110192,115894).

Hematologic ...Orally, iron supplements have been associated with hemochromatosis. In one case report, a 56-year-old female, negative for HFE mutation homozygosity, was diagnosed with acquired hemochromatosis after starting ferrous sulfate 325 mg twice daily 3 years prior, without follow-up care, for a previous iron deficiency secondary to alcoholic cirrhosis with esophageal varices and encephalopathy (113906).

Immunologic ...Although there is some clinical research associating iron supplementation with an increased rate of malaria infection (56796,95432), the strongest evidence to date does not support this association, at least for areas where antimalarial treatment is available (95433,96623). In an analysis of 14 trials, iron supplementation was not associated with an increased risk of malaria (96623). In a sub-analysis of 7 preliminary clinical studies, the effect of iron supplementation was dependent upon the access to services for antimalarial treatment. In areas where anemia is common and services are available, iron supplementation is associated with a 9% reduced risk of clinical malaria. In an area where services are unavailable, iron supplementation was associated with a 16% increased risk in malaria incidence (96623). The difference in these findings is likely associated with the use of malaria prevention methods.
A meta-analysis of clinical studies of all patient populations shows that administering intravenous (IV) iron, usually iron sucrose and ferric carboxymaltose, increases the risk of infection by 16% when compared with oral iron or no iron. However, sub-analyses suggest this increased risk is limited to patients with inflammatory bowel disease (IBD) (110186). Additionally, a meta-analysis in adults with cancer-associated anemia shows that IV iron does not increase the risk of infection when compared with oral iron or no iron therapy (115892).
Intravenously, iron has rarely resulted in allergic reactions, including anaphylactoid reactions (110185,110192,112606,112607). There is one case of Kounis syndrome, also referred to as allergic angina or allergic myocardial infarction, in a 39-year-old female patient without previous coronary artery disease given IV ferric carboxymaltose. The patient experienced anaphylactic symptoms, including headache, abdominal pain, and breathing difficulties, 3 minutes after starting the infusion. She was further diagnosed with non-ST-elevation myocardial infarction (112607).

Musculoskeletal ...Intravenous (IV) iron may trigger hypophosphatemia in some patients, and cases of osteomalacia related to hypophosphatemia subsequent to parenteral iron administration have been rarely reported (112609,113905). In one case, a 70-year-old male with a genetic hemorrhagic disorder infused with ferric carboxymaltose developed lower limb pain with hypophosphatemia and diffuse bone demineralization in the feet (112609). In a second case, a 61-year-old male developed femoral neck insufficiency fractures following repeated ferric carboxymaltose transfusions for anemia related to vascular malformation in the bowel (112603).

Oncologic ...There is a debate regarding the association between high levels of iron stores and cancer. Data are conflicting and inconclusive (1098,1099,1100,1102). Epidemiological studies suggest that increased body iron stores may increase the risk of cancer or general mortality (56703).
Occupational exposure to iron may be carcinogenic (56691). Oral exposure to iron may also be carcinogenic. Pooled analyses of population studies suggest that increasing the intake of heme iron increases the risk of colorectal cancer. For example, increasing heme iron intake by 1 mg/day is associated with an 11% increase in risk (56699,91185).

Pulmonary/Respiratory ...Orally, iron has been associated with rare reports of iron pill aspiration. This occurs when all or part of the pill is aspirated into the lungs. Once in the lungs, it can cause a chemical burn of the bronchial mucosa. Dozens of cases of iron pill aspiration have been reported in individuals ranging in age from 22 months to 92 years. Patients presented with cough, dyspnea, wheezing, and hemoptysis. The hemoptysis led to death in 2 patients due to hemorrhage. Long-term complication of fibrosis and bronchial stenosis was reported in a few of the cases. In one case, a 48-year-old female accidentally aspirated a ferrous sulfate tablet and presented to the emergency department with cough, blood-stained sputum, chest pain, dyspnea, and acute distress. Bronchoscopy was performed, parts of the pill were retrieved, and chemical burns and necrotic tissue were observed in the bronchus intermedius mucosa and throughout the middle and lower lobes. Debridement with bronchoalveolar lavage was performed. The patient was transferred to the intensive care unit, placed on mechanical ventilation for 2 days, treated with corticosteroids, and discharged on the fifth day of hospitalization. Four weeks post-discharge the patient had significantly improved but still had some reduction in lung capacity.

Other ...Intravenously, sodium ferric gluconate complex (SFGC) caused drug intolerance reactions in 0. 4% of hemodialysis patients including 2 patients with pruritus and one patient each with anaphylactoid reaction, hypotension, chills, back pain, dyspnea/chest pain, facial flushing, rash and cutaneous symptoms of porphyria (56527).

(Read more about IRON)

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

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

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

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

(Read more about TYROSINE)