Gluco-Ultra Formula by CATALO

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

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LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about GREEN TEA)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alopecia areata. It is unclear if raspberry ketone is beneficial for alopecia areata. Details: Preliminary clinical research shows that applying a raspberry ketone 0.01% solution to the scalp once daily for 5 months increases hair growth in 50% of patients with androgenic alopecia or alopecia areata when compared with baseline (17955). The validity of this finding is limited by the lack of a comparator group.
• Androgenic alopecia. It is unclear if raspberry ketone is beneficial for androgenic alopecia. Details: Preliminary clinical research shows that applying a raspberry ketone 0.01% solution to the scalp once daily for 5 months increases hair growth in 50% of patients with androgenic alopecia or alopecia areata when compared with baseline (17955). The validity of this finding is limited by the lack of a comparator group.
• Obesity. Raspberry ketone has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small, uncontrolled clinical trial in healthy adults suggests that taking raspberry ketone 200 mg with vitamin C 1200 mg daily for four weeks reduces body weight and body fat mass (19065). Another clinical study in overweight adults shows that taking a specific product (Prograde Metabolism, Ultimate Wellness Systems) containing 1000 mg of a proprietary blend of raspberry ketone, capsicum extract, caffeine, garlic root, ginger root, bitter orange, L-theanine, and black pepper twice daily for 8 weeks, in conjunction with dieting, reduces body weight, fat mass, and waist and hip circumference when compared with dieting alone (40802). More evidence is needed to rate raspberry ketone for these uses.

(Read more about RASPBERRY KETONE)

LIKELY EFFECTIVE

• Cystic fibrosis. Long-term nebulized hypertonic sodium chloride improves lung function and reduces pulmonary exacerbations in patients with cystic fibrosis. Details: Meta-analyses of clinical research in adults with cystic fibrosis show that, when taken along with a bronchodilator and other standard therapies, nebulized hypertonic sodium chloride in concentrations of 3% to 7%, up to 10 mL twice daily for 4 weeks, increases forced expiratory volume at one second (FEV1) when compared with isotonic saline (sodium chloride 0.9%) (26230,26230). This benefit was not seen at 48 weeks. Other clinical research in adults with cystic fibrosis shows that inhaling sodium chloride 7%, 4 mL twice daily for 48 weeks, does not improve FEV1 when compared with isotonic saline. However, chronic treatment with hypertonic saline does reduce the number of pulmonary exacerbations and increase the number of patients without pulmonary exacerbations when compared with isotonic saline (29402). It is not clear if this benefit occurs in children with cystic fibrosis. The Pulmonary Clinical Practice Guidelines Committee of the Cystic Fibrosis Foundation recommends that individuals with cystic fibrosis aged 6 years or older use nebulized hypertonic saline long-term to improve lung function, reduce the number of exacerbations, and improve quality of life (29403).

POSSIBLY EFFECTIVE

• Amphotericin B nephrotoxicity. Oral sodium chloride seems to prevent nephrotoxicity associated with use of amphotericin B. Details: Clinical research shows that administering oral or intravenous sodium chloride 150 mEq daily during treatment with amphotericin B can attenuate the rise in serum creatinine levels and preserve renal function when compared to treatment with amphotericin B alone (26226).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Bipolar disorder. It is unclear if oral sodium is beneficial in preventing lithium level fluctuations in patients with bipolar disorder. Details: A moderate-sized open-label clinical study in adults with type I bipolar disorder receiving lithium carbonate shows that taking sodium chloride 1 gram daily for 12 weeks along with dietary salt restriction of 1 gram daily reduces the percentage of patients with lithium level fluctuations above 0.8 mEq/L, but does not significantly affect serum sodium, potassium, aldosterone, or creatinine levels when compared with controls who were not salt restricted, but were advised not to consume additional salt at the table (112909). However, the interpretation of these findings is limited by missing data in both groups.
• Canker sores. Although there is interest in using topical sodium chloride for canker sores, there is insufficient reliable information about the clinical effects of sodium chloride for this condition.
• Congestive heart failure. It is unclear if oral sodium is beneficial in patients with acute decompensated heart failure requiring decongestive therapy with diuretics. Details: A moderate-sized clinical study in adults hospitalized with acute decompensated heart failure requiring high-dose intravenous furosemide shows that taking sodium chloride 2 grams three times daily for up to 96 hours does not affect patient weight or serum creatinine levels when compared with placebo (112911). However, the clinical relevance of this study is unclear and it may have been inadequately powered to detect a difference between groups.
• Conjunctivitis. Although there is interest in using ophthalmic sodium chloride for conjunctivitis, there is insufficient reliable information about the clinical effects of sodium chloride for this condition.
• Hyponatremia. Although there is interest in using oral sodium chloride for hyponatremia, there is insufficient reliable information about the clinical effects of oral sodium chloride for this condition.
• Pharyngitis. Although there is interest in using topical sodium chloride for pharyngitis, there is insufficient reliable information about the clinical effects of sodium chloride for this condition.
• Prematurity. It is unclear if oral sodium is beneficial for premature infants. Details: Preliminary clinical research in infants born at less than 32 weeks' gestation shows that adding sodium 4 mEq/kg daily to enteral feedings, starting from the 7th day after birth and continuing through the 35th day, reduces the risk of developing hyponatremia and improves weight gain when compared with adding water (98180). A small, open-label clinical study in newborns less than 35 weeks gestation shows that high sodium intake, defined as an average of 0.25% sodium in maintenance fluids, for 48 hours on day 2 and 3 after birth results in less weight loss within the first 72 hours of life when compared with control, but does not improve mortality, length of hospital stay, or complications from prematurity (112908). However, interpretation of these findings is limited by varied concentrations of sodium as an intervention. More evidence is needed to rate sodium for these uses.

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POSSIBLY SAFE ...when used orally and appropriately. Green coffee extracts taken in doses up to 1000 mg daily, providing up to 500 mg chlorogenic acid, have been used with apparent safety for up to 12 weeks in clinical research (17971,17972,103954). A specific green coffee extract (Svetol, Naturex) has been used with apparent safety in doses up to 200 mg five times daily for up to 12 weeks (17981,17982,17983). Green coffee also contains caffeine, although in lower amounts than regular coffee. One cup of green coffee contains about 20-50 mg of caffeine, compared with about 100 mg in one cup of regular coffee. According to a review by Health Canada, and a subsequent large meta-analysis conducted in the US, doses of caffeine up to 400 mg daily are not associated with significant adverse cardiovascular, bone, behavioral, or reproductive effects in healthy adults (11733,98806). The US Dietary Guidelines Advisory Committee states that there is strong and consistent evidence that consumption of caffeine 400 mg daily is not associated with increased risk of major chronic diseases, such as cardiovascular disease or cancer, in healthy adults (98806). Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine found in ingredients such as green coffee, which naturally contains caffeine, does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product.

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

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

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

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

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

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

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

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

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

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

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LIKELY SAFE ...when used orally in food amounts. Raspberry ketone has Generally Recognized as Safe (GRAS) status for use as a food additive (102356,102358). There is insufficient reliable information available about the safety of raspberry ketone when used in medicinal amounts. However, raspberry ketone is structurally similar to synephrine, a known stimulant agent. Orally, cases of heart palpitations, tachycardia, elevated blood pressure, coronary vasospasm, sweating, feelings of shakiness, and diarrhea are reported after taking raspberry ketone (17961,112386,112400). In one case report, pulseless electrical activity arrest followed by resistant polymorphic ventricular tachycardia occurred in a patient taking raspberry ketone (112386).

PREGNANCY AND LACTATION:
There is insufficient reliable information available about the safety of raspberry ketone; avoid using.

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LIKELY SAFE ...when used orally and appropriately. Sodium is safe in amounts that do not exceed the Chronic Disease Risk Reduction (CDRR) intake level of 2.3 grams daily (100310). Higher doses can be safely used therapeutically with appropriate medical monitoring (26226,26227).

POSSIBLY UNSAFE ...when used orally in high doses. Tell patients to avoid exceeding the CDRR intake level of 2.3 grams daily (100310). Higher intake can cause hypertension and increase the risk of cardiovascular disease (26229,98176,98177,98178,98181,98183,98184,100310,109395,109396,109398,109399). There is insufficient reliable information available about the safety of sodium when used topically.

CHILDREN: LIKELY SAFE
when used orally and appropriately (26229,100310). Sodium is safe in amounts that do not exceed the CDRR intake level of 1.2 grams daily for children 1 to 3 years, 1.5 grams daily for children 4 to 8 years, 1.8 grams daily for children 9 to 13 years, and 2.3 grams daily for adolescents (100310).

CHILDREN: POSSIBLY UNSAFE
when used orally in high doses. Tell patients to avoid prolonged use of doses exceeding the CDRR intake level of 1.2 grams daily for children 1 to 3 years, 1.5 grams daily for children 4 to 8 years, 1.8 grams daily for children 9 to 13 years, and 2.3 grams daily for adolescents (100310). Higher intake can cause hypertension (26229).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Sodium is safe in amounts that do not exceed the CDRR intake level of 2.3 grams daily (100310).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in higher doses. Higher intake can cause hypertension (100310). Also, both the highest and the lowest pre-pregnancy sodium quintile intakes are associated with an increased risk of hypertensive disorders of pregnancy, including gestational hypertension and pre-eclampsia, and the delivery of small for gestational age (SGA) infants when compared to the middle intake quintile (106264).

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ADENOSINE (Adenocard) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, green coffee might decrease the vasodilatory effects of adenosine and interfere with its use prior to stress testing.  Details Green coffee can contain caffeine. Caffeine is a competitive inhibitor of adenosine at the cellular level. However, caffeine does not seem to affect supplemental adenosine because high interstitial levels of adenosine overcome the antagonistic effects of caffeine (11771). It is recommended that methylxanthines such as caffeine, as well as methylxanthine-containing products, be stopped 24 hours prior to pharmacological stress tests (11770). However, methylxanthines appear more likely to interfere with dipyridamole (Persantine) than adenosine-induced stress testing (11771).

ALCOHOL (Ethanol) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, alcohol might increase the levels and adverse effects of caffeine.  Details Green coffee can contain caffeine. Concomitant use of alcohol can increase caffeine serum concentrations and the risk of caffeine adverse effects. Alcohol reduces caffeine metabolism (6370,24693).

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

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

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

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

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

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

CLOZAPINE (Clozaril) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, green coffee might increase the levels and adverse effects of clozapine and acutely exacerbate psychotic symptoms.  Details Green coffee can contain caffeine. Caffeine can increase the effects and toxicity of clozapine. Caffeine doses of 400-1000 mg daily inhibit clozapine metabolism (5051). Clozapine is metabolized by cytochrome P450 1A2 (CYP1A2). Researchers speculate that caffeine might inhibit CYP1A2. However, there is no reliable evidence that caffeine affects CYP1A2. There is also speculation that genetic factors might make some patients more sensitive to an interaction between clozapine and caffeine (13741).

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

DIPYRIDAMOLE (Persantine) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, green coffee might decrease the vasodilatory effects of dipyridamole and interfere with its use prior to stress testing.  Details Green coffee can contain caffeine. Caffeine is a methylxanthine that may inhibit dipyridamole-induced vasodilation (11770,11772,24974,37985,53795). It is recommended that methylxanthines such as caffeine, as well as methylxanthine-containing products such as green coffee, be stopped 24 hours prior to pharmacological stress tests (11770). Methylxanthines appear more likely to interfere with dipyridamole (Persantine) than adenosine-induced stress testing (11771).

DISULFIRAM (Antabuse) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, disulfiram might increase the levels and adverse effects of caffeine.  Details Green coffee can contain caffeine. In human research, disulfiram decreases the clearance and increases the half-life of caffeine (11840).

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

EPHEDRINE Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use might increase the risk of stimulant adverse effects.  Details Green coffee can contain caffeine. There is evidence that using ephedrine with caffeine might increase the risk of serious life-threatening or debilitating adverse effects such as hypertension, myocardial infarction, stroke, seizures, and death (1275,6486,9740,10307). Tell patients to avoid taking caffeine with ephedrine and other stimulants.

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

FLUCONAZOLE (Diflucan) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, fluconazole might increase the levels and adverse effects of caffeine.  Details Green coffee can contain caffeine. Fluconazole decreases caffeine clearance by approximately 25% (11022,24978).

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

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

MEXILETINE (Mexitil) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, mexiletine might increase the levels and adverse effects of caffeine.  Details Green coffee can contain caffeine. Mexiletine can decrease caffeine elimination by 50% (1260,11741,24981).

MONOAMINE OXIDASE INHIBITORS (MAOIs) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the risk of a hypertensive crisis.  Details Green coffee can contain caffeine. Caffeine has been shown to inhibit monoamine oxidase (MAO) A and B in laboratory studies (37724,37877,37912,38108). Concomitant intake of large amounts of caffeine with MAOIs might precipitate a hypertensive crisis (15).

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

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

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

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

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

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

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

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

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

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

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

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

ADENOSINE (Adenocard) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, green tea might decrease the vasodilatory effects of adenosine and interfere with its use prior to stress testing.  Details Green tea contains caffeine. Caffeine is a competitive inhibitor of adenosine at the cellular level. However, caffeine doesn't seem to affect supplemental adenosine because high interstitial levels of adenosine overcome the antagonistic effects of caffeine (11771). It is recommended that methylxanthines and methylxanthine-containing products be stopped 24 hours prior to pharmacological stress tests (11770). However, methylxanthines appear more likely to interfere with dipyridamole (Persantine) than adenosine-induced stress testing (11771).

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

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

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

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

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

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

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

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

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

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

CYTOCHROME P450 1A2 (CYP1A2) INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the levels and adverse effects of caffeine.  Details Green tea contains caffeine. Caffeine is metabolized by cytochrome P450 1A2 (CYP1A2) (3941,5051,11741,23557,23573,23580,24958,24959,24960,24962), (24964,24965,24967,24968,24969,24971,38081,48603). Theoretically, drugs that inhibit CYP1A2 may decrease the clearance rate of caffeine from green tea and increase caffeine levels.

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

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

DISULFIRAM (Antabuse) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, disulfiram might increase the risk of adverse effects from caffeine.  Details In human research, disulfiram decreases the clearance and increases the half-life of caffeine (11840).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

METHOXSALEN (Oxsoralen) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, methoxsalen might increase the levels and adverse effects of caffeine.  Details Green tea contains caffeine. Methoxsalen can reduce caffeine metabolism (23572). Concomitant use can increase caffeine serum concentrations and the risk of caffeine adverse effects.

MEXILETINE (Mexitil) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, mexiletine might increase the levels and adverse effects of caffeine.  Details Green tea contains caffeine. Mexiletine can decrease caffeine elimination by 50% (1260).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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STIMULANT DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, raspberry ketone might increase the risk of adverse cardiovascular effects with stimulant drugs.  Details Structurally, raspberry ketone resembles synephrine, a known stimulant agent. Heart palpitations, elevated blood pressure, coronary vasospasm, pulseless electrical activity arrest, and resistant polymorphic ventricular tachycardia have been reported in patients taking raspberry ketone (17961,112386,112400).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, raspberry ketone might increase warfarin dose requirements.  Details In one case report, a patient taking warfarin 55 mg per week had a decrease in INR over a period of one month while taking raspberry ketone 250 mg daily. A warfarin dose increase to 70 mg per week was necessary to maintain a therapeutic INR while taking raspberry ketone (17962). The mechanism for this potential interaction is not known.

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ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = A Theoretically, a high intake of dietary sodium might reduce the effectiveness of antihypertensive drugs.  Details High intake of dietary sodium can increase systolic and diastolic blood pressure (26222). Also, high intake of sodium may necessitate increased use of antihypertensive medications to achieve blood pressure control in some patients, such as those with chronic kidney disease (26223).

CORTICOSTEROIDS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Concomitant use of mineralocorticoids and some glucocorticoids with sodium supplements might increase the risk of hypernatremia.  Details Mineralocorticoids and some glucocorticoids (corticosteroids) cause sodium retention. This effect is dose-related and depends on mineralocorticoid potency. It is most common with hydrocortisone, cortisone, and fludrocortisone, followed by prednisone and prednisolone (4425).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Altering dietary intake of sodium might alter the levels and clinical effects of lithium.  Details High sodium intake can reduce plasma concentrations of lithium by increasing lithium excretion (26225). Reducing sodium intake can significantly increase plasma concentrations of lithium and cause lithium toxicity in patients being treated with lithium carbonate (26224,26225). Stabilizing sodium intake is shown to reduce the percentage of patients with lithium level fluctuations above 0.8 mEq/L (112909). Patients taking lithium should avoid significant alterations in their dietary intake of sodium.

SODIUM-CONTAINING DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Concomitant use of sodium-containing drugs with additional sodium from dietary or supplemental sources may increase the risk of hypernatremia and long-term sodium-related complications.  Details The Chronic Disease Risk Reduction (CDRR) intake level of 2.3 grams of sodium daily indicates the intake at which it is believed that chronic disease risk increases for the apparently healthy population (100310). Some medications contain high quantities of sodium. When used in conjunction with sodium supplements or high-sodium diets, the CDRR may be exceeded. Additionally, concomitant use may increase the risk for hypernatremia; this risk is highest in the elderly and people with other risk factors for electrolyte disturbances.

TOLVAPTAN (Samsca) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Theoretically, concomitant use of tolvaptan with sodium might increase the risk of hypernatremia.  Details Tolvaptan is a vasopressin receptor 2 antagonist that is used to increase sodium levels in patients with hyponatremia (29406). Patients taking tolvaptan should use caution with the use of sodium salts such as sodium chloride.

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

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

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

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

Gastrointestinal ...Orally, stomach irritation was reported by one person in a clinical trial of green coffee extract (104831).

Musculoskeletal ...Epidemiological evidence regarding the relationship between caffeine, which is found in green coffee, and the risk of osteoporosis is contradictory. Caffeine can increase urinary excretion of calcium (2669,10202,11317). Females identified with a genetic variant of the vitamin D receptor appear to be at an increased risk of the detrimental effect of caffeine on bone mass (2669). However, moderate caffeine intake, less than 300 mg per day, does not seem to significantly increase osteoporosis risk in most postmenopausal adults with normal calcium intake (2669,6025,10202,11317).

Neurologic/CNS ...Orally, dizziness was reported by one person in a clinical trial of green coffee extract (104831).

Ocular/Otic ...Conjunctivitis caused by green coffee bean dust in coffee workers has been described in case reports (53657,53589).

Psychiatric ...Chronic use of caffeine, especially in large amounts, may produce tolerance, habituation, and psychological dependence (3719). Abrupt discontinuation of caffeine may result in physical withdrawal symptoms, including headache, fatigue, drowsiness, decreased physical energy, difficulty concentrating, depression, anxiety, irritability, and reduced alertness (13738). Certain populations such as children and the elderly may be more susceptible to the adverse effects of caffeine (13736).

Pulmonary/Respiratory ...Occupational exposure to green coffee beans has been documented to cause numerous adverse respiratory reactions, including bronchial reactivity, asthma, and rhinitis (53589,53641,53644,53648,53650,53665). Healthy subjects exposed experimentally to green coffee dust displayed acute decreases in expiratory flow rates (53653). In one study, green coffee workers displayed numerous acute respiratory symptoms when exposed to dust; these included coughing, increased sputum, sneezing, difficulty in breathing, running nose, and wheezing; these symptoms resolved after leaving work (53647).

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General ...Orally, green tea is generally well tolerated when consumed as a beverage in moderate amounts. Green tea extract also seems to be well tolerated when used for up to 12 months.
Most Common Adverse Effects:
Orally: Bloating, constipation, diarrhea, dyspepsia, flatulence, and nausea.
Serious Adverse Effects (Rare):
Orally: Hepatotoxicity, hypokalemia, and thrombotic thrombocytopenic purpura have been reported rarely.

Cardiovascular ...Acute or short-term oral administration of green tea may cause hypertension (53719,54014,54065,54076,102716). The risk may be greater for green tea products containing more than 200 mg epigallocatechin gallate (EGCG) (90161). However, consumption of brewed green tea does not seem to increase blood pressure or pulse, even in mildly hypertensive patients (1451,1452). In fact, some evidence suggests that habitual tea consumption is associated with a reduced risk of developing hypertension (12518). Also, epidemiological research suggests there is no association of caffeine consumption with incidence of hypertension or with cardiovascular disease mortality in patients with hypertension (13739,111027). Rarely, green tea consumption may cause hypotension (53867).
Epidemiological research suggests that regular caffeine intake of up to 400 mg per day, or approximately 8 cups of green tea, is not associated with an increased incidence of atrial fibrillation (38018,38076,91028,91034,97451,97453), atherosclerosis (38033), cardiac ectopy (91127), stroke (37804), ventricular arrhythmia (95948,97453), and cardiovascular disease in general (37805,98806).
Combining ephedra with caffeine can increase the risk of adverse effects. Jitteriness, hypertension, seizures, and temporary loss of consciousness has been associated with the combined use of ephedra and caffeine (2729). There is also a report of ischemic stroke in an athlete who consumed ephedra 40-60 mg, creatine monohydrate 6 grams, caffeine 400-600 mg, and a variety of other supplements daily for 6 weeks (1275). In theory, combining caffeinated green tea with ephedra would have similar effects.
In a case report, the EGCG component of a specific weight loss supplement (Hydroxycut) was thought to be responsible for atrial fibrillation (54028). The patient was given two doses of intravenous diltiazem and was loaded with intravenous digoxin. Thirty-six hours after the last product dose, she spontaneously converted to normal sinus rhythm. The authors suggested that the block of the atrial-specific KCNA5 potassium channel likely played a role in this response.
A case of thrombotic thrombocytopenic purpura has been reported for a patient who consumed a weight loss product containing green tea (53978). She presented at the emergency department with a one-week history of malaise, fatigue, and petechiae of the skin. Twelve procedures of plasmapheresis were performed, and corticosteroid treatment was initiated. She was discharged after 20 days.

Dermatologic ...Orally, green tea may cause skin rashes or skin irritation (53731,54038,90161,90187,102716). Topically, green tea may cause local skin reactions or skin irritation, erythema, burning, itching, edema, and erosion (53731,54018,97136,104609,111031). A green tea extract ointment applied to the cervix can cause cervical and vaginal inflammation, vaginal irritation, and vulval burning (11310,36442,36438). When applied to external genital or perianal warts, a specific green tea extract ointment (Veregen, Bradley Pharmaceuticals) providing 15% kunecatechins can cause erythema, pruritus, local pain, discomfort and burning, ulceration, induration, edema, and vesicular rash (15067,53907).

Endocrine ...There is some concern that, due to its caffeine content, green tea may be associated with an increased risk of fibrocystic breast disease, breast cancer, and endometriosis. However, this is controversial since findings are conflicting (8043). Restricting caffeine in females with fibrocystic breast conditions doesn't seem to affect breast nodularity, swelling, or pain (8996).
A population analysis of the Women's Health Initiative observational study has found no association between consumption of caffeine-containing beverages, such as green tea, 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).
A case of hypoglycemia has been reported for a clinical trial participant with type 2 diabetes who used green tea in combination with prescribed antidiabetes medication (54035).

Gastrointestinal ...Orally, green tea beverage or supplements can cause nausea, vomiting, abdominal bloating and pain, constipation, dyspepsia, reflux, morning anorexia, increased thirst, flatulence, and diarrhea. These effects are more common with higher doses of green tea or green tea extract, equivalent to 5-6 liters of tea per day (8117,11366,36398,53719,53867,53936,54038,54076,90139,90140)(90161,90175,90187,97131,97136,102716).

Hepatic ...There is concern that some green tea products, especially green tea extracts, can cause hepatotoxicity in some patients. In 2017, the regulatory agency Health Canada re-issued a warning to consumers about this concern. The updated warning advises patients taking green tea extracts, especially those with liver disease, to watch for signs of liver toxicity. It also urges children to avoid taking products containing green tea extracts (94897). In 2020, the United States Pharmacopeia (USP) determined that any products bearing its seal of verification must include a specific warning on the label stating "Do not take on an empty stomach. Take with food. Do not use if you have a liver problem and discontinue use and consult a healthcare practitioner if you develop symptoms of liver trouble, such as abdominal pain, dark urine, or jaundice (yellowing of the skin or eyes)" (102722).
Numerous case reports of hepatotoxicity, primarily linked to green tea extract products taken in pill form, have been published. A minimum of 29 cases have been deemed at least probably related to green tea and 38 have been deemed possibly related. In addition, elevated liver enzymes have been reported in clinical research (14136,15026,53740,53746,53775,53859,54027,90139,90162,90164)(93256,94898,94899,102716,102720,102722,107158,111020). Most cases of toxicity have had an acute hepatitis-like presentation with a hepatocellular-elevation of liver enzymes and some cholestasis. Onset of hepatotoxic symptoms usually occurs within 3 months after initiation of the green tea extract supplement, and symptoms can persist from 10 days to 1 year (95439,94897,94898,107158). Some reports of hepatotoxicity have been associated with consumption of green tea-containing beverages as well (15026,53742,54016,90125,90143).
In most cases, liver function returned to normal after discontinuation of the green tea product (14136,15026,53859,93256,107158). In one case, use of a specific ethanolic green tea extract (Exolise, Arkopharma) resulted in hepatotoxicity requiring a liver transplant. Due to concerns about hepatotoxicity, this specific extract was removed from the market by the manufacturer (14310). Since then, at least 5 cases of liver toxicity necessitating liver transplantation have been reported for patients who used green tea extracts (94898,107158). In another case, use of green tea (Applied Nutrition Green Tea Fat Burner) in combination with whey protein, a nutritional supplement (GNC Mega Men Sport), and prickly pear cactus resulted in acute liver failure (90162).
Despite the numerous reports of hepatotoxicity associated with the use of green tea products, the actual number of hepatotoxicity cases is low when the prevalence of green tea use is considered. From 2006 to 2016, liver injury from green tea products was estimated have occurred in only 1 out of 2.7 million patients who used green tea products (94897,95440).
In addition to the fact that green tea hepatotoxicity is uncommon, it is also not clear which patients are most likely to experience liver injury (94897,95440). The hepatotoxicity does not appear to be an allergic reaction or an autoimmune reaction (94897). It is possible that certain extraction processes, for example, ethanolic extracts, produce hepatotoxic constituents. However, in most cases, the presence of contaminants in green tea products has not been confirmed in laboratory analyses (90162).
Although results from one analysis of 4 small clinical studies disagrees (94899), most analyses of clinical data, including one conducted by the European Food Safety Association, found that hepatotoxicity from green tea products is associated with the dose of EGCG in the green tea product. Results show that daily intake of EGCG in amounts greater than or equal to 800 mg per day is associated with a higher incidence of elevated liver enzymes such as alanine transaminase (ALT) (95440,95696,97131). However, it is still unclear what maximum daily dose of EGCG will not increase liver enzyme levels or what minimum daily dose of EGCG begins to cause liver injury. In many cases of liver injury, the dose of green tea extract and/or EGCG is not known. Therefore, a minimum level of green tea extract or EGCG that would cause liver injury in humans cannot be determined (102722). Keep in mind that daily intake of green tea infusions provides only 90-300 mg of EGCG daily. So for a majority of people, green tea infusions are likely safe and unlikely to cause liver injury (95696). Also, plasma levels of EGCG are increased when green tea catechins are taken in the fasting state, suggesting that green tea extract should be taken with food (102722).
Until more is known, advise patients that green tea products, especially those containing green tea extract, might cause liver damage. However, let them know that the risk is uncommon, and it is not clear which products are most likely to cause the adverse effect or which patients are most likely to be affected. Advise patients with liver disease to consult their healthcare provider before taking products with green tea extract and to notify their healthcare provider if they experience symptoms of liver damage, including jaundice, dark urine, sweating, or abdominal pain (102722).

Immunologic ...Orally, matcha tea has resulted in at least one case of anaphylaxis related to green tea proteins. A 9-year-old male experienced systemic redness and hives, nausea, and anaphylaxis 60 minutes after consuming matcha tea-flavored ice cream (107169). The caffeine found in green tea can also cause anaphylaxis in sensitive individuals, although true IgE-mediated caffeine allergy seems to be relatively rare (11315).

Musculoskeletal ...Orally, the ingestion of the green tea constituent epigallocatechin gallate (EGCG) or a decaffeinated green tea polyphenol mixture may cause mild muscle pain (36398).
There is some concern regarding the association between caffeinated green tea products and osteoporosis. Epidemiological evidence regarding the relationship between caffeinated beverages such as green tea and the risk for osteoporosis is contradictory. Caffeine can increase urinary excretion of calcium (2669,10202,11317). 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 of less than 400 mg per day, or about 8 cups of green tea, doesn't seem to significantly increase osteoporosis risk in most postmenopausal adults with normal calcium intake (2669,6025,10202,11317).

Neurologic/CNS ...Orally, green tea can cause central nervous system stimulation and adverse effects such as headache, anxiety, dizziness, insomnia, fatigue, agitation, tremors, restlessness, and confusion. These effects are more common with higher doses of green tea or green tea extract, equivalent to 5-6 liters of tea per day (8117,11366,53719,90139,102716). The green tea constituent epigallocatechin gallate (EGCG) or decaffeinated green tea may also cause mild dizziness and headache (36398).
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). Topically, green tea extract (Polyphenon E ointment) may cause headache when applied to the genital area (36442).

Psychiatric ...Green tea contains a significant amount of caffeine. Chronic use, especially in large amounts, can produce tolerance, habituation, and psychological dependence (11832). 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). Other researchers suggest symptoms such as headache; tiredness and fatigue; decreased energy, alertness, and attentiveness; drowsiness; decreased contentedness; depressed mood; difficulty concentrating; irritability; and lack of clear-headedness are typical of caffeine withdrawal (13738). 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).

Pulmonary/Respiratory ...A case of granulomatous alveolitis with lymph follicles has been reported for a 67-year-old female who used green tea infusions to wash her nasal cavities for 15 years (54088). Her symptoms disappeared 2 months after stopping this practice and following an undetermined course of corticosteroids. In a case report, hypersensitivity pneumonitis was associated with inhalation of catechin-rich green tea extracts (54025). Occupational exposure to green tea dust can cause sensitization, which may include nasal and asthmatic symptoms (11365).

Renal ...There are two cases of hypokalemia associated with drinking approximately 8 cups daily of green tea in an elderly couple of Asian descent. The hypokalemia improved after reducing their intake by 50%. It is possible that this was related to the caffeine in the green tea (98418).

Other ...Orally, intake of a specific green tea extract product (Polyphenon E) may cause weight gain (90139).

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General ...Orally, a thorough evaluation of safety outcomes for raspberry ketone has not been conducted. Structurally, raspberry ketone resembles synephrine, a known stimulant agent.

Cardiovascular ...Structurally, raspberry ketone resembles synephrine, a known stimulant agent. Although not well studied in humans, stimulant-related side effects are possible. Orally, cases of heart palpitations, tachycardia, elevated blood pressure, coronary vasospasm are reported after taking raspberry ketone (17961,112386,112400). In one case report, pulseless electrical activity arrest followed by resistant polymorphic ventricular tachycardia occurred in a patient taking raspberry ketone. The arrhythmia resolved after numerous defibrillation shocks and placement of a temporary transvenous pacemaker with overdrive pacing (112386). In another case report, 5 episodes of ST elevation occurred over 2 days following ingestion of raspberry ketone (112400).

Neurologic/CNS ...Structurally, raspberry ketone resembles synephrine, a known stimulant agent. Although not well studied in humans, stimulant-related side effects are possible. Two case reports describe symptoms of sweating, diarrhea, and feelings of shakiness after oral use of raspberry ketone (17961,112400).

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General ...Orally, sodium is well tolerated when used in moderation at intakes up to the Chronic Disease Risk Reduction (CDRR) intake level. Topically, a thorough evaluation of safety outcomes has not been conducted.
Serious Adverse Effects (Rare):
Orally: Worsened cardiovascular disease, hypertension, kidney disease.

Cardiovascular ...Orally, intake of sodium above the CDRR intake level can exacerbate hypertension and hypertension-related cardiovascular disease (CVD) (26229,98176,100310,106263). A meta-analysis of observational research has found a linear association between increased sodium intake and increased hypertension risk (109398). Observational research has also found an association between increased sodium salt intake and increased risk of CVD, mortality, and cardiovascular mortality (98177,98178,98181,98183,98184,109395,109396,109399). However, the existing research is unable to confirm a causal relationship between sodium intake and increased cardiovascular morbidity and mortality; high-quality, prospective research is needed to clarify this relationship (100312). As there is no known benefit with increased salt intake that would outweigh the potential increased risk of CVD, advise patients to limit salt intake to no more than the CDRR intake level (100310).
A reduction in sodium intake can lower systolic blood pressure by a small amount in most individuals, and diastolic blood pressure in patients with hypertension (100310,100311,106261). However, post hoc analysis of a small crossover clinical study in White patients suggests that 24-hour blood pressure variability is not affected by high-salt intake compared with low-salt intake (112910). Additionally, the available research is insufficient to confirm that a further reduction in sodium intake below the CDRR intake level will lower the risk for chronic disease (100310,100311). A meta-analysis of clinical research shows that reducing sodium intake increases levels of total cholesterol and triglycerides, but not low-density lipoprotein (LDL) cholesterol, by a small amount (106261).
It is unclear whether there are safety concerns when sodium is consumed in amounts lower than the adequate intake (AI) levels. Some observational research has found that the lowest levels of sodium intake might be associated with increased risk of death and cardiovascular events (98181,98183). However, this finding has been criticized because some of the studies used inaccurate measures of sodium intake, such as the Kawasaki formula (98177,98178,101259). Some observational research has found that sodium intake based on a single 24-hour urinary measurement is inversely correlated with all-cause mortality (106260). The National Academies Consensus Study Report states that there is insufficient evidence from observational studies to conclude that there are harmful effects from low sodium intake (100310).

Endocrine ...Orally, a meta-analysis of observational research has found that higher sodium intake is associated with an average increase in body mass index (BMI) of 1. 24 kg/m2 and an approximate 5 cm increase in waist circumference (98182). It has been hypothesized that the increase in BMI is related to an increased thirst, resulting in an increased intake of sugary beverages and/or consumption of foods that are high in salt and also high in fat and energy (98182). One large observational study has found that the highest sodium intake is not associated with overweight or obesity when compared to the lowest intake in adolescents aged 12-19 years when intake of energy and sugar-sweetened beverages are considered (106265). However, in children aged 6-11 years, usual sodium intake is positively associated with increased weight and central obesity independently of the intake of energy and/or sugar-sweetened beverages (106265).

Gastrointestinal ...In one case report, severe gastritis and a deep antral ulcer occurred in a patient who consumed 16 grams of sodium chloride in one sitting (25759). Chronic use of high to moderately high amounts of sodium chloride has been associated with an increased risk of gastric cancer (29405).

Musculoskeletal ...Observational research has found that low sodium levels can increase the risk for osteoporosis. One study has found that low plasma sodium levels are associated with an increased risk for osteoporosis. Low levels, which are typically caused by certain disease states or chronic medications, are associated with a more than 2-fold increased odds for osteoporosis and bone fractures (101260).
Conversely, in healthy males on forced bed rest, a high intake of sodium chloride (7.7 mEq/kg daily) seems to exacerbate disuse-induced bone and muscle loss (25760,25761).

Oncologic ...Population research has found that high or moderately high intake of sodium chloride is associated with an increased risk of gastric cancer when compared with low sodium chloride intake (29405). Other population research in patients with gastric cancer has found that a high intake of sodium is associated with an approximate 65% increased risk of gastric cancer mortality when compared with a low intake. When zinc intake is taken into consideration, the increased risk of mortality only occurred in those with low zinc intake, but the risk was increased to approximately 2-fold in this sub-population (109400).

Pulmonary/Respiratory ...In patients with hypertension, population research has found that sodium excretion is modestly and positively associated with having moderate or severe obstructive sleep apnea. This association was not found in normotensive patients (106262).

Renal ...Increased sodium intake has been associated with impaired kidney function in healthy adults. This effect seems to be independent of blood pressure. Observational research has found that a high salt intake over approximately 5 years is associated with a 29% increased risk of developing impaired kidney function when compared with a lower salt intake. In this study, high salt intake was about 2-fold higher than low salt intake (101261).

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