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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Diabetes. It is unclear if oral banaba is beneficial in patients with type 2 diabetes. Details: One preliminary clinical study in patients with type 2 diabetes shows that a specific banaba extract (Glucosol), standardized to corosolic acid 1%, taken as 32 or 48 mg daily for 2 weeks is associated with 10% lower blood glucose levels when compared with placebo (11954). Another preliminary clinical study in patients with type 2 diabetes inadequately controlled by oral antidiabetic agents shows that taking a specific combination product containing extracts of banaba leaf and Padang cassia (Inlacin, Dexa Medica) 100 mg daily for 12 weeks reduces glycated hemoglobin (HbA1c) by 0.65% when compared with baseline (92849). The validity of this finding is limited by the lack of a comparator group. Additionally, it is unclear if this effect is due to banaba, Padang cassia, or the combination.
• Impaired glucose tolerance (prediabetes). Oral banaba has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with impaired glucose tolerance shows that taking a specific combination product containing extracts of banaba leaf and Padang cassia (Inlacin, Dexa Medica) daily for 12 weeks preserves beta-cell function and insulin release and improves insulin sensitivity, but not 2-hour postprandial glucose levels, when compared with placebo. All patients received 50 mg once daily for 4 weeks, and those considered to be non-responders were titrated up to 100 mg once daily for the remaining 8 weeks (92848). It is unclear if these effects are due to banaba, Padang cassia, or the combination.
• Metabolic syndrome. It is unclear if oral banaba is beneficial in patients with metabolic syndrome. Details: A small clinical study in patients with metabolic syndrome shows that a specific banaba extract (MonoHerb), standardized to corosolic acid 1.13%, taken as 500 mg twice daily for 12 weeks improves systolic blood pressure, fasting blood glucose, triglycerides, and very low-density lipoprotein (VLDL) cholesterol when compared with baseline (108617). The lack of statistical comparison to the placebo group limits the validity of these findings. More evidence is needed to rate banaba for these uses.

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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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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Diabetes. It is unclear if oral gymnema is beneficial for diabetes. Details: A meta-analysis of 10 small clinical studies in adults with type 2 diabetes shows that taking gymnema modestly reduces fasting and postprandial blood glucose levels, and also seems to reduce glycated hemoglobin (HbA1c), when compared to baseline. Gymnema may also modestly reduce total cholesterol and triglyceride levels. (110022). Another meta-analysis of 6 small clinical studies, that includes some of the same studies, also shows that taking gymnema modestly reduces fasting blood glucose, total cholesterol, and triglyceride levels when compared with diet or placebo. However, this analysis shows that gymnema does not improve HbA1c, oral glucose tolerance, or low-density lipoprotein cholesterol (112184). The validity of these analyses is limited by the inclusion of mostly low-quality studies that enrolled heterogeneous patient populations and employed varying gymnema dosing regimens of 0.4-10 grams daily, sometimes in conjunction with antidiabetes medications. In addition, many of the included studies were non-randomized and lacked a comparator group.
• Impaired glucose tolerance (prediabetes). It is unclear if oral gymnema is beneficial for impaired glucose tolerance. Details: One small clinical study in overweight or obese patients with impaired glucose tolerance shows that taking gymnema (Swanson Superior Herbs) 300 mg twice daily for 12 weeks does not improve glucose control, lipid profile, anthropometric indices, or blood pressure when compared with placebo (105346). However, this study may have been inadequately powered to detect a difference between groups.
• Metabolic syndrome. It is unclear if oral gymnema is beneficial for metabolic syndrome. Details: One small clinical study shows that taking gymnema leaf (Swanson Premium G. sylvestre leaf, Swanson Health Products) 300 mg twice daily for 12 weeks reduces body weight by 4% and body mass index (BMI) by 2% when compared to baseline in overweight adults with metabolic syndrome. However, it is unclear if these changes are significant when compared with placebo. In addition, gymnema does not appear to improve blood glucose levels, insulin sensitivity, or blood lipid levels when compared with placebo (96235).
• Obesity. It is unclear if oral gymnema improves weight loss in overweight or obese adults. Details: One small clinical study shows that taking gymnema leaf (Swanson Premium G. sylvestre leaf, Swanson Health Products) 300 mg twice daily for 12 weeks modestly reduces body weight and body mass index (BMI) when compared to baseline in overweight adults with metabolic syndrome. However, it is unclear if these changes are significant when compared with placebo (96235). Another small clinical study by the same authors evaluating overweight adults with impaired glucose tolerance shows that taking gymnema (Swanson Superior Herbs) 300 mg twice daily for 12 weeks does not reduce body weight or BMI when compared with placebo (105346). Gymnema has also been studied in combination with other ingredients. One small clinical study shows that taking a combination of gymnema extract 400 mg, hydroxycitric acid 2800 mg, and niacin-bound chromium 4 mg orally daily for 8 weeks decreases BMI and body weight when compared to baseline in overweight and obese adults. This product provided 400 mcg of elemental chromium and 100 mg of gymnemic acids (42604). It is unclear if these effects are due to gymnema, other ingredients, or the combination. More evidence is needed to rate gymnema for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Burns. Although there has been interest in using topical tree turmeric for burns, there is insufficient reliable information about the clinical effects of tree turmeric for this purpose.
• Diabetes. Oral tree turmeric has only been evaluated in combination with other ingredients for the management of type 1 and type 2 diabetes; its effect when used alone is unclear. Details: Clinical research in patients with type 2 diabetes shows that taking a specific combination product (Berberol, PharmExtracta) containing tree turmeric extract 1176 mg and milk thistle extract 210 mg improves some measures of diabetes control. A clinical study in patients with type 2 diabetes, obesity, and metabolic syndrome shows that taking this specific product daily for 12 months reduces glycated hemoglobin (HbA1c) by approximately 18% when compared to baseline. This reduction was significant when compared with the 5% reduction in the placebo group. Fasting blood glucose and insulin resistance were also improved, with a reduction in fasting blood glucose of approximately 25% for patients in the treatment group, compared to 10% in the placebo group (97624). Several other small clinical studies in adults with poorly controlled type 2 diabetes shows that taking this same product for 12 months improves HbA1c, fasting blood glucose, and insulin resistance when compared to baseline (96140,96141). A treatment duration of 3 months does not appear to be effective for improving fasting blood glucose levels in these patients; however, it does seem to improve HbA1c when compared with baseline (96141). This product has also been evaluated in patients with type 1 diabetes. A clinical study in patients with type 1 diabetes shows that taking this product with meals for 6 months reduces the amount of insulin needed to achieve adequate glycemic control by 14.5% and lowers fasting blood glucose levels by 10% when compared with placebo (96142).
• Hypercholesterolemia. Oral tree turmeric has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of four mostly low-quality clinical studies in hypercholesterolemic adults shows that taking a specific combination product (Berberol, PharmExtracta) containing tree turmeric extract 588 mg and milk thistle extract 105 mg twice daily for 3 months, along with diet and exercise, reduces levels of low-density lipoprotein (LDL) cholesterol by an average of 33 mg/dL when compared with diet and exercise alone (101158). These studies lasted for no more than 12 months and some studies allowed for inclusion of patients who required a reduction in statin dose due to adverse effects (95019,96140,101158). Taking this product does not appear to significantly lower triglyceride levels or increase high-density lipoprotein (HDL) cholesterol levels in most of these patients (95019,96140,101158). It is unclear if any effects are due to tree turmeric, milk thistle, or the combination. Other clinical research in adults with hypercholesterolemia shows that a similar product (Berberol K, PharmExtracta) containing tree turmeric extract of berberine 500 mg, milk thistle extract 105 mg, and monacolin K and KA 10 mg, taken once daily for 3 months along with diet and exercise, reduces levels of LDL cholesterol by about 28% when compared with diet and exercise alone (97625). It is possible that any benefit of this product is due to the monacolin content. Further, since this product is standardized to monacolin content, it is considered by the US Food and Drug Administration to be a new drug rather than a dietary supplement.
• Menorrhagia. Although there has been interest in using oral tree turmeric for menorrhagia, there is insufficient reliable information about the clinical effects of tree turmeric for this purpose.
• Trachoma. Although there has been interest in using oral tree turmeric for trachoma, there is insufficient reliable information about the clinical effects of tree turmeric for this purpose.
• Wound healing. Although there has been interest in using topical tree turmeric for wound healing, there is insufficient reliable information about the clinical effects of tree turmeric for this purpose. More evidence is needed to rate tree turmeric for these uses.

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POSSIBLY SAFE ...when banaba extract is used orally and appropriately, short-term (11954,92848,92849). A specific banaba extract (Glucosol) has been safely used at doses of 32-48 mg daily for 2 weeks (11954). Another specific product containing extracts of banaba leaf and Padang cassia (Inlacin, Dexa Medica) has been safely used at doses up to 100 mg daily for 12 weeks (92848,92849). There is insufficient reliable information available about the safety of banaba extract when used long-term.

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

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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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POSSIBLY SAFE ...when used orally and appropriately. Gymnema leaf extract has been used safely in doses of 200 mg twice daily for up to 20 months or 300 mg twice daily for 12 weeks (45,46,42604,105346).

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

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LIKELY SAFE ...when a specific product (Berberol, PharmExtracta) containing tree turmeric extract 588 mg and milk thistle extract 105 mg is used. This product has been safely used twice daily for up to 12 months (95019,96140,96141,96142,101158). There is insufficient reliable information available about the safety of other forms of tree turmeric when used orally or topically in medicinal amounts.

CHILDREN: LIKELY UNSAFE
when used orally in newborns. The berberine constituent of tree turmeric can cause kernicterus in newborns, particularly preterm neonates with hyperbilirubinemia (2589). There is insufficient reliable information available about the safety of tree turmeric in older children.

PREGNANCY: LIKELY UNSAFE
when used orally. The berberine constituent of tree turmeric is thought to cross the placenta and may cause harm to the fetus. Kernicterus has developed in newborn infants exposed to berberine (2589).

LACTATION: LIKELY UNSAFE
when used orally. The berberine constituent of tree turmeric and other harmful constituents can be transferred to the infant through breast milk (2589).

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, concomitant use of banaba and hypoglycemic drugs might have additive effects.  Details Human and animal research suggests that banaba can lower blood glucose levels (11954,11955,33554,92848,92849).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, concomitant use of banaba and antihypertensive drugs might cause additive effects.  Details Human and animal research suggests that banaba can lower blood pressure (33557,92848,92849).

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of banaba with substrates of OATP might reduce the bioavailability of the OATP substrate.  Details In vitro research shows that banaba inhibits OATP, particularly OATP2B1 (35450). OATPs are expressed in the small intestine and liver and are responsible for the absorption of drugs and other compounds.

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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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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking gymnema with antidiabetes drugs might increase the risk of hypoglycemia.  Details Gymnema reduces blood glucose levels in some human and animal research. In human studies, it has been shown to enhance the blood glucose lowering effects of hypoglycemic drugs (45,46,92119,92121,92123). However, other research in adults with prediabetes or metabolic syndrome suggests that gymnema does not reduce fasting levels of blood glucose (96235,105346). Until more is known, monitor blood glucose levels closely.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, gymnema might increase levels of drugs metabolized by CYP1A2.  Details Animal and in vitro research shows that gymnema can inhibit the CYP1A2 enzyme (96236,96237,96238). In one animal study, oral administration of gymnema for 7 days increased the plasma concentrations of phenacetin, a CYP1A2 substrate, by about 1.4-fold and reduced the clearance of phenacetin by about 29% (96237).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, gymnema might increase or decrease levels of drugs metabolized by CYP2C9.  Details Animal research shows that gymnema can induce the CYP2C9 enzyme. In one animal study, gymnema caused a 2.4-fold increase in the clearance of tolbutamide, a CYP2C9 substrate, in rats (96237). In vitro research also shows that gymnema can inhibit CYP2C9 (96236,96238).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, gymnema might increase levels of drugs metabolized by CYP3A4.  Details One in vitro study using rat liver microsomes shows that gymnema can modestly inhibit the CYP3A4 enzyme (96238). However, other in vitro research using human liver microsomes shows that gymnema does not affect CYP3A4 activity (96236). Animal research also shows that gymnema does not alter the function of CYP3A4. In one study in rats, oral administration of gymnema for 7 days did not alter the clearance of amlodipine, a CYP3A4 substrate (96237).

PHENACETIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking gymnema with phenacetin might increase the levels of phenacetin.  Details Animal research shows that gymnema, administered orally for 7 days, decreases the clearance of phenacetin in a dose-dependent manner by about 21% to 29% and increases plasma levels about 1.3- to 1.4-fold when compared to control (96237,96238).

TOLBUTAMIDE (Orinase) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking gymnema with tolbutamide might the decrease levels of tolbutamide.  Details Animal research shows that gymnema, administered orally for 7 days, increases the clearance of tolbutamide by 2.4-fold when compared to control (96237).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, tree turmeric might have additive effects when used with anticoagulant and antiplatelet drugs and increase the risk of bleeding.  Details In vitro and animal research suggest that berberine, a constituent of tree turmeric, can inhibit platelet aggregation (33660,33694).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = A Theoretically, tree turmeric, taken alone or in combination with milk thistle, might increase the risk of hypoglycemia in patients taking antidiabetes drugs.  Details Clinical research shows that taking a product containing tree turmeric and milk thistle extracts can lower blood glucose levels, glycated hemoglobin (HbA1c), and insulin resistance in patients with type 2 diabetes, including those on antidiabetic agents (95019,96140,96141). Additionally, clinical research suggests that berberine, a constituent of tree turmeric, can lower blood glucose levels (20579,34247,34265,34282).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking tree turmeric along with antihypertensive drugs might have additive effects and increase the risk of hypotension.  Details Animal research suggests that berberine, a constituent of tree turmeric, can have hypotensive effects (33692,34308). Also, a meta-analysis of clinical research suggests that taking berberine in combination with amlodipine (Norvasc) can lower systolic and diastolic blood pressure when compared with taking amlodipine alone (91956).

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, use of tree turmeric along with CNS depressants might increase the risk of additive therapeutic and adverse effects.  Details Animal research suggests that berberine, a constituent of tree turmeric, can have sedative effects (13519,33650,33664,33692).

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = A Berberine, a constituent of tree turmeric, can reduce metabolism of cyclosporine and increase serum levels.  Details Some clinical evidence suggests that berberine inhibits cytochrome P450 3A4 (CYP3A4), which metabolizes cyclosporine (13524,21112,34239).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, tree turmeric might increase the levels and clinical effects of drugs metabolized by CYP2C9.  Details Preliminary clinical evidence suggests that berberine, a constituent of tree turmeric, can inhibit CYP2C9 (34279).

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, tree turmeric might increase the levels and clinical effects of drugs metabolized by CYP2D6.  Details In vitro research and preliminary clinical evidence suggest that berberine, a constituent of tree turmeric, can inhibit CYP2D6 (21117,34279,34297).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = A Theoretically, tree turmeric might increase the levels and clinical effects of drugs that are substrates of CYP3A4.  Details In vitro research and preliminary clinical evidence suggest that berberine, a constituent of tree turmeric, moderately inhibits CYP3A4 (13524,21114,34279,34297).

DEXTROMETHORPHAN (Robitussin DM, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, tree turmeric might increase levels of dextromethorphan and potentially increase the risk of adverse effects including drowsiness, confusion, and irritability.  Details Preliminary clinical research suggests that berberine, a constituent of tree turmeric, can inhibit cytochrome P450 2D6 (CYP2D6) activity and reduce the metabolism of dextromethorphan (34279).

MIDAZOLAM (Versed) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, tree turmeric might increase levels of midazolam and potentially increase the risk of adverse effects including sedation and respiratory depression.  Details Preliminary clinical evidence suggests that berberine, a constituent of tree turmeric, can inhibit cytochrome P450 3A4 (CYP3A4) activity and reduce metabolism of midazolam (34279).

PENTOBARBITAL (Nembutal) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, tree turmeric might increase the sedative effects of pentobarbital.  Details Animal research suggests that berberine, a constituent of tree turmeric, can prolong pentobarbital-induced sleeping time (13519).

TACROLIMUS (Prograf) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = D Berberine, a constituent of tree turmeric, can inhibit metabolism of tacrolimus and increase plasma levels.  Details Some clinical evidence suggests that berberine inhibits cytochrome P450 3A4 (CYP3A4), which metabolizes tacrolimus (13524,21114,34279,34297,91954). In a 16-year-old patient with idiopathic nephrotic syndrome who was being treated with prednisone 40 mg/m2 and tacrolimus 6.5 mg twice daily, concomitant use of berberine, a constituent of tree turmeric, 200 mg three times daily increased plasma levels of tacrolimus from 8 to 22 ng/mL and increased serum creatinine levels from 0.7 to 1.2 mg/dL. Following a reduction of tacrolimus dosing to 3 mg daily, the blood concentration of tacrolimus decreased to 12 ng/mL and the serum concentration of creatinine decreased to 0.9 mg/dL (91954).

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General ...Orally, banaba extract appears to be well tolerated.
Most Common Adverse Effects:
Orally: Diaphoresis, dizziness, headache, palpitations, stomach upset, tremor, and weakness have been reported with a specific product containing extracts of banaba leaf and Padang cassia (Inlacin, Dexa Medica); however, it is unclear if these adverse effects were caused by banaba extract, Padang cassia, or the combination.

Cardiovascular ...Orally, palpitations have been reported with a specific product containing extracts of banaba leaf and Padang cassia (Inlacin, Dexa Medica); however, it is unclear if this adverse effect was caused by banaba extract, Padang cassia, or the combination (92848).

Gastrointestinal ...Orally, stomach upset has been reported with a specific product containing extracts of banaba leaf and Padang cassia (Inlacin, Dexa Medica); however, it is unclear if this adverse effect was caused by banaba extract, Padang cassia, or the combination (92849).

Neurologic/CNS ...Orally, dizziness, headache, tremor, and weakness have been reported with a specific product containing extracts of banaba leaf and Padang cassia (Inlacin, Dexa Medica); however, it is unclear if these adverse effects were caused by banaba extract, Padang cassia, or the combination (92848,92849).

Other ...Orally, diaphoresis has been reported with a specific product containing extracts of banaba leaf and Padang cassia (Inlacin, Dexa Medica); however, it is unclear if this adverse effect was caused by banaba extract, Padang cassia, or the combination (92849).

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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, gymnema seems to be well tolerated.

Hepatic ...A case of drug-induced hepatitis characterized by weakness, fatigue, jaundice, and elevated liver enzymes, has been reported for a patient who consumed gymnema tea three times daily for 10 days. The patient was administered prednisone 60 mg once daily and was eventually tapered off prednisone and discharged. Laboratory values normalized after 6 months (95005). A case of hepatitis-associated aplastic anemia characterized by jaundice, elevated liver function tests, and pancytopenia has been reported for a patient who consumed gymnema 2 grams twice daily for at least a month. Treatment with ursodeoxycholic acid for 8 weeks led to resolution of cholestatic hepatitis; however, the pancytopenia was not responsive to treatment with immunosuppressive drugs and the patient died 5 months after presentation (110021). The exact reason for these adverse effects is not clear; they may have been idiosyncratic.

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General ...Orally and topically, no adverse effects have been reported with the use of tree turmeric alone. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Gastrointestinal symptoms, especially nausea, with the use of a specific product containing tree turmeric and milk thistle (Berberol, PharmExtracta).

Gastrointestinal ...Orally, the most common adverse effects of a specific product (Berberol, PharmExtracta) containing tree turmeric and milk thistle extracts include gastrointestinal symptoms, especially nausea (95019,96140,96141,96142).

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