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Sinetrol-XPur Mediterranean Citrus Blend
(std. to 20% total Flavanones)
(containing)
(Sinetrol-XPur Mediterranean Citrus Blend (Form: std. to 20% total Flavanones Note: 90 mg) Note: containing )
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450 mg |
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(fruit)
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(fruit)
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(fruit)
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(seed)
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Microcrystalline Cellulose, Vegetable Cellulose Note: capsule, Maltodextrin, Stearic Acid (Alt. Name: C18:0), Silica
Below is general information about the effectiveness of the known ingredients contained in the product Mediterranean Trim with Sinetrol-XPur. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
Below is general information about the safety of the known ingredients contained in the product Mediterranean Trim with Sinetrol-XPur. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
LIKELY SAFE ...when used orally in amounts commonly found in foods. Grapefruit has Generally Recognized as Safe status (GRAS) in the US (4912).
POSSIBLY SAFE ...when used orally and appropriately for medicinal purposes. A grapefruit seed extract has been safely used in clinical research (5866). In addition, capsules containing grapefruit pectin 15 grams daily have been used in clinical research for up to 16 weeks (2216).
POSSIBLY UNSAFE ...when used orally in excessive amounts. Preliminary population research shows that consuming a quarter or more of a whole grapefruit daily is associated with a 25% to 30% increased risk of postmenopausal breast cancer (14858). Grapefruit juice is thought to reduce estrogen metabolism resulting in increased endogenous estrogen levels. More evidence is needed to validate this finding.
PREGNANCY AND LACTATION:
There is insufficient reliable information available about the safety of using medicinal amounts of grapefruit during pregnancy and lactation; avoid using.
LIKELY SAFE ...when consumed in amounts typically found in foods. Guarana has Generally Recognized as Safe (GRAS) status for use in foods in the US (4912).
POSSIBLY SAFE ...when used orally and appropriately, short-term (12). Guarana contains caffeine. 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).
POSSIBLY UNSAFE ...when used orally long-term or in high doses. Guarana contains a significant amount of caffeine. Chronic use, especially in large amounts, can produce tolerance, habituation, psychological dependence, and other significant adverse effects. Acute use of high doses, typically above 400 mg per day, has been associated with significant adverse effects such as tachyarrhythmias and sleep disturbances (11832,95503,98806). These effects would not be expected to occur with the consumption of decaffeinated guarana.
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, or prior caffeine use (11832,54425).
PREGNANCY: POSSIBLY SAFE
when consumed in amounts commonly found in foods.
Due to the caffeine content of guarana, intake should be closely monitored during pregnancy to ensure moderate consumption. Although it is not considered a teratogen, caffeine crosses the placenta and causes dose-dependent increases in fetal blood 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 individuals 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, caffeine can be safely consumed in doses up to 300 mg daily without an increased risk of spontaneous abortion, stillbirth, preterm birth, fetal growth retardation, or congenital malformations (11733,98806). 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). Advise individuals to keep caffeine consumption below 300 mg daily during pregnancy.
PREGNANCY: POSSIBLY UNSAFE
when used orally in amounts over 300 mg daily.
Although it is not considered a teratogen, caffeine crosses the placenta and causes dose-dependent increases in fetal blood concentrations (4260,98806). Consumption of caffeine in amounts over 300 mg daily is associated with a significantly increased risk of miscarriage in some studies (16014,98806). Advise keeping caffeine consumption from all sources below 300 mg daily. High maternal doses of caffeine throughout pregnancy have resulted in symptoms of caffeine withdrawal in newborn infants (9891). High doses of caffeine have also been associated with spontaneous abortion, premature delivery, and low birth weight (2709,2711).
LACTATION: POSSIBLY SAFE
when used orally in amounts commonly found in foods.
Due to the caffeine content of guarana, intake should be closely monitored when breast-feeding. Breast milk concentrations of caffeine are thought to be approximately 50% of serum concentrations (9892).
LACTATION: POSSIBLY UNSAFE
when used orally in large amounts.
Consumption of guarana might cause irritability and increased bowel activity in nursing infants (6026). Large doses or excessive intake of guarana should be avoided when breast-feeding.
LIKELY SAFE ...when sweet orange juice or fruit is used orally in amounts commonly found in foods (1310,3340,15171,92309).
POSSIBLY SAFE ...when the essential oil of sweet orange is inhaled as aromatherapy, short-term (35735,58060,90505,105455). There is insufficient reliable information available about the safety of sweet orange peel when used orally.
CHILDREN: LIKELY SAFE
when sweet orange juice or fruit is used orally in amounts commonly found in foods.
CHILDREN: POSSIBLY UNSAFE
when the sweet orange peel is used orally in excessive amounts.
There have been reports of intestinal colic, convulsions, and death in children given large amounts of sweet orange peel (11).
PREGNANCY AND LACTATION: LIKELY SAFE
when sweet orange juice or fruit is used orally in amounts commonly found in foods (1310,3340).
Below is general information about the interactions of the known ingredients contained in the product Mediterranean Trim with Sinetrol-XPur. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
Grapefruit juice can decrease blood levels of acebutolol, potentially decreasing the clinical effects of acebutolol.
 Details
Clinical research shows that grapefruit juice can modestly decrease acebutolol levels by 7% and reduce peak plasma concentration by 19% by inhibiting organic anion transporting polypeptide (OATP) (17603,18101). The acebutolol half-life is also extended by 1.1 hours when grapefruit juice is consumed concomitantly (18101). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).
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Grapefruit juice can decrease blood levels of aliskiren, potentially decreasing the clinical effects of aliskiren.
Details
Clinical research shows that grapefruit juice can decrease aliskiren levels by approximately 60% by inhibiting organic anion transporting polypeptide (OATP) (91428). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).
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Grapefruit juice can increase blood levels of amiodarone, potentially increasing the effects and adverse effects of amiodarone.
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Grapefruit juice might decrease blood levels of amprenavir, although this is not likely to be clinically significant.
Details
Some clinical research shows that grapefruit juice can slightly decrease amprenavir levels (17673); however, this is probably not clinically significant.
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Grapefruit juice can increase blood levels of oral artemether, potentially increasing the effects and adverse effects of artemether.
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Grapefruit juice might increase blood levels of some oral benzodiazepines, potentially increasing the effects and adverse effects of these drugs.
Details
Clinical research shows that grapefruit juice can increase plasma triazolam concentrations. Repeated consumption of grapefruit juice greatly increases triazolam concentrations and prolongs the half-life, probably due to inhibition of cytochrome P450 3A4 (CYP3A4) (7776,22118,22131,22133). Some studies show that grapefruit juice, particularly when taken in large quantities, reduces the clearance and increases the maximum blood levels, area under the plasma concentration curve (AUC), and duration of effect of midazolam. However, there is no effect on intravenous midazolam (4300,10159,11275,17601,22117,22119,16711,91427,95978). Grapefruit juice has also been shown to increase the maximum blood levels and duration of effect of diazepam, but the clinical significance of this is not known (3228). This interaction does not appear to occur with alprazolam (17674).
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Grapefruit juice can increase blood levels of blonanserin, potentially increasing the effects and adverse effects of blonanserin.
Details
Blonanserin is metabolized primarily by cytochrome P450 3A4 (CYP3A4). A small clinical study shows that taking grapefruit juice along with oral blonanserin increases exposure to blonanserin almost 6-fold due to inhibition of intestinal CYP3A4 by grapefruit juice and prolongs the elimination half-life of blonanserin by 2.2-fold due to inhibition of hepatic CYP3A4 by grapefruit juice (96943).
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Grapefruit juice can increase blood levels of budesonide, potentially increasing the effects and adverse effects of budesonide.
Details
Budesonide is metabolized by cytochrome P450 3A4 (CYP3A4). A small clinical study shows that taking grapefruit juice along with oral budesonide increases the plasma concentration of budesonide. This effect is attributed to grapefruit-induced inhibition of CYP3A4 in both the colon and small intestine (91425).
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Grapefruit juice can increase blood levels of buspirone, potentially increasing the effects and adverse effects of buspirone.
Details
Clinical research shows that grapefruit juice increases absorption and plasma concentrations of buspirone (3771).
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Grapefruit juice can decrease the clearance of caffeine, potentially increasing the effects and adverse effects of caffeine.
Details
Clinical research shows that grapefruit juice decreases caffeine clearance (4300).
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Grapefruit juice can increase blood levels of oral calcium channel blockers, potentially increasing the effects and adverse effects of these drugs.
Details
Clinical research shows that grapefruit juice increases absorption and plasma concentrations of amlodipine (523), nifedipine (528,22114), nisoldipine (529), verapamil (7779,8285), felodipine, nimodipine, nicardipine, diltiazem, pranidipine, nitrendipine, and manidipine (524,528,1388,4300,7780,11276,22136,53338,22138,22139) (22140,22141,22142,22143,22147,22148,22149,53367,22158),
This interaction is likely the result of the inhibition of intestinal metabolism of these drugs by CYP3A4 (7779,7780), although some research suggests grapefruit may alter plasma drug levels by reducing the rate of gastric emptying (22167). Consuming grapefruit juice 1 liter daily increases steady state concentrations of verapamil by as much as 50% (8285). However, some references dispute the clinical relevance of the interactions with amlodipine, diltiazem, and verapamil (3230,4300,22159). Other research in healthy individuals suggests plasma levels of felodipine and nifedipine are not affected when given intravenously (22144,22146). There is considerable interindividual variability in the effect of grapefruit juice on drug metabolism, which might account for inconsistent study results (7777,7779,8285). In healthy older adults, the hemodynamic response to felodipine plus grapefruit juice might be influenced by altered autonomic regulation. In older healthy adults, a single dose of grapefruit juice and felodipine enhanced the blood pressure-lowering effects of felodipine. However, after a week of grapefruit juice and felodipine (steady state), the hypotensive activity was reduced, possibly due to compensatory tachycardia (1392). Research indicates it is necessary to withhold grapefruit juice for as long as 3 days to avoid interactions with felodipine and nisoldipine (5068,5069,6453,22145).
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Grapefruit juice can increase blood levels of carbamazepine, potentially increasing the effects and adverse effects of carbamazepine.
Details
Clinical research shows that grapefruit juice increases absorption and plasma concentrations of carbamazepine (524).
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Grapefruit juice can increase blood levels of carvedilol, potentially increasing the effects and adverse effects of carvedilol.
Details
Clinical research shows that grapefruit juice increases the bioavailability of a single dose of carvedilol by 16% (5071).
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Grapefruit juice can decrease blood levels of celiprolol, potentially decreasing the clinical effects of celiprolol.
Details
In human research, taking grapefruit juice within two hours of celiprolol appears to decrease absorption and blood levels of celiprolol by approximately 85% (91421). This interaction is due to grapefruit-induced inhibition of organic anion transporting polypeptide (OATP) (17603,17604,22161). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).
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Grapefruit juice can increase blood levels of cisapride, potentially increasing the effects and adverse effects of cisapride.
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Theoretically, grapefruit juice might increase blood levels of clomipramine, potentially increasing the effects and adverse effects of clomipramine.
Details
Case reports have shown that clomipramine trough levels increase significantly after the addition of grapefruit juice to the therapeutic regimen (5064).
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Grapefruit juice can decrease blood levels of the active metabolite of clopidogrel, thereby decreasing the antiplatelet effect of clopidogrel.
Details
Clopidogrel is an antiplatelet prodrug that is metabolized primarily by cytochrome P450 2C19 (CYP2C19) to form the active metabolite. A small clinical study shows that taking grapefruit juice with clopidogrel decreases plasma levels of the active metabolite by more than 80% and impairs the antiplatelet effect of clopidogrel. This effect is possibly due to grapefruit-induced inhibition of CYP2C19 (91419).
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Theoretically, grapefruit juice might increase blood levels of colchicine, potentially increasing the effects and adverse effects of colchicine.
Details
Colchicine is an alkaloid that undergoes P-glycoprotein (P-gp) mediated drug efflux in the intestines, followed by metabolism by cytochrome P450 3A4 (CYP3A4). There is concern that grapefruit juice will increase the effects and adverse effects of colchicine due to grapefruit-induced inhibition of P-gp and/or CYP3A4. In vitro evidence shows that grapefruit juice increases absorption of colchicine by inhibiting P-gp (94158). A case of acute colchicine toxicity has been reported for an 8-year-old female who drank grapefruit juice while taking high-dose colchicine, long-term (94157). However, one small clinical study in healthy adults shows that drinking grapefruit juice 240 mL twice daily for 4 days does not affect the bioavailability or adverse effects of a single dose of colchicine 0.6 mg taken on the fourth day (35762).
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Grapefruit juice can increase blood levels of oral cyclosporine, potentially increasing the effects and adverse effects of cyclosporine.
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Theoretically, grapefruit juice might increase levels of drugs metabolized by CYP1A2.
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In vitro research suggests that grapefruit juice might inhibit CYP1A2 enzymes (12479). So far, this interaction has not been reported in humans.
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Theoretically, grapefruit juice might increase levels of drugs metabolized by CYP2C19.
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In vitro research suggests that grapefruit juice might inhibit CYP2C19 enzymes (12479). Also, a small clinical study shows that taking grapefruit juice with clopidogrel, an antiplatelet prodrug that is metabolized primarily by CYP2C19, decreases plasma levels of the active metabolite and impairs the antiplatelet effect of clopidogrel. This effect is likely due to grapefruit-induced inhibition of CYP2C19 (91419).
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Theoretically, grapefruit juice might increase levels of drugs metabolized by CYP2C9.
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In vitro research suggests that grapefruit juice might inhibit CYP2C9 enzymes (12479). So far, this interaction has not been reported in humans.
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Grapefruit juice can increase levels of drugs metabolized by CYP3A4.
Details
Clinical research shows that grapefruit juice can inhibit CYP3A4 metabolism of drugs, causing increased drug levels and potentially increasing the risk of adverse effects (3227,3774,8283,8285,8286,22129,91427,104190). When taken orally, effects of grapefruit juice on CYP3A4 levels appear to last at least 48 hours (91427). Grapefruit's ability to inhibit CYP3A4 has even been harnessed to intentionally increase levels of venetoclax, which is metabolized by CYP3A4, in an elderly patient with acute myeloid leukemia who could not afford full dose venetoclax. The lower dose of venetoclax in combination with grapefruit juice resulted in serum levels of venetoclax in the therapeutic reference range of full dose venetoclax and positive treatment outcomes for the patient (112287).
Professional consensus recommends the consideration of patient age, existing medical conditions, additional medications, and the potential for additive adverse effects when evaluating the risks of concomitant use of grapefruit juice with any medication metabolized by CYP3A4. While all patients are at risk for interactions with grapefruit juice consumption, patients older than 70 years of age and those taking multiple medications are at the greatest risk for a serious or fatal interaction with grapefruit juice (95970,95972). |
Grapefruit juice can increase blood levels of dapoxetine, potentially increasing the effects and adverse effects of dapoxetine.
Details
Pharmacokinetic research shows that drinking grapefruit juice 250 mL prior to taking dapoxetine 60 mg can increase the maximum plasma concentration of dapoxetine by 80% and prolong the elimination half-life by 43%. This effect is attributed to the inhibition of both intestinal and hepatic cytochrome P450 3A4 (CYP3A4) by grapefruit (95975).
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Grapefruit juice can increase blood levels of dextromethorphan, potentially increasing the effects and adverse effects of dextromethorphan.
Details
Clinical research shows that grapefruit juice can inhibit cytochrome P450 3A4 (CYP3A4) metabolism, causing increased dextromethorphan levels (11362).
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Grapefruit juice can increase blood levels of erythromycin, potentially increasing the effects and adverse effects of erythromycin.
Details
Clinical research shows that concomitant use of erythromycin with grapefruit can inhibit cytochrome P450 3A4 (CYP3A4) metabolism of erythromycin, increasing plasma concentrations of erythromycin by 35% (8286).
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Grapefruit juice can increase blood levels of estrogens, potentially increasing the effects and adverse effects of estrogens.
Details
Clinical research shows that grapefruit increases the levels of endogenous and exogenous estrogens by inhibiting cytochrome P450 3A4 (CYP3A4) enzymes (525,526,14858). Grapefruit juice increases exogenously administered 17-beta-estradiol by about 20% in females without ovaries and ethinyl-estradiol in healthy females (525,526,22160).
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Grapefruit juice can decrease blood levels of etoposide, potentially decreasing the clinical effects of etoposide.
Details
Clinical research shows that grapefruit juice decreases the absorption and plasma concentrations of etoposide. There is some evidence that grapefruit juice co-administered with oral etoposide can reduce levels of etoposide by about 26% (8744). Grapefruit juice seems to inhibit organic anion transporting polypeptide (OATP), which is a drug transporter in the gut, liver, and kidney (7046,17603,17604). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).
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Grapefruit juice can decrease blood levels of fexofenadine, thereby decreasing the clinical effects of fexofenadine.
Details
Clinical research shows that grapefruit juice can significantly decrease oral absorption and blood levels of fexofenadine. In one study, consuming a drink containing grapefruit juice 25% decreased bioavailability of fexofenadine by about 24%. Consuming a full-strength grapefruit juice drink reduced bioavailability by 67% (7046). In another study, consuming grapefruit juice 300 mL decreased fexofenadine levels by 42%. Consuming 1200 mL of grapefruit juice reduced levels by 64% (17602). Similarly, drinking grapefruit juice 240 mL decreased the oral bioavailability of fexofenadine by 25% in another pharmacokinetic study (112288). Fexofenadine manufacturer data indicates that concomitant administration of grapefruit juice and fexofenadine results in larger wheal and flare sizes in research models. This suggests that grapefruit also reduces the clinical response to fexofenadine (17603).
Grapefruit juice seems to inhibit organic anion transporting polypeptide (OATP), which is a drug transporter in the gut, liver, and kidney (7046,17603,17604,22161). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604). |
Grapefruit juice can increase blood levels of fluvoxamine, potentially increasing the effects and adverse effects of fluvoxamine.
Details
Clinical research shows that grapefruit juice inhibits metabolism and increases fluvoxamine levels and peak concentration (17675).
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Grapefruit juice can increase blood levels of halofantrine, potentially increasing the effects and adverse effects of halofantrine.
Details
Clinical research shows that grapefruit juice inhibits cytochrome P450 3A4 (CYP3A4) metabolism, which increases halofantrine levels and peak concentration, as well as a marker of ventricular tachyarrhythmia potential (22129).
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Grapefruit juice can increase blood levels of statins that are metabolized by cytochrome P450 3A4 (CYP3A4), potentially increasing the effects and adverse effects of these statins. Additionally, grapefruit juice might interfere with the bioavailability of statins that are substrates of organic anion transporting polypeptides (OATP).
Details
Clinical research shows that grapefruit juice inhibits metabolism and increases absorption and plasma concentrations of statins that are metabolized by CYP3A4. These include lovastatin (527,11274), simvastatin (3774,7782,22127), and atorvastatin (3227,12179,22126). Keep in mind that there is considerable variability in the effect of grapefruit juice on drug metabolism, so individual patient response is difficult to predict (7777,7781).
Some statins, including pravastatin, fluvastatin, pitavastatin, and rosuvastatin, are not metabolized by CYP3A4. However, grapefruit juice might still affect the bioavailability of these statins. These statins are substrates of OATP. Grapefruit juice can inhibit OATP. Therefore, grapefruit juice may reduce the bioavailability or increase drug levels of these statins depending on the type of OATP. However, grapefruit juice affects OATP for only a short time. Therefore, separating drug administration by at least 4 hours is likely to avoid this interaction (3227,12179,17601,22126,91420). |
Grapefruit juice can interfere with itraconazole absorption, although the clinical significance of this interaction is unclear.
Details
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Grapefruit juice can decrease blood levels of levothyroxine, potentially decreasing the effectiveness of levothyroxine.
Details
Clinical research shows that grapefruit juice modestly decreases levothyroxine levels by 11% by inhibiting organic anion transporting polypeptide (OATP) (17604,22163). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).
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Grapefruit juice can decrease blood levels of the active metabolite of losartan, potentially decreasing the clinical effects of losartan.
Details
Losartan is an inactive prodrug which must be metabolized to its active form, E-3174, to be effective. In one human study, grapefruit juice reduced losartan metabolism, increased losartan AUC, and reduced the AUC of the major active losartan metabolite, E-3174 (1391).
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Grapefruit juice can increase blood levels of methadone, potentially increasing the effects and adverse effects of methadone.
Details
Clinical research shows that grapefruit juice inhibits the metabolism of methadone, increasing methadone levels and peak concentrations (17676). In one case, a 51-year-old male taking methadone 90 mg daily and no other medications was found unresponsive. The patient reported drinking grapefruit juice 500 mL daily for 3 days prior to the event. Methadone is a substrate of cytochrome P450 3A4 (CYP3A4), and grapefruit juice-induced inhibition of CYP3A4 is the likely cause of this interaction (102056).
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Grapefruit juice can increase blood levels of methylprednisolone, potentially increasing the effects and adverse effects of methylprednisolone.
Details
Clinical research shows that grapefruit juice can increase the plasma concentration of orally administered methylprednisolone. Grapefruit juice 200 mL three times daily given with methylprednisolone 16 mg increased methylprednisolone half-life by 35%, peak plasma concentration by 27%, and total area under the curve by 75% (3123).
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Grapefruit juice might decrease blood levels of nadolol, potentially decreasing the clinical effects of nadolol.
Details
Nadolol is a substrate of organic anion transporting polypeptide 1A2 (OATP1A2) (17603,17604,22161). Some research shows that grapefruit juice and its constituent naringin can inhibit organic anion transporting polypeptides (OATP), which can reduce the bioavailability of OATP substrates (17603,17604,22161,91427). However, preliminary clinical research shows that grapefruit juice containing a low amount of naringin does not significantly affect levels of nadolol (91422). It is not known if grapefruit juice containing higher amounts of naringin reduces the bioavailability of nadolol.
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Grapefruit juice can increase blood levels of nilotinib, potentially increasing the effects and adverse effects of nilotinib.
Details
Clinical research shows that grapefruit juice inhibits metabolism and increases absorption of nilotinib. Grapefruit juice increases nilotinib levels by 29% and peak concentration by 60% (17677).
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Grapefruit juice can decrease levels of drugs that are substrates of OATP.
Details
In vitro and clinical research show that consuming grapefruit juice inhibits OATP, which reduces the bioavailability of oral drugs that are substrates of OATP. Various clinical studies have shown reduced absorption of OATP substrates when taken with grapefruit, including fexofenadine, acebutolol, aliskiren, celiprolol, levothyroxine, nadolol, and pitavastatin (17603,17604,18101,22126,22134,22161,22163,91420,91427,91428,112288). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).
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Grapefruit juice can increase blood levels of oxycodone, potentially increasing the effects and adverse effects of oxycodone.
Details
Oxycodone is metabolized by both cytochrome P450 3A4 (CYP3A4) and cytochrome P450 2D6 (CYP2D6). A small clinical study shows that grapefruit juice can increase plasma levels of oral oxycodone about 1.7-fold by inhibiting CYP3A4. While the analgesic effects of oxycodone do not seem to be affected, taking grapefruit juice along with oxycodone may theoretically increase the adverse effects of oxycodone (91423).
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Grapefruit juice does not seem to affect renal P-glycoprotein (P-gp). Theoretically, it might inhibit intestinal P-gp, but evidence is conflicting.
Details
While most in vitro research shows that grapefruit products inhibit P-gp, (1390,11270,11278,11362,95976), research in humans is less clear. Two small clinical studies in healthy adults using digoxin as a probe substrate show that grapefruit juice does not inhibit P-gp in the kidneys (11277,11282). It is unclear whether this applies to intestinal P-gp, for which digoxin is not considered to be a sensitive probe (105568). Grapefruit juice has been shown to reduce levels of fexofenadine (7046,17602,112288), and increase levels of quinidine (5067,22121). However, as both of these drugs are also substrates of other enzymes and transporters, it is unclear what role, if any, intestinal P-gp has in these findings.
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Grapefruit juice can increase blood levels of pitavastatin, potentially increasing the effects and adverse effects of pitavastatin.
Details
Pharmacokinetic research shows that taking grapefruit juice with pitavastatin 2-4 mg can increase blood levels of pitavastatin by 13% to 14%. Unlike simvastatin and atorvastatin, pitavastatin is not significantly metabolized by cytochrome P450 3A4 (CYP3A4) enzymes. Grapefruit juice appears to increase levels of pitavastatin by inhibiting its uptake by organic anion transporting polypeptide 1B1 (OATP1B1) into hepatocytes for metabolism and clearance from the body (22126,91420). Grapefruit juice seems to increase levels of pitavastatin to a greater degree in patients homozygous for a specific polymorphism (388A>G) in the OATP1B1 gene compared to those heterozygous for this polymorphism (91420).
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Grapefruit juice can decrease blood levels of the active metabolite of prasugrel, thereby decreasing the antiplatelet effect of prasugrel.
Details
Prasugrel is a prodrug that is metabolized by cytochrome P450 3A4 (CYP3A4) into its active metabolite. A small pharmacokinetic study in healthy volunteers shows that drinking grapefruit juice 200 mL three times daily for 4 days and taking a single dose of prasugrel 10 mg with an additional 200 mL of grapefruit juice on day 3, results in a 49% lower peak plasma level and a 26% lower overall plasma exposure to the active metabolite when compared with drinking water. However, despite the reduced exposure, platelet aggregation seems to be reduced by an average of only 5% (105567). The clinical significance of this interaction is unclear.
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Grapefruit juice can increase blood levels of praziquantel, potentially increasing the effects and adverse effects of praziquantel.
Details
Clinical research shows that grapefruit juice can inhibit cytochrome P450 3A4 (CYP3A4) metabolism of praziquantel. Plasma concentrations of praziquantel can increase by as much as 160% when administered with 250 mL of commercially available grapefruit juice (8282).
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Grapefruit juice may increase blood levels of primaquine, potentially increasing the effects and adverse effects of primaquine.
Details
Clinical research shows that grapefruit juice increases the bioavailability of primaquine by approximately 20% (22130). The clinical significance of this interaction is not clear.
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Grapefruit or grapefruit juice, especially if consumed in large amounts, can cause additive QT interval prolongation when taken with QT interval-prolonging drugs, potentially increasing the risk of ventricular arrhythmias.
Details
Clinical research in healthy volunteers shows that drinking 6 liters of grapefruit juice over 6 hours prolonged the QTc by a peak amount of 14 milliseconds (ms). This prolongation was similar to the QT prolongation caused by the drug moxifloxacin. In individuals with long QT syndrome, a smaller dose of grapefruit juice, 1.5 liters, resulted in a greater peak QTc prolongation of about 30 ms (100249). The effect of smaller quantities of grapefruit juice on the QT interval is unclear.
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Grapefruit juice may increase blood levels of quetiapine, increasing the effects and adverse effects of quetiapine.
Details
Quetiapine is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit can inhibit CYP3A4 (3227,3774,8283,8285,8286,22129,91427,104190). In one case report, a healthy 28-year-old female with bipolar disorder stabilized on quetiapine 800 mg daily presented with quetiapine toxicity considered to be related to consuming a gallon of grapefruit juice over the past 24 hours (108848).
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Grapefruit juice can alter blood levels of quinidine, potentially increasing or decreasing the clinical effects of quinidine.
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Grapefruit juice can increase blood levels of saquinavir, potentially increasing the effects and adverse effects of saquinavir.
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Grapefruit juice can increase blood levels of scopolamine, potentially increasing the effects and adverse effects of scopolamine.
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Clinical research shows that grapefruit juice can inhibit cytochrome P450 3A4 (CYP3A4) metabolism of scopolamine, increasing its absorption and plasma concentrations. Oral bioavailability of scopolamine can increase by 30% when administered with 150 mL of grapefruit juice (8284).
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Grapefruit juice can increase blood levels of sertraline, potentially increasing the effects and adverse effects of sertraline.
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Clinical research shows that grapefruit juice inhibits the cytochrome P450 3A4 (CYP3A4) metabolism of sertraline, increasing blood levels of sertraline (22122).
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Grapefruit juice can increase blood levels of sildenafil, potentially increasing the effects and adverse effects of sildenafil.
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Clinical research shows that grapefruit juice inhibits cytochrome P450 3A4 (CYP3A4) metabolism of sildenafil, increasing its absorption and plasma concentrations. Oral bioavailability of sildenafil can increase by 23% when administered with 500 mL of commercially available grapefruit juice (8283).
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Grapefruit juice may slightly increase blood levels of sunitinib, potentially increasing the effects and adverse effects of sunitinib.
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Sunitinib is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit and grapefruit juice can inhibit CYP3A4 and increase levels of some drugs metabolized by this enzyme. One small clinical study shows that drinking 200 mL of grapefruit juice three times daily can increase the bioavailability of sunitinib by 11% (91429). While this effect is unlikely to be clinically significant, patients should use caution when using grapefruit along with sunitinib. Dose adjustments may be necessary.
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Grapefruit juice can increase blood levels of tacrolimus, potentially increasing the effects and adverse effects of tacrolimus.
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Clinical research shows that drinking grapefruit juice 200 mL daily while taking tacrolimus 3 mg daily increases the trough blood concentration of tacrolimus by approximately 3-fold in patients with connective tissue diseases (95974). A single case has also reported a 10-fold increase in tacrolimus trough levels after the ingestion of grapefruit juice over 3 days (22122). This effect is attributed to the inhibition of cytochrome P450 3A4 (CYP3A4) by grapefruit (95974).
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Theoretically, grapefruit juice might increase blood levels of tadalafil, potentially increasing the effects and adverse effects of tadalafil.
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Animal research shows that grapefruit juice increases tadalafil serum concentrations and overall exposure, likely through inhibition of cytochrome P450 3A4 enzymes (104189).
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Grapefruit juice might decrease blood levels of talinolol, potentially decreasing the clinical effects of talinolol.
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Clinical research suggests that grapefruit juice reduces talinolol bioavailability, likely by inhibiting intestinal uptake (22135). The clinical significance of this effect is unclear.
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Grapefruit juice can increase blood levels of terfenadine, potentially increasing the effects and adverse effects of terfenadine.
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Grapefruit juice can decrease blood levels of theophylline, potentially decreasing the effectiveness of theophylline.
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Clinical research shows that grapefruit juice seems to modestly decrease theophylline levels when given concurrently with sustained-release theophylline (11013). The mechanism of this interaction is unknown.
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Grapefruit juice can increase blood levels of ticagrelor, thereby increasing the effects and adverse effects of ticagrelor.
Details
Ticagrelor is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit can inhibit CYP3A4. A small clinical study shows that taking grapefruit juice with ticagrelor increases blood levels of ticagrelor more than two-fold and increases the antiplatelet activity of ticagrelor (91418).
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Grapefruit juice can increase blood levels of tolvaptan, potentially increasing the effects and adverse effects of tolvaptan.
Details
Tolvaptan is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit can inhibit CYP3A4. A small clinical study shows that grapefruit juice can increase the bioavailability and blood levels of tolvaptan by approximately 1.6-fold for up to 16 hours (91426).
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Theoretically, drinking large amounts of grapefruit juice might increase the effects and adverse effects of warfarin.
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In one case report, a patient experienced significantly increased international normalized ratio (INR) associated with consumption of 50 ounces of grapefruit juice daily (12061). However, smaller amounts of grapefruit juice might not be a problem. In a small clinical trial, consumption of 24 ounces of grapefruit juice daily for one week had no effect on INR in males treated with warfarin (12063).
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Theoretically, guarana might decrease the vasodilatory effects of adenosine and interfere with its use prior to stress testing.
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Guarana contains caffeine. Caffeine is a competitive inhibitor of adenosine at the cellular level. However, caffeine does not seem to affect supplemental adenosine because high interstitial levels of adenosine overcome the antagonistic effects of caffeine (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).
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Theoretically, alcohol might increase the levels and adverse effects of caffeine.
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Guarana contains caffeine. Concomitant use of alcohol can increase caffeine serum concentrations and the risk of caffeine adverse effects. Alcohol reduces caffeine metabolism (6370).
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Theoretically, guarana may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.
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Theoretically, taking guarana with antidiabetes drugs might interfere with blood glucose control.
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Theoretically, concomitant use might increase the clinical effects of beta-adrenergic agonists.
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Guarana contains caffeine. Theoretically, concomitant use of large amounts of caffeine might increase cardiac inotropic effects of beta-agonists (15).
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Theoretically, guarana might reduce the effects of carbamazepine and increase the risk for convulsions.
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Animal research suggests that taking caffeine can lower the anticonvulsant effects of carbamazepine and can induce seizures when given to animals 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 two-fold in healthy individuals (23562).
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Theoretically, concomitant use might increase the effects and adverse effects of caffeine in guarana.
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Guarana contains caffeine. Cimetidine decreases the rate of caffeine clearance by 31% to 42% (11736).
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Theoretically, guarana might increase the levels and adverse effects of clozapine and acutely exacerbate psychotic symptoms.
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Guarana contains caffeine. Caffeine can increase the effects and toxicity of clozapine. Caffeine doses of 400-1000 mg per day inhibit clozapine metabolism (5051). Clozapine is metabolized by cytochrome P450 1A2 (CYP1A2). 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 the interaction between clozapine and caffeine (13741).
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Theoretically, concomitant use might increase the effects and adverse effects of caffeine found in guarana.
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Theoretically, concomitant use might increase the levels and adverse effects of caffeine.
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Theoretically, guarana might decrease the vasodilatory effects of dipyridamole and interfere with its use prior to stress testing.
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Guarana 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 than adenosine-induced stress testing (11771).
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Theoretically, disulfiram might increase the risk of adverse effects from caffeine.
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In human research, disulfiram decreases the clearance and increases the half-life of caffeine (11840).
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Theoretically, using guarana with diuretic drugs might increase the risk of hypokalemia.
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Theoretically, concomitant use might increase the risk for stimulant adverse effects.
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Guarana contains caffeine. Use of ephedrine with caffeine can increase the risk of stimulatory adverse effects. There is evidence that using ephedrine with caffeine might increase the risk of serious life-threatening or debilitating adverse effects such as hypertension, myocardial infarction, stroke, seizures, and death (1275,6486,10307).
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Theoretically, estrogens might increase the levels and adverse effects of caffeine.
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Guarana contains caffeine. Estrogen inhibits caffeine metabolism (2714).
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Theoretically, guarana might reduce the effects of ethosuximide and increase the risk for convulsions.
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Guarana contains caffeine. Animal research shows that caffeine 92.4 mg/kg can decrease the anticonvulsant activity of ethosuximide (23560). This effect has not been observed in humans.
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Theoretically, guarana might reduce the effects of felbamate and increase the risk for convulsions.
Details
Guarana contains caffeine. Animal research shows that a high dose of caffeine 161.7 mg/kg can decreases the anticonvulsant activity of felbamate (23563). This effect has not been observed in humans.
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Theoretically, fluconazole might increase the levels and adverse effects of caffeine.
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Guarana contains caffeine. Fluconazole decreases caffeine clearance by approximately 25% (11022).
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Theoretically, guarana might increase the levels and adverse effects of flutamide.
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Guarana contains caffeine. In vitro evidence shows that caffeine can inhibit the metabolism of flutamide (23553). However, this effect has not been reported in humans.
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Theoretically, fluvoxamine might increase the levels and adverse effects of caffeine.
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Guarana contains caffeine. Fluvoxamine reduces caffeine metabolism (6370).
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Theoretically, abrupt guarana withdrawal might increase the levels and adverse effects of lithium.
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Theoretically, metformin might increase the levels and adverse effects of caffeine.
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Guarana contains caffeine. Animal research shows that metformin can reduce caffeine metabolism (23571). However, this effect has not been reported in humans.
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Theoretically, methoxsalen might increase the levels and adverse effects of caffeine.
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Guarana contains caffeine. Methoxsalen can reduce caffeine metabolism (23572).
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Theoretically, mexiletine might increase the levels and adverse effects of caffeine.
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Theoretically, concomitant use might increase the risk of a hypertensive crisis.
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Guarana contains caffeine. Caffeine has been shown to inhibit 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.
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Theoretically, concomitant use might increase the risk of hypertension.
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Guarana 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).
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Theoretically, guarana might decrease the effects of pentobarbital.
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Theoretically, guarana might reduce the effects of phenobarbital and increase the risk for convulsions.
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Theoretically, phenothiazines might increase the levels and adverse effects of caffeine.
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Theoretically, phenylpropanolamine might increase the risk of hypertension, as well as the levels and adverse effects of caffeine.
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Theoretically, guarana might reduce the effects of phenytoin and increase the risk for convulsions.
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Theoretically, guarana might increase the levels and clinical effects of pioglitazone.
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Guarana 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.
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Theoretically, quinolone antibiotics might increase the levels and adverse effects of caffeine.
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Theoretically, concomitant use might increase the levels and adverse effects of both caffeine and riluzole.
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Guarana contains caffeine. Caffeine and riluzole are both metabolized by cytochrome P450 1A2 (CYP1A2), and concomitant use might reduce the metabolism of one or both agents (11739).
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Theoretically, concomitant use might increase stimulant adverse effects.
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Guarana 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).
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Theoretically, terbinafine might increase the levels and adverse effects of caffeine.
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Guarana contains caffeine. Terbinafine decreases the clearance of intravenous caffeine by 19% (11740).
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Theoretically, guarana might increase the levels and adverse effects of theophylline.
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Guarana contains caffeine. Large amounts of caffeine might decrease theophylline clearance by 23% to 29% (11741).
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Theoretically, guarana might increase the levels and adverse effects of tiagabine.
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Guarana contains caffeine. Animal research shows 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).
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Theoretically, ticlopidine might increase the levels and adverse effects of caffeine.
Details
Guarana contains caffeine. In vitro evidence shows that ticlopidine can inhibit the metabolism of caffeine (23557). However, this interaction has not been reported in humans.
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Theoretically, guarana might reduce the effects of valproate and increase the risk for convulsions.
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Theoretically, verapamil might increase the levels and adverse effects of caffeine.
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Verapamil increases plasma caffeine concentrations by 25% (11741).
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Consuming sweet orange with celiprolol can decrease oral absorption of celiprolol.
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A pharmacokinetic study in healthy volunteers shows that celiprolol levels, after a single dose of 100 mg, are decreased by up to 90% in people who drink sweet orange juice 200 mL three times daily. It's not known if lower consumption of sweet orange juice will have the same effect. Theoretically, this occurs due to short-term inhibition of organic anion transporting polypeptide (OATP) (12115,17603,17604). Recommend separating drug administration and consumption of sweet orange by at least 4 hours (17603,17604).
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Consuming sweet orange juice with fexofenadine can decrease oral absorption of fexofenadine.
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Clinical research shows that coadministration of sweet orange juice 1200 mL decreases bioavailability of fexofenadine by about 72% (7046,17604). In an animal model, sweet orange juice decreased bioavailability of fexofenadine by 31% (17605). Fexofenadine manufacturer data indicates that concomitant administration of sweet orange juice and fexofenadine results in larger wheal and flare sizes in research models. This suggests that sweet orange reduces the clinical response to fexofenadine (17603). Theoretically, this occurs due to short-term inhibition of organic anion transporting polypeptide (OATP) (7046). Recommend separating drug administration and consumption of sweet orange by at least 4 hours (17603,17604).
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Consuming sweet orange juice with ivermectin can decrease the oral absorption of ivermectin.
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A pharmacokinetic study in healthy volunteers shows that taking ivermectin orally with sweet orange juice 750 mL over 4 hours reduces the bioavailability of ivermectin. This effect does not seem to be related to effects on P-glycoprotein. The effect on ivermectin is more pronounced in males compared to females (12154).
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Consuming sweet orange juice can decrease oral absorption of OATP substrates. Separate administration by at least 4 hours.
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Clinical research shows that consuming sweet orange juice inhibits OATP, which reduces bioavailability of oral drugs that are substrates of OATP (17603,17604). For example, sweet orange juice decreases bioavailability of fexofenadine, a substrate of OATP, by about 72% and of celiprolol, another OATP substrate, by up to 90% (7046,12115). Since sweet orange juice seems to affect OATP for a short time, recommend separating drug administration and consumption of sweet orange juice by at least 4 hours (17603,17604).
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Sweet orange juice seems to modulate P-glycoprotein (P-gp), which might affect the blood levels of P-gp substrates.
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Animal and in vitro research suggest that orange juice extract inhibits drug efflux by P-gp, increasing absorption and levels of P-gp substrates (12116,15327). In contrast, pharmacokinetic research in humans shows that drinking large amounts of sweet orange juice decreases absorption and levels of the P-gp substrate celiprolol. This suggests that orange juice actually induces drug efflux by P-gp or affects drug levels by another mechanism such as inhibiting the gut drug transporter called organic anion transporting polypeptide (OATP) (7046,12115). Until more is known, sweet orange juice should be used cautiously in people taking P-gp substrates.
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Consuming sweet orange juice with pravastatin can increase the absorption of pravastatin.
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A small pharmacokinetic study in healthy volunteers shows that consuming sweet orange juice 800 mL over 3 hours, including before, during, and after taking pravastatin 10 mg, increases pravastatin levels by about 149%, without affecting pravastatin elimination. Theoretically this effect might be due to modulation of organic anion transporting polypeptides (OATPs) by sweet orange juice (14348). Sweet orange juice does not seem to affect simvastatin levels, but it is not known if sweet orange affects any of the other statins.
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Calcium-fortified sweet orange juice might reduce quinolone absorption.
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Below is general information about the adverse effects of the known ingredients contained in the product Mediterranean Trim with Sinetrol-XPur. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
General
...Orally, grapefruit and grapefruit juice are generally well tolerated.
Serious Adverse Effects (Rare):
Orally: Allergic reactions in sensitive individuals have been reported. When large quantities are consumed, arrhythmias, mineralocorticoid excess, QT prolongation, and pseudohyperaldosteronism have been reported. There is also some concern for increased breast cancer risk with grapefruit consumption.
Cardiovascular ...Orally, consumption of pink grapefruit juice 1000 mL can cause QT prolongation and cause arrhythmias in healthy patients and worsen arrhythmias in cardiomyopathy patients (13031,91424).
Endocrine ...Orally, high doses of grapefruit juice have been observed to cause pseudohyperaldosteronism and mineralocorticoid excess (53340,53346).
Gastrointestinal ...In a case report, grapefruit juice held against the teeth resulted in enamel and tooth surface loss (53368).
Immunologic ...Orally, grapefruit can cause allergic sensitization characterized by eosinophilic gastroenteritis, urticaria, and generalized pruritus (53351,53360).
Oncologic ...Preliminary population research shows that postmenopausal adults who consume a quarter or more of a whole grapefruit daily have a 25% to 30% increased risk of developing breast cancer (14858). Grapefruit is a potent inhibitor of cytochrome P450 3A4, which metabolizes estrogen. Consuming large amounts of grapefruit might significantly increase endogenous estrogen levels and therefore increase the risk of breast cancer. More evidence is needed to validate these findings. Until more is known, advise patients to consume grapefruit in moderation.
Renal ...In population research, consumption of 240 mL/day of grapefruit juice is associated with an increased risk of kidney stones (4216,53372).
General
...Orally, guarana is typically well tolerated when used in moderation.
Due to its caffeine content, use of large doses may be unsafe.
Most Common Adverse Effects:
Orally: Stomach burning and nausea.
Cardiovascular
...Orally, a case of premature ventricular contraction has been reported for a 51-year-old female who used guarana as part of a multi-ingredient herbal product (54372).
Guarana contains caffeine. Although acute administration of caffeine can increase blood pressure, regular consumption does not seem to increase either blood pressure or pulse, even in mildly hypertensive patients (1451,1452,2722). Also, epidemiological research suggests there is no association between caffeine consumption and increased incidence of hypertension. Habitual coffee consumption doesn't seem to be related to hypertension, but habitual consumption of sugared or diet cola is associated with development of hypertension (13739).
Combining ephedra with guarana can increase the risk of adverse effects. Cases of hypertension and chest pain have been reported for patients who took products containing guarana and ephedra (8644,54376). A case of cerebral infarction has also been reported for a patient consuming ephedra extract and guarana (48746). 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 six weeks (1275).
Dermatologic ...Guarana contains caffeine. There are several case reports of urticaria after caffeine ingestion (36546,36448,36475).
Endocrine
...Guarana contains caffeine.
Some evidence shows caffeine is associated with fibrocystic breast disease, breast cancer, and endometriosis; however, this is controversial since findings are conflicting (8043). Restricting caffeine in people 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).
Although the effects of guarana alone are not clear, the combination of guarana along with ephedra has been reported to cause increased blood glucose levels and decreased blood levels of potassium (54376).
Gastrointestinal ...Orally, guarana can cause a sensation of burning in the stomach and vomiting (54414,91487). These effects may be due to caffeine in guarana. Orally, caffeine can cause gastric irritation, nausea, and vomiting (11832,11838,13735). In infants, caffeine may also cause feeding intolerance and gastrointestinal irritation (6023).
Immunologic ...Guarana contains caffeine. When taken orally, caffeine can cause anaphylaxis in sensitive individuals, although true IgE-mediated caffeine allergy seems to be relatively rare (11315).
Musculoskeletal
...In a clinical trial of guarana extract, one person abandoned treatment due to symptoms of arthritis with edema.
It is not clear if this adverse effect is due to guarana (91487).
Cases of rhabdomyolysis and myoglobinuria have been reported in individuals that have taken products containing guarana in combination with ephedra and other herbal products. These adverse effects are thought to be related to the caffeine content of guarana (19154,36466).
Epidemiological evidence regarding the relationship between caffeine use and the risk for osteoporosis is contradictory. Caffeine can increase urinary excretion of calcium (2669,10202,11317). Women identified with a genetic variant of the vitamin D receptor appear to be at an increased risk for the detrimental effect of caffeine on bone mass (2669). However, moderate caffeine intake, less than 300 mg per day, does not seem to significantly increase osteoporosis risk in most postmenopausal women with normal calcium intake (2669,6025,10202,11317).
Neurologic/CNS
...Orally, guarana can cause dizziness (91483).
The caffeine in guarana can cause insomnia (especially in children), nervousness, restlessness, dizziness, tremors, delirium, and convulsions. Other symptoms include headache, anxiety, and agitation (10755,11832,11838,13735,108016).
Taking guarana with ephedra can cause insomnia, irritability, dizziness, and headache (3719). The combination of ephedra and caffeine in guarana might also increase the risk of adverse effects such as jitteriness, seizures, and temporary loss of consciousness (2729,21015).
Ocular/Otic ...Guarana contains caffeine. When taken orally, caffeine can cause ringing in the ears (11832,11838,13735).
Psychiatric ...In a clinical trial, depression was reported by one person taking guarana extract (91483).
Renal ...Guarana contains caffeine. When taken orally, caffeine can cause diuresis (11832,11838,13735).
Other ...Guarana contains caffeine. 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).
General ...Orally, sweet orange juice or fruit seem to be well tolerated. Large amounts of sweet orange peel may be unsafe, especially for children. When inhaled, sweet orange essential oil seems to be generally well tolerated.
Gastrointestinal ...There have been reports of intestinal colic in children following ingestion of large amounts of sweet orange peel (11).
Neurologic/CNS ...There have been reports of convulsions in children following ingestion of large amounts of sweet orange peel (11).
