| Ingredients | Amount Per Serving |
|---|---|
|
Calories
|
15 Calorie(s) |
|
Total Carbohydrates
|
4 Gram(s) |
|
Total Sugars
|
4 Gram(s) |
|
Added Sugars
|
4 Gram(s) |
|
(Caffeine, Natural, Camellia sinensis)
(Organic, 6% Natural Caffeine)
|
670 mg |
|
(CBD)
(10%)
|
200 mg |
|
(Caffeine, Natural, Camellia sinensis Leaf Extract)
(Organic, 98% Natural Caffeine)
|
75 mg |
|
(Paullinia cupana )
(Caffeine, Natural)
(Organic, 10% Natural Caffeine)
|
10 mg |
Cane Sugar, Citric Acid, Natural Flavors, Stevia Genus: Stevia, Rice Fiber, Psyllium Fiber, Banana Flour
Below is general information about the effectiveness of the known ingredients contained in the product Peak +CBD Isolate. 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 Peak +CBD Isolate. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
POSSIBLY SAFE ...when used orally and appropriately in adults. Cannabidiol doses up to 200 mg daily have been used with apparent safety for up to 13 weeks (97021,105559), while higher doses of 700 mg daily for up to 6 weeks and 1200 mg daily for up to 4 weeks have been used with apparent safety (89680,105559). A prescription cannabidiol oil (Epidiolex, GW Pharmaceuticals) has been safely used in doses of 510-25 mg/kg daily, titrated based on response and tolerability for up to 20 months (97979,97980,99613,105495,106631,113034). ...when a specific cannabis extract spray that contains cannabidiol 2.5 mg and delta-9-tetrahydrocannabinol (THC) 2.7 mg per actuation (Sativex, GW Pharmaceuticals) is applied topically into the oral mucosa for up to 2 years. This product is available as a prescription drug in the UK and Canada; it is an investigational new drug in the US (61775,61820,89460,89913,111095). There is insufficient reliable information available about the safety of cannabidiol when used topically on the skin.
CHILDREN: POSSIBLY SAFE
when a prescription cannabidiol oil (Epidiolex, GW Pharmaceuticals) is used orally and appropriately.
This cannabidiol product has been safely used in clinical research at doses of 2-50 mg/kg daily in children 1 year of age and older. However, the maximum recommended dosage of this product is 12.5 mg/kg twice daily (25 mg/kg/day); higher doses seem to carry a higher risk for adverse effects. Epidiolex is titrated based on response and tolerability (97017,97018,97019,97022,97025,97979,97980,99613,103038,105495,106631,106633). There is insufficient reliable information available about the safety of other forms of cannabidiol in children.
PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally.
The US Food and Drug Administration (FDA) strongly advises against the use of cannabidiol during pregnancy. Cannabidiol products might contain delta-9-tetrahydrocannabinol (THC) or other contaminants such as pesticides, heavy metals, bacteria, and fungus, which can be dangerous to the child (100891,109172). Also, animal research shows that high levels of cannabidiol can damage the reproductive system of male offspring (100891).
LIKELY SAFE ...when green tea is consumed as a beverage in moderate amounts (733,6031,9222,9223,9225,9226,9227,9228,14136,90156)(90159,90168,90174,90184,95696). Green tea contains caffeine. According to a review by Health Canada, and a subsequent large meta-analysis conducted in the US, drinking up to 8 cups of green tea daily, or approximately 400 mg of caffeine, is not associated with significant adverse cardiovascular, bone, behavioral, or reproductive effects in healthy adults (11733,98806). The US Dietary Guidelines Advisory Committee states that there is strong and consistent evidence that consumption of caffeine 400 mg daily is not associated with increased risk of major chronic diseases, such as cardiovascular disease or cancer, in healthy adults (98806). ...when a specific green tea extract ointment is used topically and appropriately, short-term. The specific green tea extract ointment (Veregen, Bradley Pharmaceuticals) providing 15% kunecatechins is an FDA-approved prescription product. It has been safely used in trials lasting up to 16 weeks (15067). The safety of treatment beyond 16 weeks or multiple treatment courses is not known.
POSSIBLY SAFE ...when green tea extract is used orally. Green tea extract containing 7% to 12% caffeine has been used safely for up to 2 years (8117,37725). Also decaffeinated green tea extract up to 1.3 grams daily enriched in EGCG has been used safely for up to 12 months (90158,97131). In addition, green tea extract has been safely used as part of an herbal mixture also containing garcinia, coffee, and banaba extracts for 12 weeks (90137). ...when used topically and appropriately as a cream or mouthwash (6065,11310,90141,90150,90151).
POSSIBLY UNSAFE ...when consumed as a beverage in large quantities. Green tea contains a significant amount of caffeine. Chronic use, especially in large amounts, can produce tolerance, habituation, psychological dependence, and other significant adverse effects. Doses of caffeine greater than 600 mg per day, or approximately 12 cups of green tea, have been associated with significant adverse effects such as tachyarrhythmias and sleep disturbances (11832). These effects would not be expected to occur with the consumption of decaffeinated green tea. Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine found in ingredients such as green tea, which naturally contains caffeine, does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product. There is also some speculation that green tea products containing higher amounts of the catechin epigallocatechin gallate (EGCG) might have increased risk of adverse events. Some research has found that taking green tea products containing EGCG levels greater than 200 mg is associated with increased risk of mild adverse effects such as constipation, increased blood pressure, and rash (90161). Other research has found that doses of EGCG equal to or above 800 mg daily may be associated with increased risk of liver injury in humans (95440,95696,97131).
LIKELY UNSAFE ...when used orally in very high doses. The fatal acute oral dose of caffeine is estimated to be 10-14 grams (150-200 mg per kilogram). Serious toxicity can occur at lower doses depending on variables in caffeine sensitivity such as smoking, age, and prior caffeine use (11832).
CHILDREN: POSSIBLY SAFE
when used orally by children and adolescents in amounts commonly found in foods and beverages (4912,11833).
Intake of caffeine in doses of less than 2.5 mg/kg daily is not associated with significant adverse effects in children and adolescents (11733,98806). ...when used for gargling three times daily for up to 90 days (90150).
There is insufficient reliable information available about the safety of green tea extract when used orally in children. However, taking green tea extract orally has been associated with potentially serious, albeit uncommon and unpredictable cases, of hepatotoxicity in adults. Therefore, some experts recommend that children under the age of 18 years of age do not use products containing green tea extract (94897).
PREGNANCY: POSSIBLY SAFE
when used orally in moderate amounts.
Due to the caffeine content of green tea, pregnant patients should closely monitor their intake to ensure moderate consumption. Fetal blood concentrations of caffeine approximate maternal concentrations (4260). The use of caffeine during pregnancy is controversial; however, moderate consumption has not been associated with clinically important adverse fetal effects (2708,2709,2710,2711,9606,11733,16014,16015,98806). In some studies consuming amounts over 200 mg daily is associated with a significantly increased risk of miscarriage (16014). This increased risk may be most likely to occur in those with genotypes that confer a slow rate of caffeine metabolism (98806). According to a review by Health Canada, and a subsequent large meta-analysis conducted in the US, most healthy pregnant patients can safely consume doses up to 300 mg daily without an increased risk of spontaneous abortion, stillbirth, preterm birth, fetal growth retardation, or congenital malformations (11733,98806). Advise keeping caffeine consumption below 300 mg daily. This is similar to the amount of caffeine in about 6 cups of green tea. Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine found in ingredients such as green tea, which naturally contains caffeine, does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product. Based on animal models, green tea extract catechins are also transferred to the fetus, but in amounts 50-100 times less than maternal concentrations (15010). The potential impact of these catechins on the human fetus is not known, but animal models suggest that the catechins are not teratogenic (15011).
PREGNANCY: POSSIBLY UNSAFE
when used orally in amounts providing more than 300 mg caffeine daily.
Caffeine from green tea crosses the placenta, producing fetal blood concentrations similar to maternal levels (4260). Consumption of caffeine in amounts over 300 mg daily is associated with a significantly increased risk of miscarriage in some studies (16014,98806). Advise keeping caffeine consumption from all sources below 300 mg daily. This is similar to the amount of caffeine in about 6 cups of green tea. High maternal doses of caffeine throughout pregnancy have also resulted in symptoms of caffeine withdrawal in newborn infants (9891). High doses of caffeine have also been associated with spontaneous abortion, premature delivery, and low birth weight (2709,2711). However, some research has also found that intrauterine exposure to even modest amounts of caffeine, based on maternal blood levels during the first trimester, is associated with a shorter stature in children ages 4-8 years (109846). Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine found in ingredients such as green tea, which naturally contains caffeine, does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product.
There is also concern that consuming large amounts of green tea might have antifolate activity and potentially increase the risk of folic acid deficiency-related birth defects. Catechins in green tea inhibit the enzyme dihydrofolate reductase in vitro (15012). This enzyme is responsible for converting folic acid to its active form. Preliminary evidence suggests that increasing maternal green tea consumption is associated with increased risk of spina bifida (15068). Also, evidence from epidemiological research suggests that serum folate levels in pregnant patients with high green tea intake (57.3 mL per 1000 kcal) are decreased compared to participants who consume moderate or low amounts of green tea (90171). More evidence is needed to determine the safety of using green tea during pregnancy. For now, advise pregnant patients to avoid consuming large quantities of green tea.
LACTATION: POSSIBLY SAFE
when used orally in moderate amounts.
Due to the caffeine content of green tea, nursing parents should closely monitor caffeine intake. Breast milk concentrations of caffeine are thought to be approximately 50% of maternal serum concentrations (9892).
LACTATION: POSSIBLY UNSAFE
when used orally in large amounts.
Consumption of green tea might cause irritability and increased bowel activity in nursing infants (6026). There is insufficient reliable information available about the safety of green tea extracts when applied topically during breast-feeding.
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.
Below is general information about the interactions of the known ingredients contained in the product Peak +CBD Isolate. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
Cannabidiol might increase brivaracetam levels.
 Details
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Cannabidiol can increase caffeine levels.
Details
Caffeine is a substrate of CYP1A2, and cannabidiol has been shown to inhibit CYP1A2 metabolism. A pharmacokinetic study in healthy adults shows that taking oral cannabidiol, starting at 250 mg once daily and titrating to 750 twice daily over a total of 24 days, increases the peak serum level of caffeine by 15% and the overall exposure to caffeine by 95% after a single dose of caffeine 200 mg taken on day 23 (105557). Other clinical research also shows that cannabidiol modestly increases the area under the curve of caffeine but does not increase peak serum levels of caffeine (113025).
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Cannabidiol might increase carbamazepine levels.
Details
Research in murine animal models shows that giving a single oral dose of cannabidiol 50 mg/kg with carbamazepine 80 mg/kg increases carbamazepine's area under the curve (AUC) by 53% when compared with control. A higher single dose of cannabidiol 120 mg/kg has a similar effect on carbamazepine levels. Multiple doses of cannabidiol have a slightly larger effect. Giving cannabidiol daily for 14 days increases the AUC of carbamazepine by 66% (103033).
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Cannabidiol can increase citalopram levels.
Details
A small open-label study in young adults stabilized on citalopram or escitalopram shows that taking adjunctive cannabidiol 200-800 mg daily for 12 weeks increases plasma concentrations of citalopram from an average of 42 ng/mL at baseline to an average of 79 ng/mL at 8 weeks and 63 ng/mL at 12 weeks. Patients reported fatigue and gastrointestinal disturbances; there were no reports suggestive of serotonergic toxicity. In vitro evidence suggests that this interaction may be due to inhibition of cytochrome P450 (CYP) 2C19 and 3A4 by cannabidiol (105491). This finding is limited due to small study size and large interindividual variability.
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Cannabidiol might increase levels of clobazam and increase the occurrence of somnolence.
Details
In clinical studies, concomitant administration of cannabidiol and clobazam is associated with up to a 60% increase in serum levels of N-desmethylclobazam, the primary active metabolite of clobazam. This increased concentration is likely due to inhibition of CYP2C19 by cannabidiol. However, the interaction does not appear to be dose-dependent. In children and adults, concomitant use of cannabidiol and clobazam is associated with an increased occurrence of somnolence (97018,97022,97023,97979,97980,106631).
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Theoretically, cannabidiol might have additive effects if used with other CNS depressants.
Details
Preliminary clinical research, case reports, and animal studies suggest that high dose cannabidiol has sedative and hypnotic effects (61989,89986,89987,110248). Theoretically, concomitant use of cannabidiol with drugs with sedative and anesthetic properties may cause additive therapeutic and adverse effects.
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Theoretically, cannabidiol might increase levels of drugs metabolized by CYP1A1.
Details
In vitro research shows that cannabidiol inhibits CYP1A1 (89690). However, this interaction has yet to be reported in humans. Until more is known, use with caution. Theoretically, concomitant use of cannabidiol with CYP1A1 substrates might decrease the clearance of these substrates and increase the risk for adverse effects.
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Cannabidiol may increase levels of drugs metabolized by CYP1A2.
Details
In vitro research shows that cannabidiol inhibits CYP1A2 (89690,107325). Furthermore, clinical studies show that cannabidiol may inhibit the metabolism of caffeine, a CYP1A2 substrate. Two pharmacokinetic studies in healthy adults show that taking cannabidiol dosed 640 mg once up to 750 twice daily increases the area under the curve of caffeine. However, results are mixed over whether cannabidiol impacts peak serum levels of caffeine (105557,113025).
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Theoretically, cannabidiol might increase levels of drugs metabolized by CYP1B1.
Details
In vitro research shows that cannabidiol inhibits CYP1B1 (89690). However, this interaction has yet to be reported in humans. Until more is known, use with caution. Theoretically, concomitant use of cannabidiol with CYP1B1 substrates might increase the risk for adverse effects from these substrates.
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Theoretically, cannabidiol might increase levels of drugs metabolized by CYP2A6.
Details
In vitro research shows that cannabidiol inhibits CYP2A6 (89691). However, this interaction has yet to be reported in humans. Until more is known, use with caution. Theoretically, concomitant use of cannabidiol with CYP2A6 substrates might increase the risk for adverse effects from these substrates.
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Theoretically, cannabidiol might increase levels of drugs metabolized by CYP2B6.
Details
In vitro research shows that cannabidiol inhibits CYP2B6 (89691,107325). However, this interaction has yet to be reported in humans. Until more is known, use with caution. Theoretically, concomitant use of cannabidiol with CYP2B6 substrates might increase the risk for adverse effects from these substrates.
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Theoretically, CYP2C19 inducers might decrease cannabidiol levels.
Details
Cannabidiol is a substrate of CYP2C19 enzymes (99613). Theoretically, drugs that induce CYP2C19 enzymes might decrease the levels and effects of cannabidiol.
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Theoretically, CYP2C19 inhibitors might increase cannabidiol levels.
Details
Cannabidiol is a substrate of CYP2C19 enzymes (99613). Theoretically, drugs that inhibit CYP2C19 enzymes might increase levels of cannabidiol, increasing its effects and adverse effects.
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Cannabidiol may increase levels of drugs metabolized by CYP2C19.
Details
Research shows that cannabidiol inhibits CYP2C19 (89694,89695,97018,97022,107325,113025). In clinical studies and case reports, cannabidiol use resulted in significant increases in the serum levels of topiramate, methadone, citalopram, omeprazole, and N-desmethylclobazam, the primary active metabolite of clobazam. These chemicals are metabolized by CYP2C19 (97018,97022,97023,102958,105491,113025). Concomitant use of cannabidiol with CYP2C19 substrates may increase the risk for adverse effects from these substrates.
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Theoretically, cannabidiol might increase levels of drugs metabolized by CYP2C8.
Details
In vitro research shows that cannabidiol inhibits CYP2C8 (99613). However, this interaction has yet to be reported in humans. Until more is known, use with caution. Theoretically, concomitant use of cannabidiol with CYP2C8 substrates might increase the risk for adverse effects from these substrates.
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Cannabidiol may increase levels of drugs metabolized by CYP2C9.
Details
In vitro and animal research shows that cannabidiol inhibits CYP2C9 (89694,89695,107325,111098). In human studies, cannabidiol has been associated with an increase in plasma levels of topiramate and losartan, CYP2C9 substrates (97018,113025). Concomitant use of cannabidiol with CYP2C9 substrates may increase the risk for adverse effects from these substrates.
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Theoretically, cannabidiol might increase levels of drugs metabolized by CYP2D6.
Details
In vitro research shows that cannabidiol inhibits CYP2D6 (89692,107325). Theoretically, concomitant use of cannabidiol with CYP2D6 substrates might increase the risk for adverse effects from these substrates. However, a clinical crossover trial in healthy adults shows that cannabidiol does not inhibit dextromethorphan, a substrate of CYP2D6 (113025).
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Theoretically, cannabidiol might increase levels of drugs metabolized by CYP2E1.
Details
In vitro research shows that cannabidiol inhibits CYP2E1 (107325). So far, this interaction has not been reported in humans.
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Theoretically, CYP3A4 inducers might decrease cannabidiol levels.
Details
Cannabidiol is a substrate of CYP3A4 enzymes (99613). Theoretically, drugs that induce CYP3A4 enzymes might reduce the levels and effects of cannabidiol.
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Theoretically, CYP3A4 inhibitors might increase cannabidiol levels.
Details
Cannabidiol is a substrate of CYP3A4 enzymes (99747). Theoretically, drugs that inhibit CYP3A4 enzymes might increase levels of cannabidiol, increasing its effects and adverse effects.
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Cannabidiol may increase levels of drugs that are metabolized by CYP3A4.
Details
In vitro and animal research shows that cannabidiol inhibits CYP3A4 (89693,89694,89695,107325,111098). In human studies and case reports, cannabidiol has been associated with an increase in plasma levels of the CYP3A4 substrates zonisamide, tacrolimus, everolimus, citalopram, midazolam, and methadone (97018,100884,100892,102958,105491,113025).
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Cannabidiol might increase eslicarbazepine levels.
Details
In clinical research, concomitant administration of cannabidiol and eslicarbazepine is associated with a modest increase in plasma levels of eslicarbazepine. The mechanism for this interaction is unknown; eslicarbazepine is metabolized via glucuronidation. Eslicarbazepine levels stayed within the normal range and did not require dose adjustment. However, caution should be exercised when cannabidiol and eslicarbazepine are taken together (97018).
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Cannabidiol may increase everolimus levels.
Details
Everolimus is a substrate of CYP3A4 enzymes. Cannabidiol has been shown to inhibit CYP3A4 (89693,89694,89695,97018). A very small open-label clinical study shows that cannabidiol 12.5 mg/kg twice daily increases the area under the curve of a single dose of everolimus by about 2.5-fold (113053). A retrospective study in children taking everolimus for tuberous sclerosis has found that adding treatment with cannabidiol increases everolimus serum concentration by a median of 9.8 ng/mL (103035). In a case report, a 6-year-old girl stable on everolimus with refractory tonic seizures was started on cannabidiol titrated up to 200 mg daily for 6 weeks. This led to elevated levels of everolimus (100892).
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Cannabidiol might increase fluoxetine levels in certain patients.
Details
In one case report, a 17-year-old male with autism previously stabilized on fluoxetine 20 mg daily developed insomnia, agitation, hyperactivity, yelling, and worsening symptoms of obsessive-compulsive disorder after taking cannabidiol 18 mg twice daily for 2 weeks. The patient was found to be a poor cytochrome P450 2D6 (CYP2D6) metabolizer (CYP2D6*4/*4). Fluoxetine is primarily metabolized by CYP2D6, and to a lesser extent, by CYP2C9. Although fluoxetine levels weren't measured, it was hypothesized that the lack of CYP2D6 activity resulted in fluoxetine being metabolized solely by CYP2C9, which was subsequently inhibited by cannabidiol. This would have increased levels of fluoxetine, resulting in adverse effects (109186). Further research is needed to confirm this complex gene-drug interaction cascade.
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Cannabidiol might increase levels of certain glucuronidated drugs.
Details
In vitro research shows that cannabidiol inhibits uridine diphosphoglucuronosyl transferase (UGT) 1A9 and UGT2B7, enzymes responsible for glucuronidation (99613). Theoretically, this could decrease the clearance and increase levels of glucuronidated drugs.
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Cannabidiol might precipitate lithium toxicity, but the evidence is limited to a single case report.
Details
In a case report, a 13-year-old male with Lennox-Gastaut syndrome and autism, stable on lithium for one year, presented to the hospital with lithium toxicity after an increase in daily cannabidiol dose from 5 mg/kg to 10 mg/kg. Theoretically, lithium toxicity might have occurred due to cannabidiol-induced renal dysfunction (104018).
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Cannabidiol may increase levels of losartan.
Details
A crossover clinical study shows that taking cannabidiol 640 mg once increases area under the curve of losartan, a CYP2C9 substrate, by 77% (113025).
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Cannabidiol might increase levels of methadone, but the evidence is limited to a single case report.
Details
In a case report, a 13-year-old female with chronic cancer pain who was previously stabilized on methadone 7.5 mg twice daily presented to the emergency room with opioid-related side effects. She had begun experiencing increased sleepiness and fatigue after being given cannabidiol oil 1.5 grams orally in six divided doses daily by her parents. Her serum levels of methadone had risen to 271 ng/mL but decreased to 124 ng/mL after discontinuation of cannabidiol. This coincided with resolution of excessive sleepiness and fatigue (102958). Theoretically, cannabidiol increases levels of methadone by inhibiting cytochrome P450 3A4 (CYP3A4) and CYP2C19 enzymes, which metabolize methadone (99613,102958).
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Cannabidiol may increase levels of midazolam.
Details
A crossover clinical study shows that taking cannabidiol 640 mg once increases area under the curve of midazolam by 56%, likely by inhibiting CYP3A (113025).
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Cannabidiol may increase levels of omeprazole.
Details
A crossover clinical study shows that taking cannabidiol 640 mg once increases area under the curve of omeprazole by 207%, likely by inhibiting CYP2C19 (113025).
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Cannabidiol might increase rufinamide levels.
Details
In clinical research, concomitant administration of cannabidiol and rufinamide is associated with a modest increase in plasma levels of rufinamide. The mechanism for this interaction is unknown; rufinamide is metabolized via carboxyl esterases. Rufinamide levels stayed within the normal range and did not require dose adjustment. However, caution should be exercised when cannabidiol and rufinamide are taken together (97018).
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Cannabidiol might increase sirolimus levels.
Details
Sirolimus is a substrate of cytochrome P450 3A4 (CYP3A4) enzymes. Cannabidiol has been shown to inhibit CYP3A4 enzymes (89693,89694,89695,97018). A retrospective study in children taking sirolimus for tuberous sclerosis has found that adding treatment with cannabidiol increases serum sirolimus concentration by a median of 5.1 ng/mL (103035).
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Cannabidiol can increase stiripentol levels.
Details
Two clinical pharmacokinetic studies in patients stabilized on stiripentol shows that adding cannabidiol, 750 mg twice daily for 3-10 days or up to 20 mg/kg daily for 24 days, increases the average maximum concentration of stiripentol by 17% to 28% and the average area under the curve by 30% to 55% when compared with taking stiripentol alone. The mechanism for this interaction is unknown; cannabidiol might inhibit cytochrome P450 2C19 (CYP2C19) and/or UDP-glucuronosyltransferase (UGT) isoforms, which metabolize stiripentol (103030,103039). Although there were no adverse clinical outcomes, caution should be exercised when cannabidiol and stiripentol are taken together.
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Cannabidiol might increase tacrolimus levels.
Details
Tacrolimus is a cytochrome P450 3A4 (CYP3A4) substrate. Cannabidiol has been shown to inhibit CYP3A4 enzymes (89693,89694,89695,97018). In a case report, a patient stabilized on tacrolimus experienced about a 3-fold increase in tacrolimus concentrations after starting to take cannabidiol 2000-2900 mg daily for epilepsy (100884).
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Chronic use of cannabidiol 40 mg daily might modestly reduce levels of tamoxifen's active metabolites.
Details
In one case report, a 50-year-old female who was taking tamoxifen 20 mg daily for the past 5 years and cannabidiol 40 mg daily for about four months, presented with a 9.2% increase in N-desmethyltamoxifen and an 18.8% increase in endoxifen levels after discontinuing cannabidiol for 67 days. Theoretically, cannabidiol may have modestly inhibited cytochrome P450 3A4 (CYP3A4) and CYP2D6, which metabolize tamoxifen into N-desmethyltamoxifen and endoxifen, respectively. Cannabidiol discontinuation may have resulted in a return to normal enzyme activity (104886).
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Cannabidiol might increase topiramate levels.
Details
In clinical research, concomitant administration of cannabidiol and topiramate, a CYP2C9 and CYP2C19 substrate, is associated with a modest increase in plasma levels of topiramate. Topiramate levels stayed within the normal range and did not require dose adjustment. However, caution should be exercised when cannabidiol and topiramate are taken together (97018).
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Cannabidiol might increase the risk of hepatotoxicity and thrombocytopenia with valproic acid.
Details
In clinical research, concomitant administration of valproic acid and cannabidiol is associated with elevated liver transaminases and rare cases of thrombocytopenia. Liver transaminase levels and platelet counts should be closely monitored when cannabidiol and valproic acid are taken together. Liver transaminase elevation appears to be mild in the majority of cases; however, severe elevations can occur. At least 15 cases of thrombocytopenia have been reported following concomitant administration of valproic acid and cannabidiol. While thrombocytopenia is a known adverse effect with valproic acid, the risk may be modestly higher when cannabidiol and valproic acid are administered concomitantly (97017,97018,97019,97022,97979,97980,102323,103030,103039,103041). It is unclear if and how cannabidiol contributes to the risk of these adverse events, as there does not appear to be a direct pharmacokinetic interaction. Pharmacokinetic studies in humans show that coadministration of valproate with cannabidiol does not have clinically meaningful effects on levels of valproate or its metabolite 4-ene-VPA (103030,103039).
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Cannabidiol might increase warfarin levels.
Details
There are at least two case reports of patients who were previously stable on warfarin presenting with a supratherapeutic International Normalized Ratio (INR) after starting cannabidiol (Epidiolex) titrated up to a dose of 20 mg/kg daily. Warfarin dose reductions of 20% to 30% were required to normalize the INR. Cannabidiol may have inhibited cytochrome P450 2C9 (CYP2C9), resulting in decreased warfarin metabolism and increased levels (104013).
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Cannabidiol might increase zonisamide levels.
Details
In clinical research, concomitant administration of cannabidiol and zonisamide, a cytochrome P450 3A4 (CYP3A4) substrate, is associated with a modest increase in plasma levels of zonisamide. Zonisamide levels stayed within the normal range and did not require dose adjustment. However, caution should be exercised when cannabidiol and zonisamide are taken together (97018).
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Theoretically, high doses of green tea might increase the effects and side effects of 5-fluorouracil.
Details
Animal research shows that taking green tea in amounts equivalent to about 6 cups daily in humans for 4 weeks prior to receiving a single injection of 5-fluorouracil increases the maximum plasma levels of 5-fluorouracil by about 2.5-fold and the area under the curve by 425% (98424).
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Theoretically, green tea might decrease the vasodilatory effects of adenosine and interfere with its use prior to stress testing.
Details
Green tea contains caffeine. Caffeine is a competitive inhibitor of adenosine at the cellular level. However, caffeine doesn't seem to affect supplemental adenosine because high interstitial levels of adenosine overcome the antagonistic effects of caffeine (11771). It is recommended that methylxanthines and methylxanthine-containing products be stopped 24 hours prior to pharmacological stress tests (11770). However, methylxanthines appear more likely to interfere with dipyridamole (Persantine) than adenosine-induced stress testing (11771).
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Theoretically, alcohol might increase the levels and adverse effects of caffeine.
Details
Green tea contains caffeine. Concomitant use of alcohol and caffeine can increase caffeine serum concentrations and the risk of caffeine adverse effects. Alcohol reduces caffeine metabolism (6370).
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Theoretically, green tea may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.
Details
Conflicting reports exist regarding the effect of green tea on bleeding risk when used with anticoagulant or antiplatelet drugs; however, most evidence suggests that drinking green tea in moderate amounts is unlikely to cause a significant interaction. Green tea contains small amounts of vitamin K, approximately 7 mcg per cup (100524). Some case reports have associated the antagonism of warfarin with the vitamin K content of green tea (1460,1461,1463,4211,6048,8028,20868). However, these reports are rare, and very large doses of green tea (about 8-16 cups daily) appear to be needed to cause these effects. Furthermore, the catechins and caffeine in green tea are reported to have antiplatelet activity (733,8028,8029,12882,100524).
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Theoretically, taking green tea with antidiabetes drugs might interfere with blood glucose control.
Details
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Green tea extract seems to reduce the levels and clinical effects of atorvastatin.
Details
In healthy humans, taking green tea extract 300 mg or 600 mg along with atorvastatin reduces plasma levels of atorvastatin by approximately 24%. The elimination of atorvastatin is not affected (102714). Atorvastatin is a substrate of organic anion-transporting polypeptides (OATPs). Research shows that two of the major catechins found in green tea, epicatechin gallate (ECG) and epigallocatechin gallate (EGCG), inhibit OATPs. Some OATPs are expressed in the small intestine and are responsible for the uptake of drugs and other compounds, which may have resulted in reduced plasma levels of atorvastatin (19079). It is not clear if drinking green tea alters the absorption of atorvastatin.
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Green tea contains caffeine. Theoretically, concomitant use of large amounts of caffeine might increase cardiac inotropic effects of beta-agonists (15).
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Theoretically, green tea might interfere with the effects of bortezomib.
Details
In vitro research shows that green tea polyphenols, such as epigallocatechin gallate (EGCG), interact with bortezomib and block its proteasome inhibitory action. This prevents the induction of cell death in multiple myeloma or glioblastoma cancer cell lines (17212). Advise patients taking bortezomib, not to take green tea.
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Theoretically, green tea might reduce the effects of carbamazepine and increase the risk for convulsions.
Details
Green tea contains caffeine. Animal research suggests that taking caffeine can lower the anticonvulsant effects of carbamazepine and can induce seizures when taken in doses above 400 mg/kg (23559,23561). Human research has shown that taking caffeine 300 mg in three divided doses along with carbamazepine 200 mg reduces the bioavailability of carbamazepine by 32% and prolongs the plasma half-life of carbamazepine 2-fold in healthy individuals (23562).
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Theoretically, green tea might reduce the levels and clinical effects of celiprolol.
Details
In a small human study, taking green tea daily for 4 days appears to decrease blood and urine levels of celiprolol by at least 98% (104607). This interaction is possibly due to the inhibition of organic anion transporting polypeptide (OATP). Green tea catechins have been shown to inhibit organic anion transporting polypeptides (OATP), one of which, OATP1A2, is found in the intestine (19079,19080,98461) The interaction is thought to be due primarily to the epigallocatechin gallate (EGCG) content of green tea (98461).
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Theoretically, concomitant use might increase the effects and adverse effects of caffeine in green tea.
Details
Green tea contains caffeine. Cimetidine can reduce caffeine clearance by 31% to 42% (11736).
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Theoretically, green tea might increase the levels and adverse effects of clozapine and acutely exacerbate psychotic symptoms.
Details
Animal research suggests that, although green tea extract does not affect the elimination of clozapine, it delays the time to reach peak concentration and reduces the peak plasma levels (90173). Also, concomitant administration of green tea and clozapine might theoretically cause acute exacerbation of psychotic symptoms due to the caffeine in green tea. Caffeine can increase the effects and toxicity of clozapine. Caffeine doses of 400-1000 mg daily inhibit clozapine metabolism (5051). Clozapine is metabolized by cytochrome P450 1A2 (CYP1A2). Researchers speculate that caffeine might inhibit CYP1A2. However, there is no reliable evidence that caffeine affects CYP1A2. There is also speculation that genetic factors might make some patients be more sensitive to the interaction between clozapine and caffeine (13741).
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Theoretically, concomitant use might increase the effects and adverse effects of caffeine found in green tea.
Details
Green tea contains caffeine. Oral contraceptives can decrease caffeine clearance by 40% to 65% (8644).
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Theoretically, concomitant use might increase the levels and adverse effects of caffeine.
Details
Green tea contains caffeine. Caffeine is metabolized by cytochrome P450 1A2 (CYP1A2) (3941,5051,11741,23557,23573,23580,24958,24959,24960,24962), (24964,24965,24967,24968,24969,24971,38081,48603). Theoretically, drugs that inhibit CYP1A2 may decrease the clearance rate of caffeine from green tea and increase caffeine levels.
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Green tea is unlikely to produce clinically significant changes in the levels and clinical effects of CYP3A4 substrates.
Details
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Theoretically, green tea might decrease the vasodilatory effects of dipyridamole and interfere with its use prior to stress testing.
Details
Green tea contains caffeine. Caffeine might inhibit dipyridamole-induced vasodilation (11770,11772). It is recommended that methylxanthines and methylxanthine-containing products be stopped 24 hours prior to pharmacological stress tests (11770). Methylxanthines appear more likely to interfere with dipyridamole (Persantine) than adenosine-induced stress testing (11771).
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Theoretically, disulfiram might increase the risk of adverse effects from caffeine.
Details
In human research, disulfiram decreases the clearance and increases the half-life of caffeine (11840).
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Theoretically, using green tea with diuretic drugs might increase the risk of hypokalemia.
Details
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Theoretically, concomitant use might increase the risk for stimulant adverse effects.
Details
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Theoretically, estrogens might increase the levels and adverse effects of caffeine.
Details
Green tea contains caffeine. Estrogen inhibits caffeine metabolism (2714).
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Theoretically, green tea might reduce the effects of ethosuximide and increase the risk for convulsions.
Details
Green tea contains caffeine. Animal research suggests that caffeine 92.4 mg/kg can decrease the anticonvulsant activity of ethosuximide (23560). However, this effect has not been reported in humans.
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Theoretically, green tea might reduce the effects of felbamate and increase the risk for convulsions.
Details
Green tea contains caffeine. Animal research suggests that a high dose of caffeine 161.7 mg/kg can decreases the anticonvulsant activity of felbamate (23563). However, this effect has not been reported in humans.
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Green tea can decrease blood levels of fexofenadine.
Details
Clinical research shows that green tea can significantly decrease blood levels and excretion of fexofenadine. Taking green tea extract with a dose of fexofenadine decreased bioavailability of fexofenadine by about 30%. In vitro, green tea inhibits the cellular accumulation of fexofenadine by inhibiting the organic anion transporting polypeptide (OATP) drug transporter (111029). Research shows that two of the major catechins found in green tea, epicatechin gallate (ECG) and epigallocatechin gallate (EGCG), inhibit OATPs, specifically OATP1A2, OATP1B1, and OATP2B1. In addition, green tea has been shown to reduce the absorption of some drugs that are OATP substrates (19079,102714,102730).
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Theoretically, fluconazole might increase the levels and adverse effects of caffeine.
Details
Green tea contains caffeine. Fluconazole decreases caffeine clearance by approximately 25% (11022).
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Theoretically, green tea might increase the levels and adverse effects of flutamide.
Details
Green tea contains caffeine. In vitro evidence suggests that caffeine can inhibit the metabolism of flutamide (23553). Theoretically, concomitant use of caffeine and flutamide might increase serum concentrations of flutamide and increase the risk adverse effects.
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Theoretically, fluvoxamine might increase the levels and adverse effects of caffeine.
Details
Green tea contains caffeine. Fluvoxamine reduces caffeine metabolism (6370).
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Theoretically, concomitant use might have additive adverse hepatotoxic effects.
Details
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Theoretically, green tea might reduce the levels and clinical effects of imatinib.
Details
In animal research, a single dose of green tea extract reduces the area under the curve (AUC) of imatinib by up to approximately 64% and its main metabolite N-desmethyl imatinib by up to approximately 81% (104600). This interaction has not been shown in humans. The mechanism of action is unclear but may involve multiple pathways.
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Theoretically, green tea might reduce the levels and clinical effects of lisinopril.
Details
Preliminary clinical research shows that a single dose of green tea extract reduces plasma concentrations of lisinopril. Compared to a control group, peak levels and area under the curve (AUC) of lisinopril were reduced by approximately 71% and 66%, respectively (104599). This may be due to inhibition of organic anion transporting polypeptides (OATP) by green tea catechins (19079,19080,98461) The interaction is thought to be due primarily to the epigallocatechin gallate (EGCG) content of green tea (98461).
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Theoretically, abrupt green tea withdrawal might increase the levels and adverse effects of lithium.
Details
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Theoretically, metformin might increase the levels and adverse effects of caffeine.
Details
Green tea contains caffeine. Animal research suggests that metformin can reduce caffeine metabolism (23571). Theoretically, concomitant use can increase caffeine serum concentrations and the risk of caffeine adverse effects.
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Theoretically, methoxsalen might increase the levels and adverse effects of caffeine.
Details
Green tea contains caffeine. Methoxsalen can reduce caffeine metabolism (23572). Concomitant use can increase caffeine serum concentrations and the risk of caffeine adverse effects.
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Theoretically, mexiletine might increase the levels and adverse effects of caffeine.
Details
Green tea contains caffeine. Mexiletine can decrease caffeine elimination by 50% (1260).
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Theoretically, green tea might increase the levels and adverse effects of midazolam.
Details
Animal research suggests that green tea extract can increase the maximum plasma concentration, but not the half-life, of oral midazolam. This effect has been attributed to the inhibition of intestinal cytochrome P450 3A4 (CYP3A4) and induction of hepatic CYP3A4 enzymes by green tea constituents (20896). However, it is unlikely that this effect is clinically significant, as the dose used in animals was 50 times greater than what is commonly ingested by humans.
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Theoretically, concomitant use might increase the risk of a hypertensive crisis.
Details
Green tea contains caffeine. Caffeine has been shown to inhibit monoamine oxidase (MAO) A and B in laboratory studies (37724,37877,37912,38108). Concomitant intake of large amounts of caffeine with MAOIs might precipitate a hypertensive crisis (15). In a case report, a patient that consumed 10-12 cups of caffeinated coffee and took the MAOI tranylcypromine presented with severe hypertension (91086). Hypertension was resolved after the patient switched to drinking decaffeinated coffee.
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Green tea seems to reduce the levels and clinical effects of nadolol.
Details
Preliminary clinical research shows that green tea consumption reduces plasma concentrations of nadolol. Compared to a control group, both peak levels and total drug exposure (AUC) of nadolol were reduced by approximately 85% in subjects who drank green tea daily for two weeks. Drinking green tea with nadolol also significantly reduced nadolol's systolic blood pressure lowering effect (19071). Other clinical research shows that a single dose of green tea can affect plasma nadolol levels for at least one hour (102721). Green tea catechins have been shown to inhibit organic anion transporting polypeptides (OATP), one of which, OATP1A2, is involved in the uptake of nadolol in the intestine (19071,19079,19080,98461) The interaction is thought to be due primarily to the epigallocatechin gallate (EGCG) content of green tea (98461).
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Theoretically, green tea might increase the levels and adverse effects of nicardipine.
Details
Green tea contains EGCG. Animal research shows that EGCG increases the area under the curve (AUC) and absolute oral bioavailability of nicardipine. The mechanism of action is thought to involve inhibition of both intestinal P-glycoprotein and hepatic cytochrome P450 3A (90136). The effect of green tea itself on nicardipine is unclear.
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Theoretically, concomitant use might increase the risk of hypertension.
Details
Green tea contains caffeine. Concomitant use of caffeine and nicotine has been shown to have additive cardiovascular effects, including increased heart rate and blood pressure. Blood pressure was increased by 10.8/12.4 mmHg when the agents were used concomitantly (36549).
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Green tea seems to reduce the levels of nintedanib.
Details
Clinical research shows that green tea can significantly decrease blood levels of nintedanib. Taking green tea extract twice daily for 7 days 30 minutes prior to a meal along with nintedanib with the meal decreased the 12-hour area under the curve (AUC) values for nintedanib by 21%. There was no effect on the maximum concentration of nintedanib (111028).
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Theoretically, green tea might reduce the absorption of organic anion-transporting polypeptide (OATP) substrates.
Details
OATPs are expressed in the small intestine and liver and are responsible for the uptake of drugs and other compounds. Research shows that two of the major catechins found in green tea, epicatechin gallate (ECG) and epigallocatechin gallate (EGCG), inhibit OATPs, specifically OATP1A2, OATP1B1, and OATP2B1. In addition, green tea has been shown to reduce the absorption of some drugs that are OATP substrates, including lisinopril and celiprolol (19079,102714,102730).
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Theoretically, green tea might decrease the effects of pentobarbital.
Details
Green tea contains caffeine. Theoretically, caffeine might negate the hypnotic effects of pentobarbital (13742).
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Theoretically, green tea might reduce the effects of phenobarbital and increase the risk for convulsions.
Details
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Theoretically, phenothiazines might increase the levels and adverse effects of caffeine.
Details
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Theoretically, phenylpropanolamine might increase the risk of hypertension, as well as the levels and adverse effects of caffeine.
Details
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Theoretically, green tea might reduce the effects of phenytoin and increase the risk for convulsions.
Details
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Theoretically, green tea might increase the levels and clinical effects of pioglitazone.
Details
Green tea contains caffeine. Animal research suggests that caffeine can modestly increase the maximum concentration, area under the curve, and half-life of pioglitazone, and also reduce its clearance. This increased the antidiabetic effects of pioglitazone (108812). However, the exact mechanism of this interaction is unclear.
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Theoretically, quinolone antibiotics might increase the levels and adverse effects of caffeine.
Details
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Theoretically, concomitant use might increase the levels and adverse effects of both caffeine and riluzole.
Details
Green tea contains caffeine. Caffeine and riluzole are both metabolized by cytochrome P450 1A2, and concomitant use might reduce metabolism of one or both agents (11739).
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Theoretically, green tea extract might alter the absorption and distribution of rosuvastatin.
Details
In animal research, giving green tea extract with rosuvastatin increased plasma levels of rosuvastatin. Rosuvastatin is a substrate of organic anion-transporting polypeptide (OATP)1B1, which is expressed in the liver. The increased plasma levels may have been related to inhibition of OATP1B1 (102717). However, in humans, taking EGCG with rosuvastatin reduced plasma levels of rosuvastatin, suggesting an inhibition of intestinal OATP (102730). It is not clear if drinking green tea alters the absorption of rosuvastatin.
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Theoretically, concomitant use might increase stimulant adverse effects.
Details
Green tea contains caffeine. Due to the central nervous system (CNS) stimulant effects of caffeine, concomitant use with stimulant drugs can increase the risk of adverse effects (11832).
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Theoretically, terbinafine might increase the levels and adverse effects of caffeine.
Details
Green tea contains caffeine. Terbinafine decreases the clearance of intravenous caffeine by 19% (11740).
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Theoretically, green tea might increase the levels and adverse effects of theophylline.
Details
Green tea contains caffeine. Large amounts of caffeine might inhibit theophylline metabolism (11741).
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Theoretically, green tea might increase the levels and adverse effects of tiagabine.
Details
Green tea contains caffeine. Animal research suggests that chronic caffeine administration can increase the serum concentrations of tiagabine. However, concomitant use does not seem to reduce the antiepileptic effects of tiagabine (23561).
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Theoretically, ticlopidine might increase the levels and adverse effects of caffeine.
Details
Green tea contains caffeine. In vitro evidence suggests that ticlopidine can inhibit caffeine metabolism (23557). However, this effect has not been reported in humans.
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Theoretically, green tea might reduce the effects of valproate and increase the risk for convulsions.
Details
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Theoretically, concomitant use might increase the levels and adverse effects of both verapamil and caffeine.
Details
Animal research suggests that the green tea constituent EGCG increases the area under the curve (AUC) values for verapamil by up to 111% and its metabolite norverapamil by up to 87%, likely by inhibiting P-glycoprotein (90138). Also, theoretically, concomitant use of verapamil and caffeinated beverages such as green tea might increase plasma caffeine concentrations and the risk of adverse effects, due to the caffeine contained in green tea. Verapamil increases plasma caffeine concentrations by 25% (11741).
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Theoretically, green tea may increase the risk of bleeding if used with warfarin.
Details
Conflicting reports exist regarding the potential of green tea to antagonize the effect of warfarin; however, most evidence suggests that drinking green tea in moderation is unlikely to cause a significant interaction. Green tea contains a small amount of vitamin K, approximately 7 mcg per cup (100524). Some case reports have associated the antagonism of warfarin with the vitamin K content of green tea (1460,1461,1463,4211,6048,8028,20868). However, these reports are rare, and very large doses of green tea (about 8-16 cups daily) appear to be needed to cause these effects (1460,1461,1463,8028). Therefore, use of green tea in moderate amounts is unlikely to antagonize the effects of warfarin; however, very large doses should be avoided.
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Theoretically, guarana might decrease the vasodilatory effects of adenosine and interfere with its use prior to stress testing.
Details
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.
Details
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.
Details
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Theoretically, taking guarana with antidiabetes drugs might interfere with blood glucose control.
Details
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Theoretically, concomitant use might increase the clinical effects of beta-adrenergic agonists.
Details
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.
Details
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.
Details
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.
Details
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.
Details
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Theoretically, concomitant use might increase the levels and adverse effects of caffeine.
Details
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Theoretically, guarana might decrease the vasodilatory effects of dipyridamole and interfere with its use prior to stress testing.
Details
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.
Details
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.
Details
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Theoretically, concomitant use might increase the risk for stimulant adverse effects.
Details
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.
Details
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.
Details
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.
Details
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.
Details
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.
Details
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.
Details
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Theoretically, metformin might increase the levels and adverse effects of caffeine.
Details
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.
Details
Guarana contains caffeine. Methoxsalen can reduce caffeine metabolism (23572).
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Theoretically, mexiletine might increase the levels and adverse effects of caffeine.
Details
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Theoretically, concomitant use might increase the risk of a hypertensive crisis.
Details
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.
Details
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.
Details
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Theoretically, guarana might reduce the effects of phenobarbital and increase the risk for convulsions.
Details
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Theoretically, phenothiazines might increase the levels and adverse effects of caffeine.
Details
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Theoretically, phenylpropanolamine might increase the risk of hypertension, as well as the levels and adverse effects of caffeine.
Details
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Theoretically, guarana might reduce the effects of phenytoin and increase the risk for convulsions.
Details
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Theoretically, guarana might increase the levels and clinical effects of pioglitazone.
Details
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.
Details
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Theoretically, concomitant use might increase the levels and adverse effects of both caffeine and riluzole.
Details
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.
Details
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.
Details
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.
Details
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.
Details
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.
Details
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Theoretically, verapamil might increase the levels and adverse effects of caffeine.
Details
Verapamil increases plasma caffeine concentrations by 25% (11741).
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Below is general information about the adverse effects of the known ingredients contained in the product Peak +CBD Isolate. 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, cannabidiol seems to be well tolerated.
Most Common Adverse Effects:
Orally: For prescription cannabidiol (Epidiolex), somnolence in up to 30% of patients and diarrhea in up to 24% of patients. Also, decreased appetite, drowsiness, dry mouth, fatigue, pyrexia, vomiting, and weight loss. Higher doses over 15-20 mg/kg daily are more likely to cause somnolence, decreased appetite, diarrhea, liver enzyme elevations, and weight loss. Pharmacogenetic variation may also affect susceptibility to certain adverse effects, particularly diarrhea, sedation, and abnormal liver enzyme levels.
Serious Adverse Effects (Rare):
Orally: There have been rare case reports of hepatitis, respiratory depression, and pneumonia.
Cardiovascular ...Orally, cannabidiol has been associated with cardiovascular effects in some reports. In one clinical study, some patients experienced hypotension, orthostatic hypotension, and lightheadedness (89700). Also, cannabidiol has also been linked to tachycardia and hypertension. In Poison Control Center reports of up to 5248 oral single-substance exposures to cannabidiol in adults and children, up to 7% of cases involved tachycardia (105493,110248). However, the doses of cannabidiol that precipitated these reports are unclear. Other research suggests that taking cannabidiol orally does not significantly change blood pressure or heart rate when compared with placebo (61832,89675,89909). A case of ventricular bigeminy and a case of circulatory collapse have been considered to be related to treatment with a specific oromucosal spray that contains cannabidiol 2.5 mg and delta-9-tetrahydrocannabinol (THC) 2.7 mg per actuation (Sativex, GW Pharmaceuticals) (61759,61820).
Dermatologic
...Orally, cannabidiol might cause rare skin reactions (105696,109178).
In a clinical study in healthy adults, 2 cases of skin reactions, one severe and one mild, were reported (105696). These and 2 additional cases were reported in a follow-up publication specific to cannabidiol-induced skin rash (109178). The rash occurred in 4 female patients after taking oral cannabidiol 300 mg daily for up to 9 days. The earliest case started 6 hours after initial use; all rashes resolved within 5-11 days of treatment discontinuation (105696,109178). The cannabidiol was 99.6% pure (PurMed Global; United States) and dissolved in medium chain triglyceride oil (109178). Taking the medium chain triglyceride oil alone did not reproduce symptoms. In one case, the patient required treatment with oral prednisone 0.5 mg/kg daily (109178). A systematic review of randomized controlled trials suggests that rash makes up approximately 6% of all adverse effects related to oral cannabidiol use, and one meta-analysis of 3 clinical trials in patients with epilepsy shows that taking cannabidiol is associated with about a 3-fold relative risk of rash compared with placebo (110244,113032).
Topically, cannabidiol has resulted in pain on application, as well as dryness, rash, and itching (110243).
Gastrointestinal
...Orally, cannabidiol has caused dry mouth in some patients in clinical research (89700,105559,109177,110245,110249).
In children and adults, cannabidiol oil has caused mild to moderate diarrhea, decreased appetite, weight loss, nausea, and vomiting. Diarrhea, decreased appetite, and weight loss or weight gain have been reported at a higher frequency with doses greater than 15-20 mg/kg daily (97017,97019,97021,97022,97025,97979,97980,102323,103031,103042)(104884,105493,105495,106631,106633,107327,109176,109177,110248). In one case, persistent diarrhea and eosinophilic esophagitis due to cannabidiol oil were resolved with dose reduction from 20 mg/kg/day to 15 mg/kg/day in a 13-year-old female with epilepsy (113049). Weight loss also seems to be more prevalent with long-term cannabidiol use. Other adverse effects like diarrhea and vomiting also seem to be more prevalent during long-term (42-96 weeks) cannabidiol treatment when compared with short-term (about 12-14 weeks) (103034). Pharmacogenetic variation has also been shown to affect susceptibility to cannabidiol-associated diarrhea (107324). In a 75-year-old female, chronic cannabidiol use for one year was associated with microscopic colitis. Colitis resolved when cannabidiol was discontinued, and recurred after a re-challenge (104885). A systematic review of randomized controlled trials shows that gastrointestinal symptoms, including diarrhea, nausea, vomiting, abdominal pain, abdominal distention, and constipation, make up approximately 60% of all adverse effects related to oral cannabidiol use. About 17% of patients report loss of appetite (110244). However, other rare gastrointestinal events are reported. One case reports cannabinoid hyperemesis syndrome that resolved completely 2 months after cessation in a teenaged male taking cannabidiol 15 mg/kg/day chronically (113040).
Cannabis oromucosal spray that contains cannabidiol 2.5 mg and delta-9-tetrahydrocannabinol (THC) 2.7 mg per actuation (Sativex, GW Pharmaceuticals) can cause dizziness, dry mouth, nausea, and bad taste (61759,61764,61820,61896,61909,108698). Less commonly, this product may cause red and white buccal mucosal patches to develop inside the mouth (61820).
Hepatic
...Orally, cannabidiol oil has been associated with an elevation in liver transaminases and drug-induced liver injury (DILI).
A meta-analysis of 12 clinical trials shows that taking cannabidiol daily is associated with approximately 5 times greater odds of DILI and 6 times greater odds of liver enzyme elevations when compared with placebo (113045). However, many patients were on concomitant medications that can also cause liver injury. A systematic review has also found that elevated liver transaminases make up about 13% of adverse effects related to cannabidiol use (110244). In another study, abnormal liver transaminases occurred in 4 of 25 patients after taking cannabidiol up to 20 mg/kg daily for 4 weeks; levels normalized within 4 weeks of study completion (109176). In an observational study, elevated liver function tests occurred in 2.7% of patients who took prescription cannabidiol oil (Epidiolex) and were the reason for discontinuation in 1 of 25 patients (113034). Pharmacogenetic variation has also been shown to affect susceptibility to liver transaminase elevations with cannabidiol use (107324).
Conversely, 2 large observational studies suggest that the prevalence of elevated liver transaminases in those taking cannabidiol for at least 30 days is similar when compared with the general adult population. The mean daily dose of cannabidiol used in these studies was about 50-55 mg, which is much lower than the doses reported in cases of elevated liver transaminases (107336,113041).
The elevation in liver transaminases appears to occur more frequently at higher doses (20-25 mg/kg), in patients with elevated levels at baseline, and in patients already taking valproic acid or clobazam. While most reported elevations have been mild, some patients taking cannabidiol oil alone or with valproic acid have experienced significant elevations which required discontinuation of either valproic acid or cannabidiol (97017,97018,97019,97022,97025,97979,97980,102323,103031,104884)(104890,106631,106633,107327,110244,113024).
Neurologic/CNS
...Orally, cannabidiol has been most commonly reported to cause somnolence, sedation, dizziness, agitation, and fatigue (61989,100883,102323,103031,104884,105493,105495,105559,109177,110245)(110248,110249,113024,113034), with a significantly higher incidence when used in conjunction with clobazam (97017,97019,97022,97025,97979,106631).
Hallucinations, delusions, confusion, and slurred speech have been reported in a Poison Control Center report (110248). Other symptoms reported in clinical research include low mood, temperature dysregulation, and insomnia, although the prevalence and clinical significance is unclear (109177). Cannabidiol has been reported to cause sedation and psychomotor slowing in some patients (89700,103029). In an observational study, sedation occurred in approximately 17% of patients who took prescription cannabidiol oil (Epidiolex) and was the reason for discontinuation in about 1 in 5 patients (113034). Pharmacogenetic variation has been shown to affect susceptibility to cannabidiol-associated sedation (107324). There is concern that cannabidiol can cause cognitive impairments when used for a long duration. However, cannabidiol does not seem to negatively impact cognition in adults with treatment-resistant epilepsy used for up to one-year (100885). Cannabis extract oromucosal spray that contains cannabidiol 2.5 mg and delta-9-tetrahydrocannabinol (THC) 2.7 mg per actuation (Sativex, GW Pharmaceuticals) can cause dizziness, lightheadedness, sleepiness, and fatigue (61759,61764,61820,61896,61909,96814). Additionally, a small study in healthy adults shows that consumption of brownies containing cannabidiol 640 mg plus THC 20 mg increases feelings of sedation and memory impairment when compared with brownies containing only THC 20 mg (111092). In children, cannabidiol oil has caused drowsiness, fatigue, sedation, and gait disturbance (97017,97019,97022,97025).
Cannabidiol does not seem to be associated with withdrawal symptoms. Clinical research in healthy volunteers taking cannabidiol daily for 4 weeks shows that stopping cannabidiol abruptly does not cause withdrawal symptoms (103042).
Limited research suggests that cannabidiol does not cause driving impairment. A small study has found that inhaling vaporized cannabis containing cannabidiol 13.75 mg does not increase lane weaving when compared with placebo. The lane weaving seen in those inhaling this product was equivalent to having a blood alcohol concentration (BAC) of 0.02%, which is below the lower limit of clinically relevant impairment that is considered to occur with a BAC of 0.05% (104482). Other research shows that taking a single oral dose of cannabidiol (GD Cann-C; GD Pharma Pty Ltd) 15 mg, 300 mg, or 1500 mg, confirmed to be devoid of delta-9-tetrahydrocannabinol (THC) and other cannabinoids, does not affect cognitive function or driving performance after 15-240 minutes when compared with placebo (109179). The validity of these findings is limited because these studies only tested a single dose of cannabidiol, which does not mimic real-world use (104484,109179).
Ocular/Otic ...Ocular pain and irritation and mydriasis related to oral cannabidiol exposures have been reported in a Poison Control Center report (110248).
Psychiatric ...Limited research suggests that consuming large amounts of cannabidiol might increase the adverse effects of delta-9-tetrahydrocannabinol (THC). A small study in healthy adults shows that consumption of brownies containing cannabidiol 640 mg plus THC 20 mg increases feelings of anxiety, paranoia, and irritability when compared with brownies containing only THC 20 mg (111092).
Pulmonary/Respiratory
...Orally, cannabidiol oil has been associated with rare respiratory depression and increased odds of pneumonia (103029,103031,106631,106633).
In a case report, a 56-year-old obese male presented to the emergency room with severe respiratory depression 3 hours after consuming two packages of gummies labeled to contain cannabidiol 370 mg. Symptoms included respiratory acidosis, slurred speech, bradycardia, and vomiting. The patient was treated with supportive care (103029). It is uncertain whether these effects were caused by cannabidiol or other adulterant substances in the gummies.
A small clinical trial in patients with cancer found that taking cannabidiol (GD-Cann C, Norwood, South Australia) in median doses of 400 mg daily for up to 2 weeks results in an increased number of patients with dyspnea when compared with placebo (110247).
Using a specific oromucosal spray that contains cannabidiol 2.5 mg and delta-9-tetrahydrocannabinol 2.7 mg (THC) per actuation (Sativex, GW Pharmaceuticals) may cause pharyngitis, hoarseness, and throat irritation (61759).
Other ...There is some concern that cannabidiol could be used as a substance of abuse. Cannabidiol derived from marijuana is classified as a Schedule I controlled substance by the United States Drug Enforcement Administration (DEA). Epidiolex, an approved prescription formulation of cannabidiol, is classified as a schedule V controlled substance (99606). In a clinical study of healthy recreational polydrug abusers, a single dose of cannabidiol 750 mg was rated no differently than placebo for drug-liking, likelihood of repeat use, or the occurrence of positive effects, such as feeling high or feeling stoned. However, a single dose of cannabidiol 1500 mg or 4500 mg scored higher for likelihood of repeat use and occurrence of positive effects when compared with placebo, although these ratings were lower than those for dronabinol and alprazolam (99605).
General
...Orally, green tea is generally well tolerated when consumed as a beverage in moderate amounts.
Green tea extract also seems to be well tolerated when used for up to 12 months.
Most Common Adverse Effects:
Orally: Bloating, constipation, diarrhea, dyspepsia, flatulence, and nausea.
Serious Adverse Effects (Rare):
Orally: Hepatotoxicity, hypokalemia, and thrombotic thrombocytopenic purpura have been reported rarely.
Cardiovascular
...Acute or short-term oral administration of green tea may cause hypertension (53719,54014,54065,54076,102716).
The risk may be greater for green tea products containing more than 200 mg epigallocatechin gallate (EGCG) (90161). However, consumption of brewed green tea does not seem to increase blood pressure or pulse, even in mildly hypertensive patients (1451,1452). In fact, some evidence suggests that habitual tea consumption is associated with a reduced risk of developing hypertension (12518). Also, epidemiological research suggests there is no association of caffeine consumption with incidence of hypertension or with cardiovascular disease mortality in patients with hypertension (13739,111027). Rarely, green tea consumption may cause hypotension (53867).
Epidemiological research suggests that regular caffeine intake of up to 400 mg per day, or approximately 8 cups of green tea, is not associated with an increased incidence of atrial fibrillation (38018,38076,91028,91034,97451,97453), atherosclerosis (38033), cardiac ectopy (91127), stroke (37804), ventricular arrhythmia (95948,97453), and cardiovascular disease in general (37805,98806).
Combining ephedra with caffeine can increase the risk of adverse effects. Jitteriness, hypertension, seizures, and temporary loss of consciousness has been associated with the combined use of ephedra and caffeine (2729). There is also a report of ischemic stroke in an athlete who consumed ephedra 40-60 mg, creatine monohydrate 6 grams, caffeine 400-600 mg, and a variety of other supplements daily for 6 weeks (1275). In theory, combining caffeinated green tea with ephedra would have similar effects.
In a case report, the EGCG component of a specific weight loss supplement (Hydroxycut) was thought to be responsible for atrial fibrillation (54028). The patient was given two doses of intravenous diltiazem and was loaded with intravenous digoxin. Thirty-six hours after the last product dose, she spontaneously converted to normal sinus rhythm. The authors suggested that the block of the atrial-specific KCNA5 potassium channel likely played a role in this response.
A case of thrombotic thrombocytopenic purpura has been reported for a patient who consumed a weight loss product containing green tea (53978). She presented at the emergency department with a one-week history of malaise, fatigue, and petechiae of the skin. Twelve procedures of plasmapheresis were performed, and corticosteroid treatment was initiated. She was discharged after 20 days.
Dermatologic ...Orally, green tea may cause skin rashes or skin irritation (53731,54038,90161,90187,102716). Topically, green tea may cause local skin reactions or skin irritation, erythema, burning, itching, edema, and erosion (53731,54018,97136,104609,111031). A green tea extract ointment applied to the cervix can cause cervical and vaginal inflammation, vaginal irritation, and vulval burning (11310,36442,36438). When applied to external genital or perianal warts, a specific green tea extract ointment (Veregen, Bradley Pharmaceuticals) providing 15% kunecatechins can cause erythema, pruritus, local pain, discomfort and burning, ulceration, induration, edema, and vesicular rash (15067,53907).
Endocrine
...There is some concern that, due to its caffeine content, green tea may be associated with an increased risk of fibrocystic breast disease, breast cancer, and endometriosis.
However, this is controversial since findings are conflicting (8043). Restricting caffeine in females with fibrocystic breast conditions doesn't seem to affect breast nodularity, swelling, or pain (8996).
A population analysis of the Women's Health Initiative observational study has found no association between consumption of caffeine-containing beverages, such as green tea, and the incidence of invasive breast cancer in models adjusted for demographic, lifestyle, and reproductive factors (108806). Also, a dose-response analysis of 2 low-quality observational studies has found that high consumption of caffeine is not associated with an increased risk of breast cancer (108807).
A case of hypoglycemia has been reported for a clinical trial participant with type 2 diabetes who used green tea in combination with prescribed antidiabetes medication (54035).
Gastrointestinal ...Orally, green tea beverage or supplements can cause nausea, vomiting, abdominal bloating and pain, constipation, dyspepsia, reflux, morning anorexia, increased thirst, flatulence, and diarrhea. These effects are more common with higher doses of green tea or green tea extract, equivalent to 5-6 liters of tea per day (8117,11366,36398,53719,53867,53936,54038,54076,90139,90140)(90161,90175,90187,97131,97136,102716).
Hepatic
...There is concern that some green tea products, especially green tea extracts, can cause hepatotoxicity in some patients.
In 2017, the regulatory agency Health Canada re-issued a warning to consumers about this concern. The updated warning advises patients taking green tea extracts, especially those with liver disease, to watch for signs of liver toxicity. It also urges children to avoid taking products containing green tea extracts (94897). In 2020, the United States Pharmacopeia (USP) formed an expert panel to review concerns of green tea extract-related hepatotoxicity. Based on their findings, USP determined that any products claiming compliance with USP quality standards for green tea extract must include a specific warning on the label stating "Do not take on an empty stomach. Take with food. Do not use if you have a liver problem and discontinue use and consult a healthcare practitioner if you develop symptoms of liver trouble, such as abdominal pain, dark urine, or jaundice (yellowing of the skin or eyes)" (102722).
Numerous case reports of hepatotoxicity, primarily linked to green tea extract products taken in pill form, have been published. A minimum of 29 cases have been deemed at least probably related to green tea and 38 have been deemed possibly related. In addition, elevated liver enzymes have been reported in clinical research (14136,15026,53740,53746,53775,53859,54027,90139,90162,90164)(93256,94898,94899,102716,102720,102722,107158,111020). Most cases of toxicity have had an acute hepatitis-like presentation with a hepatocellular-elevation of liver enzymes and some cholestasis. Onset of hepatotoxic symptoms usually occurs within 3 months after initiation of the green tea extract supplement, and symptoms can persist from 10 days to 1 year (95439,94897,94898,107158). Some reports of hepatotoxicity have been associated with consumption of green tea-containing beverages as well (15026,53742,54016,90125,90143).
In most cases, liver function returned to normal after discontinuation of the green tea product (14136,15026,53859,93256,107158). In one case, use of a specific ethanolic green tea extract (Exolise, Arkopharma) resulted in hepatotoxicity requiring a liver transplant. Due to concerns about hepatotoxicity, this specific extract was removed from the market by the manufacturer (14310). Since then, at least 5 cases of liver toxicity necessitating liver transplantation have been reported for patients who used green tea extracts (94898,107158). In another case, use of green tea (Applied Nutrition Green Tea Fat Burner) in combination with whey protein, a nutritional supplement (GNC Mega Men Sport), and prickly pear cactus resulted in acute liver failure (90162).
Despite the numerous reports of hepatotoxicity associated with the use of green tea products, the actual number of hepatotoxicity cases is low when the prevalence of green tea use is considered. From 2006 to 2016, liver injury from green tea products was estimated have occurred in only 1 out of 2.7 million patients who used green tea products (94897,95440).
In addition to the fact that green tea hepatotoxicity is uncommon, it is also not clear which patients are most likely to experience liver injury (94897,95440). The hepatotoxicity does not appear to be an allergic reaction or an autoimmune reaction (94897). It is possible that certain extraction processes, for example, ethanolic extracts, produce hepatotoxic constituents. However, in most cases, the presence of contaminants in green tea products has not been confirmed in laboratory analyses (90162).
Although results from one analysis of 4 small clinical studies disagrees (94899), most analyses of clinical data, including one conducted by the European Food Safety Association, found that hepatotoxicity from green tea products is associated with the dose of EGCG in the green tea product. Results show that daily intake of EGCG in amounts greater than or equal to 800 mg per day is associated with a higher incidence of elevated liver enzymes such as alanine transaminase (ALT) (95440,95696,97131). However, it is still unclear what maximum daily dose of EGCG will not increase liver enzyme levels or what minimum daily dose of EGCG begins to cause liver injury. In many cases of liver injury, the dose of green tea extract and/or EGCG is not known. Therefore, a minimum level of green tea extract or EGCG that would cause liver injury in humans cannot be determined (102722). Keep in mind that daily intake of green tea infusions provides only 90-300 mg of EGCG daily. So for a majority of people, green tea infusions are likely safe and unlikely to cause liver injury (95696). Also, plasma levels of EGCG are increased when green tea catechins are taken in the fasting state, suggesting that green tea extract should be taken with food (102722).
Until more is known, advise patients that green tea products, especially those containing green tea extract, might cause liver damage. However, let them know that the risk is uncommon, and it is not clear which products are most likely to cause the adverse effect or which patients are most likely to be affected. Advise patients with liver disease to consult their healthcare provider before taking products with green tea extract and to notify their healthcare provider if they experience symptoms of liver damage, including jaundice, dark urine, sweating, or abdominal pain (102722).
Immunologic ...Orally, matcha tea has resulted in at least one case of anaphylaxis related to green tea proteins. A 9-year-old male experienced systemic redness and hives, nausea, and anaphylaxis 60 minutes after consuming matcha tea-flavored ice cream (107169). The caffeine found in green tea can also cause anaphylaxis in sensitive individuals, although true IgE-mediated caffeine allergy seems to be relatively rare (11315).
Musculoskeletal
...Orally, the ingestion of the green tea constituent epigallocatechin gallate (EGCG) or a decaffeinated green tea polyphenol mixture may cause mild muscle pain (36398).
There is some concern regarding the association between caffeinated green tea products and osteoporosis. Epidemiological evidence regarding the relationship between caffeinated beverages such as green tea and the risk for osteoporosis is contradictory. Caffeine can increase urinary excretion of calcium (2669,10202,11317). Females with a genetic variant of the vitamin D receptor appear to be at an increased risk for the detrimental effect of caffeine on bone mass (2669). However, moderate caffeine intake of less than 400 mg per day, or about 8 cups of green tea, doesn't seem to significantly increase osteoporosis risk in most postmenopausal adults with normal calcium intake (2669,6025,10202,11317).
Neurologic/CNS
...Orally, green tea can cause central nervous system stimulation and adverse effects such as headache, anxiety, dizziness, insomnia, fatigue, agitation, tremors, restlessness, and confusion.
These effects are more common with higher doses of green tea or green tea extract, equivalent to 5-6 liters of tea per day (8117,11366,53719,90139,102716). The green tea constituent epigallocatechin gallate (EGCG) or decaffeinated green tea may also cause mild dizziness and headache (36398).
Combining ephedra with caffeine can increase the risk of adverse effects. Jitteriness, hypertension, seizures, temporary loss of consciousness, and hospitalization requiring life support has been associated with the combined use of ephedra and caffeine (2729).
Topically, green tea extract (Polyphenon E ointment) may cause headache when applied to the genital area (36442).
Psychiatric ...Green tea contains a significant amount of caffeine. Chronic use, especially in large amounts, can produce tolerance, habituation, and psychological dependence (11832). The existence or clinical importance of caffeine withdrawal is controversial. Some researchers think that if it exists, it appears to be of little clinical significance (11839). Other researchers suggest symptoms such as headache; tiredness and fatigue; decreased energy, alertness, and attentiveness; drowsiness; decreased contentedness; depressed mood; difficulty concentrating; irritability; and lack of clear-headedness are typical of caffeine withdrawal (13738). Withdrawal symptoms such as delirium, nausea, vomiting, rhinorrhea, nervousness, restlessness, anxiety, muscle tension, muscle pains, and flushed face have been described. However, these symptoms may be from nonpharmacological factors related to knowledge and expectation of effects. Clinically significant symptoms caused by caffeine withdrawal may be uncommon (2723,11839).
Pulmonary/Respiratory ...A case of granulomatous alveolitis with lymph follicles has been reported for a 67-year-old female who used green tea infusions to wash her nasal cavities for 15 years (54088). Her symptoms disappeared 2 months after stopping this practice and following an undetermined course of corticosteroids. In a case report, hypersensitivity pneumonitis was associated with inhalation of catechin-rich green tea extracts (54025). Occupational exposure to green tea dust can cause sensitization, which may include nasal and asthmatic symptoms (11365).
Renal ...There are two cases of hypokalemia associated with drinking approximately 8 cups daily of green tea in an elderly couple of Asian descent. The hypokalemia improved after reducing their intake by 50%. It is possible that this was related to the caffeine in the green tea (98418).
Other ...Orally, intake of a specific green tea extract product (Polyphenon E) may cause weight gain (90139).
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).
