Paullinia cupana
Guarana/Drug Interactions:
AcetaminophenAcetaminophen: Caffeine combined with analgesics has been reported to increase the analgesic effect by 40% (317). In treatment of menstruation-associated migraine and of severe migraine attacks, a combination of N-acetyl-para-aminophenol acetaminophen (APAP), aspirin, and caffeine was found to be highly effective (318; 83). Caffeine plus codeine also enhanced APAP in reducing dental and oral surgery pain (115; 319). The pharmacokinetics of 500mg APAP was studied when given together with 60mg caffeine in ten healthy males. A significant increase was found in the area under the curve and area under the moment curve (p<0.01), in the Cmax (p<0.05) and a decrease in the clearance (p<0.05) of APAP (320). AdenosineAdenosine: Caffeine is an adenosine antagonist and inhibits A1-receptors. Therefore the actions of caffeine are directly negated by adenosine and adenosine directly negates the effects of caffeine (321; 322). AlcoholAlcohol: Alcohol consumption may increase caffeine serum concentrations and the risk of caffeine adverse effects (323). AmphetamineAmphetamine: There is one case report of ischemic stroke after the nasal ingestion of amphetamine and caffeine (324). Anticoagulant/antiplatelet drugsAnticoagulant/antiplatelet drugs: Caffeine has been reported to have antiplatelet activity (231; 233; 232). Antidiabetic agentsAntidiabetic agents: Caffeine might increase or decrease blood sugar. Theoretically, concomitant use of guarana and diabetes drugs might interfere with blood glucose control (325). AspirinAspirin: Caffeine increases the peak plasma concentration, rate of absorption and bioavailability of aspirin (326; 327). The addition of caffeine to aspirin has significant benefits on mood and performance (328). An aspirin/butalbital/caffeine/codeine combination is considered superior to acetaminophen/codeine in relieving oral surgery pain (329). BenzodiazepinesBenzodiazepines: In a study with 18 normal volunteers, lorazepam (2.5mg) and caffeine (125-500mg) were given and mental performance tests were administered and compared (330). The effect of caffeine counteracted both the effect of reducing anxiety and the reduction in mental performance caused by lorazepam alone. Rush et al. found that caffeine (0, 250mg and 500mg/70kg) attenuates the behavioral and self-reported effects of lorazepam (0, 2.8, and 5.6mg/70kg) (331). Two studies of caffeine (250 or 500mg) or theophylline (10mg/kg) and diazepam (10 or 20mg) as a one dose trial of 237 healthy volunteers showed similar results by counteracting the drowsy effects and mental slowness of diazepam (332; 333). Sedative doses may need to be raised. Beta-adrenergic agonistsBeta-adrenergic agonists: Concomitant use of guarana may increase the inotropic effects of beta agonists.CarbamazepineCarbamazepine: The plasma half-life of 200mg carbamazepine may be increased two fold by 300mg of caffeine (334). The bioavailability may be reduced by 32% when co-administered with caffeine. CimetidineCimetidine: Cimetidine may decrease caffeine clearance by inhibiting the microsomal metabolism of caffeine (335). CiprofloxacinCiprofloxacin: Ciprofloxacin significantly inhibits caffeine elimination (336; 337). ClozapineClozapine: In a case study, a man experienced tardive dyskinesia, hallucinations, and akathisia believed to be caused by clozapine; discontinuation of his normal daily caffeine intake relieved these symptoms (338). The plasma concentrations of clozapine in seven schizophrenic patients increased by an average of 19% when caffeine intake was 500-700mg daily (339). CNS stimulantsCNS stimulants: Concomitant use of CNS stimulants and caffeine may increase the risk of stimulant adverse effects.Cytochrome P450 metabolized agentsCytochrome P450 metabolized agents: CYP 450 1A2 is the primary metabolic pathway for caffeine (340). Substances that induce the specific CYP 450 enzymes may decrease the t? of CYP 450 metabolized drugs and therefore decrease their effectiveness. DexamethasoneDexamethasone: The clearance of caffeine was increased in the presence of dexamethasone in 60 neonates and young infants (341). DiazepamDiazepam: Caffeine has been found to antagonize diazepam effects (333; 332). DipyridamoleDipyridamole: Caffeine was shown to attenuate the hemodynamic response to dipyridamole (342). DisulfiramDisulfiram: Taking disulfiram for at least four days showed a significantly increased half-life (4.1-5.7 hours, p<0.01) and decreased clearance (142-99mL/min, p<0.005) of caffeine in normal volunteers (343). This may increase the risk for caffeine toxicity. DiureticsDiuretics: In a single blind, randomized, cross-over trial an increase in diuresis, urinary sodium excretion, and urinary potassium excretion was observed within 1 hour of ingestion of 250mg caffeine (183). EnoxacinEnoxacin: Enoxacin may significantly inhibit caffeine elimination (p<0.001) (336). Ephedrine/pseudoephedrine (Sudafed?)Ephedrine/pseudoephedrine (Sudafed?): Ephedrine in combination with guarana may increase blood pressure and therefore the risk of stroke and other cardiovascular events (285). Thermogenic synergism between ephedrine and caffeine may enhance activity of ephedrine (344; 345; 346; 347). Theoretically, pseudoephedrine would be expected to have the same effect on blood pressure when used in combination with guarana. Ergotamine tartrateErgotamine tartrate: Caffeine may enhance the effectiveness in the treatment of migraine headaches (Cafergot?: ergotamine tartrate, USP 1mg, and caffeine, USP 100mg) (81). ErythropoietinErythropoietin: In preterm infants, caffeine has been found to be equivalent to theophylline in attenuating erythropoietin production (222). EsmololEsmolol: In a case report, esmolol (500microg/kg bolus, 50microg/kg/min continuous infusion) was an effective treatment of caffeine toxicity resulting from a suicide attempt of ingesting 35g caffeine (348). EstrogenEstrogen: Estrogen contained in oral contraceptives and hormone replacement therapy (HRT) has been shown to lengthen the t? of caffeine (349; 350; 351). Caffeine metabolism was also inhibited in postmenopausal women using hormone replacement estrogen (352). FluvoxamineFluvoxamine: Fluvoxamine may be a potent inhibitor of caffeine metabolism via the cytochrome P450 system (353). HydrocortisoneHydrocortisone: Caffeine may enhance topically applied hydrocortisone in the treatment of atopic dermatitis (36). IbuprofenIbuprofen: A clinical trial showed an increase in pain reduction of 2.4 to 2.8 times when ibuprofen was used in combination with caffeine compared to ibuprofen alone (354). The combination of ibuprofen and caffeine had a greater analgesic effect in women suffering from primary dysmenorrhea (355). IronIron: Impaired iron metabolism and microcytic anemia may occur in infants of breastfeeding women consuming caffeine (297). LithiumLithium: Theophylline and caffeine are reported to increase the renal clearance of lithium and may reduce the plasma levels in stabilized patients (356). Abrupt discontinuation of a consistent caffeine intake may cause an increase in lithium tremors and an increase in serum lithium levels (357; 275). Bioavailability and elimination of a single dose of lithium was found to be unaffected by caffeine at a dose of 200mg four times a day (189). Monoamine oxidase inhibitors (MAOIs)Monoamine oxidase inhibitors (MAOIs): According to a case report, caffeine and MAOIs may cause encephalopathy, neuromuscular irritability, hypotension, sinus tachycardia, rhabdomyolysis and hyperthermia (358). MethoxsalenMethoxsalen: Methoxsalen was shown to decrease the clearance of caffeine, resulting in a lengthened t? from 5.6 hours to 57 hours (359). MexiletineMexiletine: Mexiletine was shown to decrease the clearance of caffeine by 50% without an effect of caffeine on the clearance of mexiletine (360). NicotineNicotine: Caffeine shows additive effects on cardiovascular parameters with nicotine (190) and concomitant consumption of caffeine and cigarettes during pregnancy may place the developing fetus at higher risk for diminished growth (361). Oral contraceptivesOral contraceptives: Concomitant use of oral contraceptives and caffeine may increase serum caffeine concentrations and increase the risk of adverse effects, as oral contraceptives decrease the rate of caffeine clearance by 40-65% (362; 363; 364). PentobarbitalPentobarbital: The caffeine in guarana may negate the hypnotic effects of pentobarbital. However, in an animal study guarana did not alter the hypnotic effect of pentobarbital (149). PhenylpropanolaminePhenylpropanolamine: The combination of phenylpropanolamine and caffeine caused a manic psychosis in 1 woman with no previous history of mental disturbances (365). It is noted that phenylpropanolamine can increase the peak levels reached by caffeine by almost four-fold (366). An additive increase in blood pressure has occurred when using the combination of phenylpropanolamine and caffeine (367; 368). PhenytoinPhenytoin: Caffeine degradation may be impaired by phenytoin (369). PropyphenazonePropyphenazone: When used in combination with caffeine, there may be a significant amplification of the antinociceptive effect of propyphenazone (370). QuinolonesQuinolones: Caffeine administration in patients pretreated with norfloxacin, pipemidic acid or placebo, may result in decreased caffeine clearance (371). Ciprofloxacin was shown to slightly increase the t? of caffeine from 5.2 hours to 8.2 hours (372; 337). RiluzoleRiluzole: Caffeine and riluzole are both metabolized by cytochrome P450 1A2. Theoretically, concomitant use could reduce their metabolism.TerbinafineTerbinafine: Terbinafine may increase serum caffeine concentrations and increase the risk of adverse effects, as terbinafine decreases the rate of caffeine clearance.TheophyllineTheophylline: Caffeine may decrease total body clearance and elimination rate of theophylline (373). VerapamilVerapamil: The mean half-life of caffeine was increased by 25% when co-administered with verapamil and may increase the risk of side effects (374).Guarana/Herb/Supplement Interactions:
GeneralGeneral: Herb and supplement interactions associated with guarana are predominantly theoretical and generally based upon the adverse effect profile of caffeine.Anticoagulant/antiplatelet herbsAnticoagulant/antiplatelet herbs: Caffeine has been reported to have antiplatelet activity (231; 233; 232). Antidiabetic herbsAntidiabetic herbs: Caffeine might increase or decrease blood sugar (325). Bitter orangeBitter orange: Bitter orange may add to the possible hypertensive effects of caffeine (375). Black teaBlack tea: Black tea contains caffeine and may have additive effects if used in combination with guarana.CaffeineCaffeine: Other caffeine containing products (black tea, cocoa, coffee, cola nut, green tea, yerba mate, etc.) used in combination with guarana may have additive effects.CocoaCocoa: Black tea contains caffeine and may have additive effects if used in combination with guarana.CoffeeCoffee: Black tea contains caffeine and may have additive effects if used in combination with guarana.Cola nutCola nut: Black tea contains caffeine and may have additive effects if used in combination with guarana.Cytochrome P450 metabolized herbsCytochrome P450 metabolized herbs: CYP 450 1A2 is the primary metabolic pathway for caffeine (340). Substances that induce the specific CYP 450 enzymes may decrease the t? of herbs metabolized by CYP 450 and therefore decrease their effectiveness. DiureticsDiuretics: In a single blind, randomized, cross-over trial an increase in diuresis, urinary sodium excretion, and urinary potassium excretion was observed within 1 hour of ingestion of 250mg caffeine (183). Ephedra (Ma huang)Ephedra (Ma huang): Avoid use of combination products of Ma huang (ephedra) and guarana due to the reports of death and permanent disability associated with this combination (such as Metabolife-356?). Reports include intrathalamic hemorrhage, cardiac arrest, stroke, and unstable angina requiring coronary bypass surgery (285). This effect is theoretically due to the reported increase in pulse and blood pressure due to the ephedra and the increase in pulse and blood pressure and suspected decrease in platelet function from guarana (231; 137). Estrogenic herbsEstrogenic herbs: Estrogen has been shown to lengthen the t? of caffeine (349; 350; 351). Caffeine metabolism was also inhibited in postmenopausal women using hormone replacement estrogen (352). Green teaGreen tea: Black tea contains caffeine and may have additive effects if used in combination with guarana.IronIron: Impaired iron metabolism and microcytic anemia may occur in infants of breastfeeding women consuming caffeine (297). Monoamine oxidase inhibitors (MAOIs)Monoamine oxidase inhibitors (MAOIs): According to a case report, caffeine and MAOIs may cause encephalopathy, neuromuscular irritability, hypotension, sinus tachycardia, rhabdomyolysis and hyperthermia (358). Nicotine/tobaccoNicotine/tobacco: Additive effects on cardiovascular parameters may occur with nicotine (190). Concomitant consumption of caffeine and cigarettes during pregnancy may place the developing fetus at higher risk for diminished growth (361). Yerba mateYerba mate: Black tea contains caffeine and may have additive effects if used in combination with guarana.Guarana/Food Interactions:
GeneralGeneral: Food interactions associated with guarana are predominantly theoretical and based upon the adverse effect profile of caffeine.Dairy milkDairy milk: Caffeine-associated osteoporosis has been shown to be offset by daily dairy milk consumption (235). Grapefruit juiceGrapefruit juice: The caffeine in guarana may interact with grapefruit juice, resulting in increased caffeine levels.Theophylline-containing foodsTheophylline-containing foods: The theophylline in guarana may interact additively with the theophylline in foods, such as chocolate or tea.Guarana/Lab Interactions:
GeneralGeneral: Lab interactions associated with guarana are predominantly theoretical and based upon the adverse effect profile of caffeine.5-Hydroxyindoleacetic acid5-Hydroxyindoleacetic acid: Caffeine may increase 5-hydroxyindoleacetic acid concentrations (376). Bleeding timeBleeding time: In human in vitro and rabbit in vivo trials, guarana had both an anti-aggregatory and de-aggregatory action on platelets thought to be attributed to a decreased thromboxane formation (231; 233; 232). CatecholaminesCatecholamines: Caffeine overdose has been associated with elevated levels of plasma catecholamines (377; 378; 379). CreatineCreatine: Caffeine may increase urine creatine concentrations. Creatinine in combination with caffeine inhibits net muscle phosphocreatine resynthesis during exercise (380).ElectrolytesElectrolytes: Serum potassium levels may decrease significantly (p<0.05) with moderate caffeine ingestion (180mg and 360mg) (381). ErythropoietinErythropoietin: In preterm infants, caffeine has been found to be equivalent to theophylline in attenuating erythropoietin production (222). HomocysteineHomocysteine: There may be a dose-dependent relationship between caffeine consumption and plasma homocysteine levels (382; 383). IronIron: Impaired iron metabolism and microcytic anemia may occur in infants of breastfeeding women consuming caffeine (297). LactateLactate: The combination of ephedrine and caffeine may increase blood lactate levels (378). Liver enzymesLiver enzymes: Regular caffeine consumption may dose dependently lower levels of gamma-glutamyl transferase, alanine-amino transferase and alkaline phosphatase (384).Serum glucose levelsSerum glucose levels: Caffeine consumption has resulted in an increase and decrease in glucose (378). Serum lipid levelsSerum lipid levels: In 361 patients, LDL-cholesterol levels were found to be significantly higher when smoking and consuming greater than five cups of coffee daily were combined (385). Three studies found caffeine ingestion to have no effect on serum lipids (205; 386; 387; 388). Liver enzymesLiver enzymes: Regular caffeine consumption may dose dependently lower levels of gamma-glutamyl transferase, alanine-amino transferase and alkaline phosphatase (384).TheophyllineTheophylline: Intake of caffeine may cause increases in serum levels of theophylline (377). TriglyceridesTriglycerides: A combination of ephedrine and caffeine decreased plasma triglyceride concentration in obese females (389). Uric acidUric acid: Caffeine may falsely elevate uric acid concentrations (390). Urine testsUrine tests: Caffeine may increase diuresis, urinary sodium excretion, and urinary potassium excretion (183). Vanillylmandelic acid (VMA)Vanillylmandelic acid (VMA): Caffeine may cause small increases in VMA concentrations (391).