1,3,7-trimethyl-2, 6-dioxopurine

Caffeine/Drug Interactions:

  • AcetaminophenAcetaminophen: Caffeine is frequently added to analgesics such as acetaminophen, ibuprofen, and aspirin to enhance their efficacy, an effect that is well documented (691; 692; 694; 695; 696; 693; 697; 698; 21; 699; 700; 701; 702). Some research suggests that the effect is small (703) but statistically significant (704). In humans, caffeine accelerated the absorption of acetaminophen (705). In pharmacokinetic research in humans, caffeine has been found to increase the area-under-the-curve (AUC) and maximum plasma concentration (Cmax) and decrease clearance of acetaminophen (706).
  • AdenosineAdenosine: According to secondary sources, caffeine is widely known as an adenosine receptor antagonist. The effects of adenosine may be antagonized by caffeine (68).
  • AlcoholAlcohol: The Centers for Diseases Control and Prevention (CDC) states that caffeinated alcoholic beverages may mask the depressant effects of alcohol. Consumption of these beverages may also be associated with social problems, including binge drinking, risky sexual activity, and drinking and driving. According to a review, caffeine may reduce the effects of alcohol by blocking the effects of upregulated A1 receptors and may contribute to the reinforcing effects of alcohol by blocking A2A receptors (669). According to expert opinion, caffeine decreases physical and mental impairment from alcohol at low blood levels, but appears to have less effect at higher blood levels (357). In humans, combined use of a caffeine-containing energy drink with alcohol resulted in lowered cognitive functioning (707). However, a lack of effects was noted on driving performance with concurrent use of caffeine and alcohol (708). In laboratory research, caffeine administration during ethanol withdrawal produced additive neurotoxic effects (709). In animal research, coadministration of a rum-containing beverage and a caffeine-containing soft drink resulted in elevated levels of triacyl glycerol, glucose, aspartate amino transferase (AST), alanine amino transferase (ALT), and alkaline phosphatase (ALP) in serum, with no effect on total cholesterol or high-density lipoprotein (HDL) cholesterol (710).
  • Alzheimer's agentsAlzheimer's agents: Several preliminary studies have examined the effects of caffeine, tea, or coffee use on short and long-term memory and alertness (378; 711). Research on the effects of caffeine on Alzheimer's agents is lacking.
  • AmphetamineAmphetamine: Combination use of caffeine and other stimulants may theoretically result in additive stimulant effects and increase the risk of adverse effects such hypertension, tachycardia, insomnia, and nervousness. There is a case report of ischemic stroke after intranasal use of amphetamine and caffeine (348).
  • AnalgesicsAnalgesics: Caffeine is frequently added to analgesics such as acetaminophen, ibuprofen, and aspirin to enhance their efficacy, an effect that is well documented (691; 692; 693; 694; 695; 696; 697; 712; 713; 698; 21; 699; 700; 701; 702). Some research suggests that the effect is small (703) but statistically significant (704). In animals, caffeine increased the analgesic effect of aspirin by pharmacodynamic mechanism (696). Furthermore, in laboratory research, caffeine inhibited cyclooxygenase-2 (COX-2), which explained its benefit as an analgesic adjuvant (714). In humans, caffeine accelerated the absorption of acetaminophen (705). In human pharmacokinetic research, caffeine increased the AUC and Cmax and decreased clearance of acetaminophen (706). In animal research, a synergistic effect on antinociception was noted between caffeine and tramadol (698).
  • AntiandrogensAntiandrogens: In laboratory research, caffeine inhibited the CYP-mediated metabolism of flutamide (an antiandrogen) (229).
  • AntiarrhythmicsAntiarrhythmics: In a review, mexiletine, a potent inhibitor of CYP1A2 and antiarrhythmic drug, inhibited caffeine metabolism (212). In humans, mexiletine decreased caffeine elimination by 50% (222).
  • Antiasthma drugsAntiasthma drugs: In systematic review and meta-analysis, caffeine improved airway function and reduced asthma symptoms in asthmatic patients (715; 716). In humans, caffeine acted as a bronchodilator (717; 718). It may also reduce respiratory muscle fatigue (715; 716). In humans, administration of single doses of furafylline resulted in accumulation of caffeine by blocking N3-demethylation of caffeine to paraxanthine (235). In humans and according to a review, caffeine reduced clearance and prolonged the half-life of theophylline (231; 232; 233).
  • AntibioticsAntibiotics: According to secondary sources, certain antibiotics may interfere with the breakdown of caffeine. In humans, quinolone antibiotics (ciprofloxacin, enoxacin (not available in the United States), and pipemidic acid (an agent similar to nalidixic acid; not available in the United States)) inhibited caffeine elimination and increased caffeine blood levels and the risk of adverse effects (206; 193; 207; 208; 209; 210), likely due to inhibition of CYP1A2-mediated metabolism of caffeine (211). In humans, ciprofloxacin decreased the metabolic conversion of caffeine to its major metabolite, paraxanthine, resulting in increased caffeine clearance and prolongation of caffeine's half-life (210).
  • Anticoagulants and antiplateletsAnticoagulants and antiplatelets: In humans, ticlopidine inhibited caffeine metabolism through the CYP1A2 enzyme system (196). According to anecdotal evidence, caffeine may prolong bleeding time. However, one study found that coffee lacked an effect on fibrinogen, clotting factor VII activity, factor VIII antigen, protein C, and protein S (719). In secondary information, green tea and coffee, including decaffeinated coffee, contained significant amounts of vitamin K.
  • AnticonvulsantsAnticonvulsants: In humans and animals, and according to reviews, acute and chronic caffeine ingestion reduced the anticonvulsant effects of carbamazepine, phenobarbital, phenytoin, valproate, and ethosuximide (257; 258; 259; 260; 261). In humans, coadministration of caffeine (single dose) with carbamazepine resulted in prolonged half-life and reduced bioavailability, plasma concentration, and the AUC of carbamazepine (261). In animals, single doses of caffeine reduced the anticonvulsant and protective effects of phenobarbital and valproate (257). In animals, chronic administration of caffeine increased tiagabine concentrations but did not impair the effects (630). In humans, phenytoin increased the clearance of caffeine and reduced its half-life from 4.8 to 2.4 hours (720). Additionally, phenytoin impaired the validity of caffeine liver function tests (720). In animals, felbamate had a low interaction potential with caffeine, as reduced anticonvulsant activity was only demonstrated with high doses (161.7mg/kg) (721). In animals and according to a review, the drug levels and anticonvulsant effects of lamotrigine and oxcarbazepine, however, were unaltered (630).
  • AntidepressantsAntidepressants: In a case report, concurrent use of caffeine and serotonergic antidepressants increased the risk of serotonin syndrome (263). In animals and humans, caffeine and caffeine analogs inhibited monoamine oxidase isoforms A- and B- (MAO-A and -B) (264; 265; 266; 267; 268; 269; 270; 271). In vitro, fluvoxamine inhibited the CYP1A2-mediated metabolism of caffeine (220). In humans, fluvoxamine decreased the clearance and increased the half-life of caffeine; N1-, N3-, and N7-demethylation clearances decreased (221). In rat liver microsomes, amitriptyline and imipramine inhibited CYP1A2-mediated metabolism of caffeine (224).
  • AntidiabeticsAntidiabetics: In animal research, metformin increased plasma concentrations of caffeine; a lack of effects were noted, however, with coadministration of caffeine and gliclazide (279). In animals and humans, and according to reviews, caffeine consumption impaired insulin sensitivity and increase blood glucose concentrations (272; 273; 251; 274; 275; 276; 277; 278). Theoretically, caffeine may reduce or interfere with the effects of agents used for diabetes.
  • AntifungalsAntifungals: In humans, fluconazole decreased clearance and inhibited the elimination of caffeine (238; 239). In human and laboratory research, administration of terbinafine had minimal effects of CYP1A2 substrates like caffeine (722; 723; 724). In vitro, caffeine weakly inhibited terfenadine metabolism (724).
  • Antiglaucoma agentsAntiglaucoma agents: In individuals with glaucoma, coffee consumption and caffeine intake increased intraocular pressure (280; 281; 282; 283). Theoretically, caffeine may reduce the effects of antiglaucoma agents. However, in humans, caffeine lacked an effect on timolol maleate on intraocular pressure (725).
  • AntihypertensivesAntihypertensives: According to a review, meta-analysis, and clinical research, caffeine increased blood pressure (242; 243; 244; 245; 246; 247; 248; 249; 250) and theoretically may reduce the effects of antihypertensive agents.
  • AntilipemicsAntilipemics: According to clinical review, meta-analysis, and animal research, caffeine may increase cholesterol and triglyceride levels (251; 252; 539). In laboratory research, the vasodilatory effects and activity of rosuvastatin on ecto-5'-nucleotidase activity was attenuated by caffeine (253). Researchers suggest abstaining from caffeine while using 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) in order to obtain the full clinical benefit (253).
  • AntineoplasticsAntineoplastics: In humans, caffeine increased the antitumor therapeutic effects of chemotherapy, particularly genotoxic agents (such as cisplatin, doxorubicin, ifosfamide, cyclophosphamide, mitomycin C, temozolomide) that modify DNA (726; 727; 728; 729; 730; 731). In patients with soft tissue sarcoma, caffeine potentiated the effects of chemotherapy (cisplatin, ifosfamide, doxorubicin), resulting in favorable radiographic response and improved survival outcomes (728). In osteosarcoma cells, high concentrations of caffeine enhanced the antitumor effects of cisplatin (32; 729; 730). In laboratory research, caffeine, a multiple kinase inhibitor, enhanced the cytotoxicity of radiation in combination with temozolomide (726). In humans, pazopanib, however, had a lack of effect on caffeine CYP1A2-mediated metabolism in patients with solid tumors (187).
  • Antiobesity agentsAntiobesity agents: In humans, caffeine, either alone or in combination with other agents like ephedra, had weight-reducing effects (49; 732; 733; 251). In humans, concurrent use resulted in synergism in thermogenic response (734; 735; 736).
  • AntiparkinsoniansAntiparkinsonians: In humans, pretreatment with caffeine before levodopa resulted in improved pharmacokinetics in patients with Parkinson's disease (737).
  • AntipyrineAntipyrine: According to secondary sources, caffeine and antipyrine were metabolized by CYP1A2. In human evidence, antipyrine increased elimination of caffeine (241).
  • AntipsychoticsAntipsychotics: According to secondary sources, clozapine was metabolized CYP1A2 isoenzyme, thus caffeine and clozapine may compete for the CYP1A2 isoenzyme. In humans, caffeine reduced clozapine clearance due to CYP1A2 inhibition (228). In vitro, phenothiazines (chlorpromazine, levomepromazine, thioridazine, perazine) inhibited CYP1A2, as evidenced by inhibition of 3-N-demethylation to paraxanthine, 1-N-demethylation to theobromine, and 7-N-demethylation to theophylline (223). In other human research, however, coffee or tea lacked an effect on altering blood levels of antipsychotics, fluphenazine, and haloperidol (738).
  • Antiulcer agentsAntiulcer agents: In humans, cimetidine inhibited caffeine metabolism, as evidenced by increased plasma and salivary AUC and decreased elimination rate constant and systemic clearance (204; 205). According to a review and secondary sources, famotidine and ranitidine (other histamine-2 [H2]-receptor antagonists) had minimal effects on the cytochrome P450 system (739) and likely will not alter the effects of caffeine (740). In humans, omeprazole has been found to induce CYP1A2 activity, as evidenced by increased N-3-demethylation in the 13C-[N-3-methyl]-caffeine breath test (230). In other human research, pantoprazole, omeprazole, and lansoprazole did not induce CYP1A2 activity, as evidenced by caffeine breath test and the urinary ratio of caffeine metabolites (741).
  • AspirinAspirin: Caffeine is frequently added to analgesics such as aspirin to enhance their efficacy, an effect that is well documented (691; 692; 693; 694; 698; 21; 699; 700; 701; 702; 695; 696; 697). Some research suggests that the effect is small (703) but significant (704). In animals, caffeine increased the analgesic effect of aspirin by pharmacodynamic mechanism (696). In other human research, combined use of caffeine and aspirin had a significant benefit on mood and performance (742). Rectal administration of acetyl salicylic acid-caffeine complex was found to be safe (743).
  • BarbituratesBarbiturates: Caffeine is a known stimulant, thus it may antagonize the effects of CNS depressants. In animals, caffeine has been shown to shorten barbital-induced sleeping time (744). In humans, caffeine antagonized the hypnotic effects of pentobarbital (745). In animals, caffeine reduced the anticonvulsant and protective effects of phenobarbital (257).
  • BenzodiazepinesBenzodiazepines: Caffeine is a known stimulant, thus it may antagonize the effects of CNS depressants. Specifically, in humans, caffeine has been shown to antagonize the sedative and anxiolytic effects of midazolam (179), lorazepam (180), triazolam (178), and diazepam (180; 176; 177). In other human research, triazolam blocked the discriminative stimulus effects of caffeine (746).
  • Beta-agonistsBeta-agonists: In humans, combined use of caffeine and ephedrine (a beta-agonist) resulted in thermogenic synergism (734). According to secondary sources, caffeine may increase the inotropic effects of beta-agonists.
  • Beta-blockersBeta-blockers: Theoretically, caffeine may interfere with the blood pressure-lowering effects of beta-blockers like propranolol and metoprolol. In humans and animals, propranolol reversed the negative impact of caffeine on glucose tolerance (747; 748).
  • BronchodilatorsBronchodilators: In humans, caffeine has been found to act as a bronchodilator, as evidenced by improvements in pulmonary function test parameters (forced expiratory volume [FEV], forced vital capacity [FVC]) (717; 718). It may also reduce respiratory muscle fatigue (715; 716). Theoretically, concurrent use with other bronchodilating agents may cause additive effects.
  • Calcium saltsCalcium salts: In humans and according to a review, caffeine may increase urinary excretion of calcium which may be due to adenosine antagonism (307) and/or a reduction in renal reabsorption of calcium (308). However, the research is inconsistent (749). According to review, the negative effects may be negligible in individuals who consume the recommended daily allowance of calcium (750).
  • CarbamazepineCarbamazepine: In humans, coadministration of caffeine with carbamazepine resulted in prolonged half-life and reduced bioavailability, plasma concentration, and the AUC of carbamazepine (261).
  • CelecoxibCelecoxib: In vivo, celecoxib did not alter the caffeine test (751). In laboratory research, caffeine enhanced the solubility and dissolution of celecoxib (752).
  • CimetidineCimetidine: In humans, cimetidine inhibited caffeine metabolism (204; 205).
  • CiprofloxacinCiprofloxacin: In humans, quinolone antibiotics, including ciprofloxacin, inhibited caffeine elimination and increased caffeine blood levels and the risk of adverse effects (206; 193; 207; 208; 209; 210), likely due to inhibition of CYP1A2-mediated metabolism of caffeine (211). In humans, ciprofloxacin decreased the metabolic conversion of caffeine to its major metabolite, paraxanthine, resulting in increased caffeine clearance and prolongation of caffeine's half-life (210).
  • CisplatinCisplatin: In humans, caffeine increased the antitumor therapeutic effects of chemotherapy, particularly genotoxic agents like cisplatin, that modify DNA (726; 727; 728; 729; 730; 731). In patients with soft tissue sarcoma, caffeine potentiated the effects of chemotherapy (cisplatin, ifosfamide, doxorubicin), resulting in favorable radiographic response and improved survival outcomes (728). In osteosarcoma cells, high concentrations of caffeine enhanced the antitumor effects of cisplatin (32; 729; 730).
  • ClozapineClozapine: According to secondary sources, clozapine is metabolized CYP1A2 isoenzyme, thus caffeine and clozapine may compete for the CYP1A2 isoenzyme. In humans, caffeine reduced clozapine clearance due to CYP1A2 inhibition (228).
  • CNS depressantsCNS depressants: Caffeine is a known stimulant, thus it may antagonize the effects of CNS depressants. Specifically, in humans, caffeine has been shown to antagonize the effects of CNS depressants, including, but not limited to, diazepam, triazolam, midazolam, zolpidem, and zopiclone (176; 177; 178; 179; 180; 181; 182). According to a clinical review, the additive effects of caffeine on zolpidem sedation were caused by a reduction of reactive oxygen species and increased bioavailability of endogenous melatonin (181). In other human research, triazolam blocked the discriminative stimulus effects of caffeine (746). In humans, zopiclone antagonized the effects of caffeine better than caffeine on zopiclone (178).
  • CNS stimulantsCNS stimulants: Combination use of caffeine and other stimulants may theoretically result in additive stimulant effects and increase the risk of adverse effects such hypertension, tachycardia, insomnia, and nervousness. There is a case report of ischemic stroke after intranasal use of amphetamine and caffeine (348). In animals, caffeine may potentiate the reinforcing and discriminative effects of cocaine (353; 354; 355; 356). In humans, there was a lack of physiologic response to cocaine with infrequent acute caffeine administration, with the exception of augmenting blood pressure (349). In humans, combined use of phenylpropanolamine and caffeine may result in increases in blood pressure (169; 170; 171; 172; 173; 174), which may be due to pharmacokinetic and pharmacodynamic mechanisms (173). It has also been shown to have additive effects on cardiovascular parameters with nicotine (549). In animal research, coadministration of caffeine and methylphenidate resulted in long-term changes in locomotor activity and cross-sensitization through dopamine- and cAMP-regulated phosphoproteins of the 32kDa (DARPP-32)-dependent pathway (352).
  • CocaineCocaine: In animals, caffeine potentiated the reinforcing and discriminative effects of cocaine (353; 354; 355; 356). In humans, however, there was a lack of physiologic response to cocaine with infrequent acute caffeine administration, with the exception of augmenting blood pressure (349).
  • ContraceptivesContraceptives: In humans, exogenous estrogen inhibited caffeine clearance, metabolism, and elimination (214; 215; 216; 217; 218; 219), which may be due to inhibition of CYP1A1 (in the gut) and/or CYP1A2 (in the liver) (214; 219). In humans, higher levels of estradiol were associated with few or a lack of subjective responses to caffeine, but lower levels of estradiol were associated with negative subjective responses to caffeine (540).
  • CorticosteroidsCorticosteroids: Theoretically, combined use of caffeine and corticosteroids may increase the risk of adverse effects such as hypokalemia and bone loss. In clinical research, caffeine enhanced topically applied hydrocortisone in the treatment of atopic dermatitis (42).
  • CyclophosphamideCyclophosphamide: In humans, caffeine may increase the antitumor therapeutic effects of chemotherapy, particularly genotoxic agents like cyclophosphamide, that modify DNA (726; 727; 728; 729; 730; 731).
  • Cytochrome P450-metabolized agentsCytochrome P450-metabolized agents: In animal and laboratory research and according to clinical reviews, cytochrome P450 1A2 was involved in the metabolism of caffeine (183; 184; 185; 186; 187; 188; 189; 190; 191; 192; 193; 194; 195; 196; 197; 198; 199; 200; 201; 202; 203). According to a review, agents such as serotonin reuptake inhibitors (fluvoxamine), antiarrhythmics (mexiletine), antipsychotics (clozapine), psoralens (methoxsalen), phenylpropanolamine, bronchodilators, and quinolone antibiotics (ciprofloxacin), which are inhibitors of CYP1A2, may result in inhibition of caffeine metabolism (212).
  • DarifenacinDarifenacin: In humans, caffeine was not found to affect the efficacy of darifenacin (753).
  • DecongestantsDecongestants: Theoretically, concurrent use of decongestants and caffeine may result in increased blood pressure. In humans, combined use of phenylpropanolamine and caffeine resulted in increases in blood pressure (169; 170; 171; 172; 173; 174), which may be due to pharmacokinetic and pharmacodynamic mechanisms (173). In humans, phenylpropanolamine enhanced absorption or inhibited elimination of caffeine (171). Additionally, in animals, phenylpropanolamine increased the neurotoxic effects of caffeine (174). In rats, intraperitoneal administration of caffeine with phenylpropanolamine resulted in a 1.6-fold increase in the AUC of phenylpropanolamine in the brain (175).
  • DiazepamDiazepam: Caffeine is a known stimulant, thus it may antagonize the effects of CNS depressants. In humans, caffeine has been shown to antagonize the sedative and anxiolytic effects of diazepam (180; 176; 177).
  • DipyridamoleDipyridamole: In humans, caffeine has been shown to induce a false-negative using dipyridamole stress testing (66; 359; 360). In humans, caffeine may inhibit the vasodilation effect of dipyridamole (66).
  • DisulfiramDisulfiram: In humans, disulfiram inhibited the elimination and decreased the clearance of caffeine, which may increase the risk of cardiovascular and CNS stimulatory effects (213).
  • DiureticsDiuretics: According to secondary sources and review, caffeine is a known diuretic (40). Theoretically, concurrent use with other diuretics may increase the risk of dehydration and electrolyte imbalances.
  • Dopamine agonistsDopamine agonists: In animal laboratory research, caffeine enhanced dopamine release n the striatum and hypothalamus via adenosine (A2) antagonism (292; 293; 294). In animals, as caffeine tolerance develops, dopamine receptors may become less responsive to dopamine agonists (295).
  • Dopamine antagonistsDopamine antagonists: In animals, caffeine may alter locomotor activation of dopamine antagonists (eticlopride, sulpiride) via adenosine antagonism (296).
  • DoxorubicinDoxorubicin: In humans, caffeine may increase the antitumor therapeutic effects of chemotherapy, particularly genotoxic agents, like doxorubicin, that modify DNA (726; 727; 728; 729; 730; 731). In patients with soft tissue sarcoma, caffeine potentiated the effects of chemotherapy (cisplatin, ifosfamide, doxorubicin), resulting in favorable radiographic response and improved survival outcomes (728).
  • Drugs that may lower the seizure thresholdDrugs that may lower the seizure threshold: In review, methylxanthines like caffeine have been linked to seizures, likely due to adenosine-antagonizing effects (262). Theoretically, combined use of caffeine with other agents that may lower the seizure threshold may increase the risk of seizures.
  • EphedrineEphedrine: According to meta-analysis and systematic review, combined use of ephedra or ephedrine with caffeine may increase the risk of psychiatric, cardiovascular, autonomic, and gastrointestinal adverse effects (350; 351). Although, some research has noted a lack of adverse cardiovascular effects with prescription ephedrine and caffeine (754). In humans, concurrent use resulted in synergism in thermogenic response (734; 735; 736).
  • Ergot derivativesErgot derivatives: According to secondary sources, caffeine promotes the absorption of ergot alkaloids. According to review, caffeine may be used with ergot alkaloids for synergistic effects (755)
  • EstrogensEstrogens: In humans, exogenous estrogen inhibited caffeine clearance, metabolism, and elimination (214; 215; 216; 217; 218; 219), which may be due to inhibition of CYP1A1 (in the gut) and/or CYP1A2 (in the liver) (214; 219). In humans, higher levels of estradiol were associated with few or no subjective responses to caffeine, but lower levels of estradiol were associated with negative subjective responses to caffeine (540).
  • EthosuximideEthosuximide: In animals, acute caffeine exposure reduced the anticonvulsant effects of ethosuximide (259).
  • FelbamateFelbamate: In animals, felbamate had a low potential of interaction with caffeine, as reduced anticonvulsant activity was only demonstrated with high doses (161.7mg/kg) (721).
  • FlubendiamideFlubendiamide: In laboratory research, flubendiamide (an insecticide) marginally reduced the sensitivity of caffeine on lepidopterous ryanodine receptors (756).
  • FluconazoleFluconazole: In humans, fluconazole decreased clearance and inhibited the elimination of caffeine (238; 239).
  • FlutamideFlutamide: In laboratory research, caffeine inhibited the CYP-mediated metabolism of flutamide, an antiandrogen (229).
  • FluvoxamineFluvoxamine: In vitro, fluvoxamine inhibited the CYP1A2-mediated metabolism of caffeine (220). In humans, fluvoxamine decreased the clearance and increased the half-life of caffeine; N1-, N3-, and N7-demethylation clearances decreased (221).
  • FurafyllineFurafylline: In humans, administration of single doses of furafylline (an antiasthma agent and methylxanthine derivative) resulted in accumulation of caffeine by blocking N3-demethylation of caffeine to paraxanthine (235).
  • Growth hormoneGrowth hormone: In humans, growth hormone induced CYP1A2, as evidenced by an increased metabolic ratio of caffeine (297). In growth hormone-deficient children, growth hormone decreased CYP450-dependent 3-N-demethylation of caffeine (298). However, using caffeine as a probe drug, recombinant human growth hormone lacked effect on CYP1A2 enzyme activity in growth hormone-deficient children (757).
  • H2 blockersH2 blockers: In humans, cimetidine inhibited caffeine metabolism, as evidenced by increased plasma and salivary AUC and decreased elimination rate constant and systemic clearance(204; 205). In a review, famotidine and ranitidine (other histamine-2 [H2]-receptor antagonists) had minimal effects on the cytochrome P450 system (739) and likely will not alter the effects of caffeine (740).
  • HydrocortisoneHydrocortisone: In clinical research, caffeine enhanced topically applied hydrocortisone in the treatment of atopic dermatitis, likely by increasing levels of cAMP by phosphodiesterase inhibition (42).
  • IbuprofenIbuprofen: In humans, caffeine enhanced the analgesic effects of ibuprofen (712; 713).
  • IfosfamideIfosfamide: In humans, caffeine may increase the antitumor therapeutic effects of chemotherapy, particularly genotoxic agents like ifosfamide, that modify DNA (726; 727; 728; 758; 759; 731). In patients with soft tissue sarcoma, caffeine potentiated the effects of chemotherapy (cisplatin, ifosfamide, doxorubicin), resulting in favorable radiographic response and improved survival outcomes (728).
  • ImmunosuppressantsImmunosuppressants: According to secondary sources, chronic and excessive amounts of caffeine may deplete the immune system. In humans, caffeine has been found to exert immunomodulatory effects, as evidenced by suppressed lymphocyte function and altered lymphocyte counts (49; 51; 53; 54). According to a review and laboratory research, the immunomodulatory effects of caffeine may be due to inhibition of cAMP-phosphodiesterase (PDE), leading to increases in intracellular cAMP concentrations (55; 54).
  • InotropesInotropes: Theoretically, concurrent use of positive inotropes and caffeine may result in additive sympathomimetic effects.
  • Iron saltsIron salts: According to secondary sources, caffeine may inhibit iron absorption. Experts suggest separating caffeine and iron-containing foods or supplements by at least one hour.
  • LevodopaLevodopa: In humans, pretreatment with caffeine before levodopa resulted in improved pharmacokinetics in patients with Parkinson's disease, as evidenced by shorted peak plasma concentration of levodopa, decreased latency to levodopa walking and tapping motor response, and increased walking response (737). Other human research found that caffeine did not cause changes in therapeutic response, but the duration of involuntary movements increased in patients with levodopa dyskinesias (760).
  • LithiumLithium: According to secondary sources, concurrent use of lithium and caffeine may increase the urinary excretion of lithium and thus reduce its effects. According to human data, caffeine withdrawal may produce lithium toxicity in patients maintained on high-baseline lithium blood levels (316). In heavy caffeine-consuming, lithium-maintained patients, abruptly discontinuing daily caffeine consumption resulted in an increase (24%) in lithium blood levels in one study.
  • LorazepamLorazepam: Caffeine is a known stimulant, thus it may antagonize the effects of CNS depressants. In humans, caffeine has been shown to antagonize the sedative and anxiolytic effects of lorazepam (180).
  • Magnesium supplementsMagnesium supplements: In humans, caffeine decreased magnesium excretion, which may be due to a reduction in renal reabsorption of magnesium (309; 308; 310).
  • MetforminMetformin: In animal research, metformin increased plasma concentrations of caffeine through competitive inhibition of binding to plasma protein (279).
  • MethoxsalenMethoxsalen: In a review, agents such methoxsalen, a potent inhibitor of CYP1A2, resulted in inhibition of caffeine metabolism (212). In humans, methoxsalen decreased the clearance and increased the half-life of caffeine (761).
  • Methylenedioxymethamphetamine (MDMA, "Ecstasy")Methylenedioxymethamphetamine (MDMA, "Ecstasy"): In animal research, caffeine has been shown to exacerbate MDMA-induced hyperthermia, likely due to adenosine receptor antagonism, phosphodiesterase (PDE) inhibition, and promotion of dopamine D(1) over D(2) receptor-related responses (762; 763). In animal research, combined use increased glial activation, leading to harmful consequences (764).
  • MethylphenidateMethylphenidate: Combination use of caffeine and other stimulants such as methylphenidate may theoretically result in additive stimulant effects and increase the risk of adverse effects such hypertension, tachycardia, insomnia, and nervousness. In animal research, coadministration of caffeine and methylphenidate resulted in long-term changes in locomotor activity and cross-sensitization through dopamine- and cAMP-regulated phosphoproteins of the 32kDa (DARPP-32)-dependent pathway (352).
  • MethylxanthinesMethylxanthines: In humans and according to reviews, coadministration of caffeine and theophylline may result in increased concentrations of theophylline, likely due to competitive inhibition of theophylline metabolism by CYP1A2 (231; 232; 233). In humans, caffeine reduced clearance and prolonged the half-life of theophylline (methylxanthine) (231; 232). In humans, administration of single doses of furafylline (an antiasthma agent and methylxanthine derivative) resulted in accumulation of caffeine by blocking N3-demethylation of caffeine to paraxanthine (235).
  • MexiletineMexiletine: In a review, mexiletine, a potent inhibitor of CYP1A2, inhibited caffeine metabolism (212). In humans, mexiletine decreased caffeine elimination by 50% (222).
  • MidazolamMidazolam: Caffeine is a known stimulant, thus it may antagonize the effects of CNS depressants. In humans, caffeine has been shown to antagonize the sedative and anxiolytic effects of midazolam (179).
  • Mitomycin CMitomycin C: In humans, caffeine may increase the antitumor therapeutic effects of chemotherapy, particularly genotoxic agents, like mitomycin C, that modify DNA (726; 727; 728; 729; 730; 731).
  • MorphineMorphine: In advanced cancer patients, caffeine in conjunction with morphine decreased pain intensity and moderately increased cognitive performance (765).
  • NicotineNicotine: Theoretically, concurrent use of caffeine and nicotine may increase the risk of psychiatric and cardiovascular adverse effects, as both agents are known stimulants. In humans, caffeine enhanced the thermogenic response observed following ingestion of nicotine gum (766). None of the nicotine-caffeine combinations changed the respiratory quotient compared to placebo, indicating that glucose and fat oxidation rates were increased to a similar extent. Caffeine showed additive effects on cardiovascular parameters with nicotine (549). In humans, however, infrequent acute caffeine administration attenuated the "high" of nicotine (349). Concomitant consumption of caffeine and cigarettes during pregnancy placed the developing fetus at higher risk for diminished growth (767). In humans, patients with schizophrenia who smoked had higher serum caffeine levels (768). In some young women, attention was improved following nicotine use in those consuming the greatest amounts of caffeine (769).
  • NifedipineNifedipine: In humans, pretreatment with caffeine was not found to alter the cardiovascular effects of nifedipine; however, nifedipine reversed the vasopressor effects of caffeine (770). In animals, concurrent administration of nifedipine and caffeine inhibited the vasodilator response to ethyladenosine (771). This loss of coronary dilation and adenosine A3 receptor expression was reportedly due to changes in signaling pathways.
  • OmeprazoleOmeprazole: In humans, omeprazole has been found to induce CYP1A2 activity, as evidenced by increased N-3-demethylation in the 13C-[N-3-methyl]-caffeine breath test (230). In other human research, omeprazole did not induce CYP1A2 activity, as evidenced by caffeine breath test and the urinary ratio of caffeine metabolites (741).
  • OseltamivirOseltamivir: In animal research, caffeine with oseltamivir (Tamiflu?) enhanced the effects on light-dark behavior and open-field behavior, likely due to adenosine antagonism (772).
  • PazopanibPazopanib: In humans, pazopanib had a lack of effect on caffeine CYP1A2-mediated metabolism in patients with solid tumors (187).
  • PentobarbitalPentobarbital: Caffeine is a known stimulant, thus it may antagonize the effects of CNS depressants. In humans, caffeine antagonized the hypnotic effects of pentobarbital (745).
  • PerazinePerazine: In vitro, perazine inhibited CYP1A2, as evidenced by inhibition of 3-N-demethylation to paraxanthine, 1-N-demethylation to theobromine, and 7-N-demethylation to theophylline (223; 201).
  • PhenobarbitalPhenobarbital: In humans and animals, and according to reviews, acute and chronic caffeine ingestion reduced the anticonvulsant effects like phenobarbital (257; 260). In animals, single doses of caffeine reduced the anticonvulsant and protective effects of phenobarbital (257).
  • PhenothiazinesPhenothiazines: In vitro, phenothiazines (chlorpromazine, levomepromazine, thioridazine, perazine) inhibited CYP1A2, as evidenced by inhibition of 3-N-demethylation to paraxanthine, 1-N-demethylation to theobromine, and 7-N-demethylation to theophylline (223).
  • Phenylpropanolamine (PPA)Phenylpropanolamine (PPA): In humans, combined use of phenylpropanolamine and caffeine resulted in increased blood pressure (169; 170; 171; 172; 173; 174), which may be due to pharmacokinetic and pharmacodynamic mechanisms (173). In humans, phenylpropanolamine enhanced absorption or inhibited elimination of caffeine (171). Additionally, in animals, phenylpropanolamine increased the neurotoxic effects of caffeine (174). In rats, intraperitoneal administration of caffeine with phenylpropanolamine resulted in a 1.6-fold increase in the AUC of phenylpropanolamine in the brain (175).
  • PhenytoinPhenytoin: In humans, phenytoin increased the clearance of caffeine and reduced its half-life from 4.8 to 2.4 hours (720). Additionally, phenytoin impaired the validity of caffeine liver function tests (720).
  • Potassium saltsPotassium salts: In a review and in humans, caffeine, particularly in excessive amounts, reduced potassium levels following exercise due to stimulation of the sodium-potassium pump (311; 312; 313; 314; 315).
  • Potassium-depleting drugsPotassium-depleting drugs: According to a review and in humans, caffeine, particularly in excessive amounts, reduced potassium levels following exercise due to stimulation of the sodium-potassium pump (311; 312; 313; 314; 315). Theoretically, concurrent use of caffeine with other potassium-depleting agents may increase the risk of hypokalemia.
  • PropranololPropranolol: Theoretically, caffeine may interfere with the blood pressure lowering effects of beta-blockers like propranolol. In humans and animals, propranolol reversed the negative impact of caffeine on glucose tolerance (747; 748).
  • Proton pump inhibitors (PPIs)Proton pump inhibitors (PPIs): In humans, omeprazole has been found to induce CYP1A2 activity, as evidenced by increased N-3-demethylation in the 13C-[N-3-methyl]-caffeine breath test (230). In other human research, pantoprazole, omeprazole and lansoprazole did not induce CYP1A2 activity, as evidenced by caffeine breath test and the urinary ratio of caffeine metabolites (741).
  • QuinolonesQuinolones: In humans, quinolone antibiotics (ciprofloxacin, enoxacin, and pipemidic acid (an agent similar to nalidixic acid)) inhibited caffeine elimination and increased caffeine blood levels and risk of adverse effects (206; 193; 207; 208; 209; 210), likely due to inhibition of CYP1A2-mediated metabolism of caffeine (211). In humans, ciprofloxacin decreased the metabolic conversion of caffeine to its major metabolite, paraxanthine, resulting in increased caffeine clearance and prolongation of caffeine's half-life (210).
  • RiluzoleRiluzole: According to secondary sources, CYP1A is involved in the metabolism of riluzole. In humans, a relationship between the caffeine:paraxanthine ratio and riluzole clearance was demonstrated (773).
  • RosuvastatinRosuvastatin: In laboratory research, the vasodilatory effects and activity of rosuvastatin on ecto-5'-nucleotidase activity was attenuated by caffeine (253).
  • SedativesSedatives: In humans, caffeine has been shown to antagonize the effects of sedatives (176; 177; 178; 179; 180; 181).
  • SympathomimeticsSympathomimetics: In humans, combined use of phenylpropanolamine and caffeine resulted in increases in blood pressure (169; 170; 171; 172; 173; 174). In humans, phenylpropanolamine enhanced absorption or inhibited elimination of caffeine (171). Additionally, in animals, phenylpropanolamine increased the neurotoxic effects of caffeine (174). In rats, intraperitoneal administration of caffeine with phenylpropanolamine resulted in a 1.6-fold increase in the AUC of phenylpropanolamine in the brain (175).
  • TemozolomideTemozolomide: In humans, caffeine increased the antitumor therapeutic effects of chemotherapy, particularly genotoxic agents, like temozolomide, that modify DNA (726; 727; 728; 729; 730; 731). In laboratory research, caffeine, a multiple kinase inhibitor, enhanced the cytotoxicity of radiation in combination with temozolomide (726).
  • TerbinafineTerbinafine: In humans, terbinafine slightly decreased clearance and increased the half-life of caffeine (722).
  • TerfenadineTerfenadine: In vitro, caffeine weakly inhibited terfenadine metabolism (724).
  • TheophyllineTheophylline: In humans and according to reviews, caffeine reduced clearance and prolonged the half-life of theophylline (231; 232; 233).
  • TiagabineTiagabine: In animals, chronic administration of caffeine resulted in increased tiagabine concentrations but did not impair the effects (630).
  • TiclopidineTiclopidine: In humans, ticlopidine inhibited caffeine metabolism through the CYP1A2 enzyme system (196).
  • TramadolTramadol: In animal research, a synergistic effect on antinociception was noted between caffeine and tramadol (698).
  • TriazolamTriazolam: Caffeine is a known stimulant, thus it may antagonize the effects of CNS depressants. In humans, caffeine antagonized the effects of triazolam (178). In other human research, triazolam blocked the discriminative stimulus effects of caffeine (746).
  • Valproic acidValproic acid: In animals and review, chronic caffeine ingestion may reduce the anticonvulsant effects of valproate (257; 260). Acute doses of caffeine, however, were not found to alter the pharmacokinetic profile of sodium valproate in humans (261).
  • VasodilatorsVasodilators: In humans, caffeine inhibited adenosine-induced vasodilation (66; 68). In humans, pretreatment with caffeine had a lack of an effect on the cardiovascular effects of nifedipine; however, nifedipine reversed the vasopressor effects of caffeine (770). In animals, concurrent administration of nifedipine and caffeine inhibited the vasodilator response to ethyladenosine (771). This loss of coronary dilation and adenosine A3 receptor expression was reportedly due to changes in signaling pathways.
  • VasopressorsVasopressors: Theoretically, concurrent use of a vasopressor (or vasoconstrictor) with caffeine (a known vasoconstrictor) may result in additive effects and thereby increase blood pressure.
  • ZolpidemZolpidem: Caffeine is a known stimulant, thus it may antagonize the effects of CNS depressants. According to a clinical review, caffeine had additive effects on zolpidem sedation (181).
  • ZopicloneZopiclone: Caffeine is a known stimulant, thus it may antagonize the effects of CNS depressants. In humans, zopiclone antagonized the effects of caffeine better than caffeine did on zopiclone (178).

    • Caffeine/Herb/Supplement Interactions:

  • Agents that lower seizure thresholdAgents that lower seizure threshold: According to a review, methylxanthines like caffeine have been linked to seizures, likely due to adenosine-antagonizing effects (262). Theoretically, combined use of caffeine with other agents that may lower the seizure threshold may increase the risk of seizures.
  • Alzheimer's agentsAlzheimer's agents: Several preliminary studies have examined the effects of caffeine, tea, or coffee use on short and long-term memory and alertness (378; 711). Research on the effects of caffeine on Alzheimer's agents is lacking.
  • AnalgesicsAnalgesics: Caffeine is popularly added to analgesics to enhance their efficacy, an effect that is well documented (691; 692; 693; 694; 695; 696; 697; 712; 713; 698; 21; 699; 700; 701; 702). Some research suggests that the effect is small (703).
  • Antiasthma agentsAntiasthma agents: According to a systematic review and meta-analysis, caffeine improved airway function and reduced asthma symptoms in asthmatic patients (715; 716). In humans, caffeine acted as a bronchodilator (717; 718).
  • AntibacterialsAntibacterials: According to secondary sources, certain antibiotics may interfere with the breakdown of caffeine.
  • Anticoagulants and antiplateletsAnticoagulants and antiplatelets: According to anecdotal evidence, caffeine may prolong bleeding time. One study, however, found that coffee significant lack of an effect on fibrinogen, clotting factor VII activity, factor VIII antigen, protein C, and protein S (719). According to secondary information, green tea and coffee, including decaffeinated coffee, contain significant amounts of vitamin K.
  • AnticonvulsantsAnticonvulsants: In humans and animals, and according to reviews, acute and chronic caffeine ingestion reduced the anticonvulsant effects (257; 258; 259; 260; 261).
  • Antidepressant agents, monoamine oxidase inhibitors (MAOIs)Antidepressant agents, monoamine oxidase inhibitors (MAOIs): According to a case report, concurrent use of caffeine and serotonergic antidepressants increased the risk of serotonin syndrome (263). In animals and humans, caffeine and caffeine analogs inhibited monoamine oxidase isoforms A- and B- (MAO-A and -B) (264; 265; 266; 267; 268; 269; 270; 271).
  • Antidepressant agents,selective serotonin reuptake inhibitors (SSRI)Antidepressant agents,selective serotonin reuptake inhibitors (SSRI): According to a case report, concurrent use of caffeine and serotonergic antidepressants increased the risk of serotonin syndrome (263). In humans and laboratory research, certain SSRI antidepressants inhibited CYP1A2-mediated metabolism of caffeine (220; 224; 221).
  • Antiglaucoma agentsAntiglaucoma agents: In individuals with glaucoma, coffee consumption and caffeine intake increased intraocular pressure (280; 281; 282; 283). Theoretically, caffeine may reduce the effects of antiglaucoma agents.
  • AntilipemicsAntilipemics: In animals, clinical review, and meta-analysis, caffeine increased cholesterol and triglyceride levels (251; 252; 539).
  • AntineoplasticsAntineoplastics: In humans, caffeine increased the antitumor therapeutic effects of chemotherapy, particularly genotoxic agents that modify DNA (726; 727; 728; 729; 730; 731). In breast cancer cells, caffeine enhanced the inhibitory effects of genistein on cell proliferation and reversed genistein-induced G2/M cell cycle arrest (774).
  • Antiobesity agentsAntiobesity agents: In humans, caffeine, either alone or in combination with other weight-loss agents like ephedra, had weight-reducing effects (49; 732; 733; 251). In humans, concurrent use resulted in synergism in thermogenic response (734; 735; 736).
  • AntioxidantsAntioxidants: In animal research, intragastrically administered caffeine reduced the adverse effects of fluoride (23). Antioxidant capacity was increased following caffeine use in humans (24).
  • Antiulcer herbs and supplementsAntiulcer herbs and supplements: According to secondary sources, some antiulcer drugs may decrease the rate at which the body metabolizes caffeine.
  • Athletic performance enhancersAthletic performance enhancers: In systematic reviews and meta-analyses, caffeine improved exercise endurance and exerted ergogenic effects (775; 776; 777; 778; 779). Various mechanisms may play a role in these effects, such as enhanced fat utilization and consequent glycogen sparing, enhanced calcium mobilization, and phosphodiesterase inhibition.
  • B vitaminsB vitamins: According to secondary sources, caffeine consumption may result in a loss of B vitamins, including thiamine (B1), riboflavin (B2), and pyridoxine (B6).
  • Bitter orangeBitter orange: Theoretically, concurrent use of bitter orange (an agent that may increase blood pressure) and caffeine may result in adverse cardiovascular effects. However, in human research examining the adverse effects of a supplement containing caffeine and bitter orange extract, there was a lack of effect on cardiovascular endpoints (heart rate and blood pressure) (780).
  • Black teaBlack tea: Theoretically, concurrent use of caffeine with herbal agents containing caffeine, such as black tea, may result in increased caffeine levels and additive stimulant effects. In humans, caffeine concentrations increased following black tea consumption (781). In humans and according to reviews, concurrent use of L-theanine (an amino acid present in the tea plant) and caffeine resulted in increased cognitive activity (attention, memory) and alertness (782; 783; 368; 784; 785; 373), which was demonstrated by oscillatory alpha-band activity (373).
  • BronchodilatorsBronchodilators: In humans, caffeine has been found to act as a bronchodilator, as evidenced by improvements in pulmonary function test parameters (forced expiratory volume [FEV], forced vital capacity [FVC]) (717; 718). It may also reduce respiratory muscle fatigue (715; 716). Theoretically, concurrent use with other bronchodilating agents may cause additive effects.
  • Caffeine-containing agentsCaffeine-containing agents: Theoretically, concurrent use of caffeine with herbal agents containing caffeine (guarana, black tea, yerba mate, cola nut) may result in increased caffeine levels and additive stimulant effects.
  • CalciumCalcium: In a review and in humans, caffeine increased urinary excretion of calcium, which may be due to adenosine antagonism (307) and/or a reduction in renal reabsorption of calcium (308). However, research is inconsistent (749). According to review, the negative effects may be negligible in individuals who consume the recommended daily allowance of calcium (750).
  • CapsicumCapsicum: In humans, capsaicin, a major constituent of chili pepper, used in conjunction with caffeine resulted in reduced energy intake (786).
  • CoffeeCoffee: Coffee is known to contain significant amounts of caffeine. Theoretically, concurrent use of caffeine with herbal agents containing caffeine, such as coffee, may result in increased caffeine levels and additive stimulant effects. In humans, consumption of coffee resulted in increased concentrations of caffeine and its metabolites (in plasma) (787).
  • Cola nutCola nut: Theoretically, concurrent use of caffeine with herbal agents containing caffeine, such as cola nut, may result in increased caffeine levels and additive stimulant effects.
  • CreatineCreatine: In humans, acute caffeine consumption following six days of creatine use (and caffeine abstinence) yielded ergogenic activity (788). In other human research, creatine supplementation, in conjunction with short-term intake of caffeine, and caffeine loading have been found counteract the ergogenic effects of creatine (318; 319). The beneficial effects of creatine on relaxation time were offset by caffeine. Ischemic stroke was reported in an athlete who consumed caffeine (400-600mg), ephedra (40-60mg), and creatine monohydrate (6,000mg) in addition to other supplements for six weeks (789).
  • ContraceptivesContraceptives: In humans, exogenous estrogen inhibited caffeine clearance, metabolism, and elimination (214; 215; 216; 217; 218; 219) which may be due to inhibition of CYP1A1 (in the gut) and/or CYP1A2 (in the liver) (214; 219). In humans, higher levels of estradiol were associated with few or no subjective responses to caffeine, but lower levels of estradiol were associated with negative subjective responses to caffeine (540).
  • Cytochrome P450-metabolized herbs and supplementsCytochrome P450-metabolized herbs and supplements: In animal and laboratory research and according to clinical reviews, cytochrome P450 1A2 was involved in the metabolism of caffeine (183; 184; 185; 186; 187; 188; 189; 190; 191; 192; 193; 194; 195; 196; 197; 198; 199; 200; 201; 202; 203).
  • DamianaDamiana: In humans, the herbal preparation, YGD containing yerba mate (containing caffeine), guarana (containing caffeine), and damiana delayed gastric emptying, increased satiety, and induced weight loss (790).
  • DanshenDanshen: In laboratory research, danshen (single and continuous administration) inhibited the metabolism of caffeine to paraxanthine (191).
  • DiureticsDiuretics: In a review, caffeine was suggested to be a known diuretic (40). Theoretically, concurrent use with other diuretics may increase the risk of dehydration and electrolyte imbalances.
  • EchinaceaEchinacea: In vivo and according to a review, echinacea inhibited caffeine clearance and metabolism by inhibiting CYP1A2 activity (203; 225).
  • Ephedra (ma huang)Ephedra (ma huang): According to a meta-analysis and a systematic review, combined use of ephedra or ephedrine with caffeine increased the risk of psychiatric, cardiovascular, autonomic, and gastrointestinal adverse effects (350; 351). Ischemic stroke was reported in an athlete who consumed caffeine (400-600mg), ephedra (40-60mg), and creatine monohydrate (6,000mg) in addition to other supplements for six weeks (789).Although, some research has noted a lack of adverse cardiovascular effects with prescription ephedrine and caffeine (754). In humans, concurrent use resulted in synergism in thermogenic response (734; 735; 736). In obese humans, the combination of caffeine and ephedrine resulted in increased peak oxygen consumption (733)
  • GenisteinGenistein: In humans, genistein reduced CYP1A2 activity, as evidenced by a decreased urinary caffeine metabolite ratio (227). In breast cancer cells, caffeine enhanced the inhibitory effects of genistein on cell proliferation and reversed genistein-induced G2/M cell cycle arrest (774).
  • GeraniumGeranium: In humans, geranium extract with caffeine resulted in additive effects on the percent increase in rate pressure product, in a dose-dependent manner (317).
  • GrapefruitGrapefruit: In vivo, grapefruit juice decreased the clearance of caffeine and prolonged its half-life by CYP1A2 inhibition by grapefruit juice (226). However, this effect was reportedly small and not likely to have therapeutic consequence. In humans, grapefruit juice lacked effect on caffeine pharmacokinetic and pharmacodynamic parameters (791).
  • Green teaGreen tea: The evidence regarding the synergistic effects of (-)-epigallocatethin-3-O-gallate (EGCG), a catechin found in green tea, and caffeine are mixed. In humans, coadministration of caffeine and EGCG modulated the absorption and metabolism of EGCG (792). In other research, combined use increased UV protection in a synergistic manner (793). In one human study, a lack of synergism was noted between EGCG and caffeine on fat oxidation (794). In animal research, EGCG antagonized the anxiogenic-like effects and inhibited hyperactivity induced by caffeine (795; 796). According to a review and in humans, concurrent use of L-theanine (an amino acid present in the tea plant) and caffeine resulted in increased cognitive activity (attention, memory) and alertness (782; 783; 368; 784; 785; 373), which was demonstrated by oscillatory alpha-band activity (373)
  • GuaranaGuarana: Theoretically, concurrent use of caffeine with herbal agents containing caffeine, such as guarana, may result in increased caffeine levels and additive stimulant effects. According to a review, it was noted that combined use of guarana with caffeine resulted in caffeine toxicity (797).
  • HypertensivesHypertensives: According to a review, meta-analysis and clinical research, caffeine may increase blood pressure (242; 243; 244; 245; 246; 247; 248; 249; 250).
  • HypoglycemicsHypoglycemics: In animals and humans, and according to reviews, caffeine consumption may impair insulin sensitivity and increase blood glucose concentrations (272; 273; 251; 274; 275; 276; 277; 278).
  • HypotensivesHypotensives: According to a review, meta-analysis, and clinical research, caffeine may increase blood pressure (242; 243; 244; 245; 246; 247; 248; 249; 250) and theoretically may reduce the effects of antihypertensive agents.
  • ImmunosuppressantsImmunosuppressants: According to secondary sources, chronic and excessive amounts of caffeine may deplete the immune system. In humans, caffeine has been found to exert immunomodulatory effects, as evidenced by suppressed lymphocyte function and altered lymphocyte counts (49; 51; 53; 54). According to review and laboratory research, the immunomodulatory effects of caffeine may be due to inhibition of cAMP-phosphodiesterase (PDE), leading to increases in intracellular cAMP concentrations (55; 54).
  • InotropesInotropes: Theoretically, concurrent use of positive inotropes and caffeine may result in additive sympathomimetic effects.
  • Intraocular pressure-altering agentsIntraocular pressure-altering agents: In individuals with glaucoma, coffee consumption and caffeine intake has been found to increase intraocular pressure (280; 281; 282; 283). Theoretically, caffeine may reduce the effects of antiglaucoma agents.
  • Iron saltsIron salts: According to secondary sources, caffeine may inhibit iron absorption. Experts recommend separating caffeine and iron-containing foods or supplements by at least one hour.
  • KudzuKudzu: In vivo, puerarin, a constituent of Pueraria lobata (kudzu), induced CYP1A2 activity (234).
  • Liu Wei Di Huang WanLiu Wei Di Huang Wan: In vivo, Liu Wei Di Huang Wan, a traditional Chinese medicine (typically containing Rehmanniae radix, Corni fructus, Dioscoreae rhizome, Poria, and Paeoniae suffruticosa cortex), induced CYP1A2 and altered the metabolism of caffeine (190).
  • MelatoninMelatonin: In humans, coadministration of caffeine and melatonin increased the Cmax and AUC of melatonin, likely due to inhibition of CYP1A2 activity (236; 237).
  • MagnesiumMagnesium: In humans, caffeine decreased magnesium excretion, which may be due to a reduction in renal reabsorption of magnesium (309; 308; 310).
  • Ophiocordyceps sinensisOphiocordyceps sinensis: In laboratory research, fermented powder caterpillar fungus (Ophiocordyceps sinensis) induced CYP1A2, thereby accelerating the metabolism of caffeine (199).
  • PotassiumPotassium: In a review and in humans, caffeine, particularly in excessive amounts, may cause reduced potassium levels following exercise, due to stimulation of the sodium-potassium pump (311; 312; 313; 314; 315).
  • Potassium depleting herbs and supplementsPotassium depleting herbs and supplements: In a review and in humans, caffeine, particularly in excessive amounts, may cause reduced potassium levels following exercise, due to stimulation of the sodium-potassium pump (311; 312; 313; 314; 315). Theoretically, concurrent use of caffeine with other potassium-depleting agents may increase the risk of hypokalemia.
  • PhytoestrogensPhytoestrogens: In humans, exogenous estrogen inhibited caffeine clearance, metabolism, and elimination (214; 215; 216; 217; 218; 219), which may be due to inhibition of CYP1A1 (in the gut) and/or CYP1A2 (in the liver) (214; 219). In humans, higher levels of estradiol were associated with few or no subjective responses to caffeine, but lower levels of estradiol were associated with negative subjective responses to caffeine (540).
  • SedativesSedatives: Caffeine is a known stimulant, thus it may antagonize the effects of CNS depressants, which has been demonstrated in humans (176; 177; 178; 179; 180; 181).
  • StimulantsStimulants: Theoretically, concurrent use of caffeine with other stimulants may result in additive effects.
  • SympathomimeticsSympathomimetics: Theoretically, concurrent use of sympathomimetics and caffeine may result in increased blood pressure.
  • Sulfo-carrabioseSulfo-carrabiose: In humans, sulfo-carrabiose (a sugar-based anticellulite agent) combined with caffeine resulted in a reduction in lipogenesis and increased lipolysis (732)
  • TheanineTheanine: According to a review and in humans, concurrent use of L-theanine (an amino acid present in the tea plant) and caffeine resulted in increased cognitive activity (attention, memory) and alertness (782; 783; 368; 784; 785; 373), which was demonstrated by oscillatory alpha-band activity (373).
  • VasoconstrictorsVasoconstrictors: Theoretically, concurrent use of a vasopressor (or vasoconstrictor) with caffeine (a known vasoconstrictor) may result in additive effects and thereby increase blood pressure.
  • VasodilatorsVasodilators: In humans, caffeine inhibited adenosine-induced vasodilation (66; 68).
  • Vitamin CVitamin C: According to secondary information, caffeine consumption may result in a loss of vitamin C.
  • Vitamin KVitamin K: According to secondary information, green tea and coffee, including decaffeinated coffee, contain significant amounts of vitamin K.
  • Yerba mateYerba mate: Theoretically, concurrent use of caffeine with herbal agents containing caffeine, such as yerba mate, may result in increased caffeine levels and additive stimulant effects. In humans, the herbal preparation YGD, containing yerba mate (containing caffeine), guarana (containing caffeine), and damiana, delayed gastric emptying, increased satiety, and induced weight loss (790).
  • ZincZinc: According to secondary information, caffeine consumption may result in a loss of zinc.

    • Caffeine/Food Interactions:

  • Caffeine-containing foods and beveragesCaffeine-containing foods and beverages: Theoretically, concurrent use of caffeine with foods and/or beverages that contain caffeine (coffee, tea, chocolate, energy drinks) may result in increased caffeine levels and additive stimulant effects. Coffee is known to contain significant amounts of caffeine. In humans, consumption of coffee resulted in increased concentrations of caffeine and its metabolites (in plasma) (787).
  • Calcium-containing foodsCalcium-containing foods: In humans and according to a review, caffeine may increase urinary excretion of calcium, which may be due to adenosine antagonism (307) and/or a reduction in renal reabsorption of calcium (308). However, the research is inconsistent (749). According to review, the negative effects may be negligible in individuals who consume the recommended daily allowance of calcium (750). In humans, the effects of caffeinated coffee on bone density were counteracted by daily milk consumption (798).
  • Coconut products (coconut milk, coconut water)Coconut products (coconut milk, coconut water): In animals, caffeine with coconut milk or coconut water increased protein values and protein:RNA ratios and decreased alanine and aspartate amino transferase (ALT and AST) activity, leading to enhanced metabolizing enzyme induction and faster clearance and elimination of caffeine (240).
  • Grapefruit juiceGrapefruit juice: In vivo, grapefruit juice decreased the clearance of caffeine and prolonged its half-life by CYP1A2 inhibition by grapefruit juice (226). However, this effect was reportedly small and not likely to have therapeutic consequence. In humans, grapefruit juice lacked effect on caffeine pharmacokinetic and pharmacodynamic parameters (791).
  • High-carbohydrate mealHigh-carbohydrate meal: In humans, coingestion of caffeine with a high-carbohydrate meal resulted in reduced insulin sensitivity (273).
  • Iron-containing foodsIron-containing foods: According to secondary sources, caffeine may inhibit iron absorption. Experts suggest separating caffeine and iron-containing foods or supplements by at least one hour.
  • Isoflavone-containing foods (e.g., soybeans)Isoflavone-containing foods (e.g., soybeans): In humans, genistein (an isoflavone) reduced CYP1A2 activity, as evidenced by a decreased urinary caffeine metabolite ratio (227). In breast cancer cells, caffeine enhanced the inhibitory effects of genistein on cell proliferation and reversed genistein-induced G2/M cell cycle arrest (774).
  • Potassium-containing foodsPotassium-containing foods: According to a review and in humans, caffeine, particularly in excessive amounts, may cause reduced potassium levels following exercise, due to stimulation of the sodium-potassium pump (311; 312; 313; 314; 315).
  • Red pepperRed pepper: In humans, capsaicin, a major constituent of red pepper, used in conjunction with caffeine resulted in reduced energy intake, which may be due to increases in the SNS and PNS activity ratio, as measured by heart rate variability (786).
  • TeaTea: Theoretically, concurrent use of caffeine with herbal agents containing caffeine, such as black and green tea, may result in increased caffeine levels and additive stimulant effects. In humans, caffeine concentrations increased following black tea consumption (781). The evidence regarding the synergistic effects of (-)-epigallocatethin-3-O-gallate (EGCG), a catechin found in green tea, and caffeine is mixed. In humans, coadministration of caffeine and EGCG modulated the absorption and metabolism of EGCG (792). In other research, combined use increased UV protection in a synergistic manner (793). In one human study, a lack of synergism was noted between EGCG and caffeine on fat oxidation (794). In animal research, EGCG antagonized the anxiogenic-like effects and inhibited hyperactivity induced by caffeine (795; 796). In humans and according to reviews, concurrent use of L-theanine (an amino acid present in the tea plant) and caffeine may result in increased cognitive activity (attention, memory) and alertness (782; 783; 368; 784; 785; 373), which was demonstrated by oscillatory alpha-band activity (373)
  • Tryptophan-containing foodsTryptophan-containing foods: In animals, acute caffeine administration raised brain levels of tryptophan (799). In other animal research, single and repeated doses of caffeine increased hepatic tryptophan pyrrolase activity (the enzyme involved in liver tryptophan breakdown pathways) (800).
  • Vitamin B-containing foodsVitamin B-containing foods: According to secondary information, caffeine consumption may result in a loss of B vitamins, including thiamine (B1), riboflavin (B2), and pyridoxine (B6).
  • Vitamin C-containing foodsVitamin C-containing foods: According to secondary information, caffeine consumption may result in a loss of vitamin C.
  • Vitamin K-containing foodsVitamin K-containing foods: According to secondary information, green tea and coffee, including decaffeinated coffee, contain significant amounts of vitamin K.
  • Zinc-containing foodsZinc-containing foods: According to secondary information, caffeine consumption may result in a loss of zinc.

    • Caffeine/Therapies:

  • Electroconvulsive therapy (ECT)Electroconvulsive therapy (ECT): According to review, pretreatment with caffeine and other xanthines prolonged the duration of ECT seizures, but not necessarily efficacy (627).

    • Caffeine/Lab Interactions:

  • 5-HT (5-hydroxytryptamine, serotonin) levels5-HT (5-hydroxytryptamine, serotonin) levels: In animals, chronic administration of caffeine increased 5-HT in the brain (801; 802).
  • 5-Hydroxyindoleacetic acid (5-HIAA)5-Hydroxyindoleacetic acid (5-HIAA): In animals, chronic administration of caffeine increased 5-HIAA in the brain (801; 802; 799).
  • AdiponectinAdiponectin: In humans, consumption of coffee with caffeine was associated with increased adiponectin levels (803). In animals, caffeine administration resulted in increased adiponectin (804).
  • Anterior cerebral artery velocityAnterior cerebral artery velocity: In infants, caffeine administration resulted in a reduction at one hour postdose in mean anterior cerebral artery peak (cerebral blood flow velocity), with partial recovery at four hours (805).
  • Blood glucoseBlood glucose: In animals, humans, and according to reviews, caffeine consumption impaired insulin sensitivity and increased blood glucose concentrations (272; 273; 251; 806; 274; 275; 807; 391; 808; 276; 277; 278; 422; 809). Consumption of caffeinated coffee increased glucose levels during an oral glucose tolerance test (810).
  • Blood pressureBlood pressure: According to a review, meta-analysis, and clinical research, caffeine (alone or associated with caffeine-containing beverages) increased blood pressure (242; 243; 244; 245; 246; 247; 248; 249; 250; 150; 540; 541; 542; 543; 544; 545; 546; 547; 548; 549).
  • Body fatBody fat: In animals, chronic caffeine administration resulted in reduced body fat deposition (811).
  • Body weightBody weight: In animals, caffeine administration resulted in reduced body weight (804; 251).
  • Bone mineral density (BMD)Bone mineral density (BMD): In humans, caffeine may decrease BMD (299; 300; 301; 302; 303; 304; 305; 306)
  • CalciumCalcium: In a review and in humans, caffeine increased urinary excretion of calcium (307; 308).
  • Cardiac indexCardiac index: In a study on the effects of caffeine administration in premature infants with apnea of prematurity, intravenous administration of caffeine citrate increased the cardiac index in 100% of infants tested (812).
  • Cardiac stress testingCardiac stress testing: In humans, regular caffeine consumption (2-4 cups of coffee daily) prior to single-photon emission computed tomography (SPECT) myocardial perfusion imaging testing interfered with the validity (358). In humans, caffeine induced a false-negative using dipyridamole stress testing (66; 359; 360). Experts also suggest abstaining from caffeine prior to adenosine stress tests (361; 359).
  • Cerebral tissue oxygenation indexCerebral tissue oxygenation index: In infants, caffeine administration resulted in a reduction at one hour postdose in cerebral tissue oxygenation index (cerebral oxygenation), with partial recovery at four hours (805).
  • Coagulation panelCoagulation panel: According to anecdote, caffeine may prolong bleeding time. One study, however, found that coffee lacked a significant effect on fibrinogen, clotting factor VII activity, factor VIII antigen, protein C, and protein S (719).
  • CortisolCortisol: In humans, caffeine intake resulted in elevated cortisol, epinephrine, and norepinephrine (577; 579; 813). Additionally, in humans, caffeine ingestion prior to exercise has been found to increase cortisol, in a dose-dependent manner (814).
  • C-reactive proteinC-reactive protein: In humans, caffeine decreased C-reactive protein (CRP) (533).
  • Creatine kinaseCreatine kinase: In humans, caffeine ingestion before resistance exercise increased creatine kinase (CK) concentrations (52; 815).
  • CreatinineCreatinine: In preterm infants, caffeine increased creatinine clearance (816)
  • CytokinesCytokines: In animals, caffeine was associated with changes in cytokine profile, as evidenced by increased levels of interleukin (IL)-1alpha, IL-6, and tumor necrosis factor (TNF)-alpha, along with decreased IL-10 (817). In preterm infants, caffeine correlated with changes in TNF-alpha and IL-1beta and inversely correlated with IL-10 (818). In humans, consumption of coffee with caffeine increased IL-6 levels (803).
  • ElectrocardiogramElectrocardiogram: In healthy human volunteers, caffeine and caffeinated coffee did not produce changes on ECG variables (including PR, QRS, QT, QTc, and RR intervals, or QT and QTc interval dispersion) (819; 820). In animals, however, caffeine altered the QT interval (821). Using ECG, intravenous caffeine increased stroke volume and cardiac output in premature infants (812).
  • Electroencephalogram (EEG)Electroencephalogram (EEG): In humans, caffeine decreased EEG alpha activity (822).
  • ElectrolytesElectrolytes: In a review, caffeine, a known diuretic, altered electrolyte levels (602; 603). However, in humans, black tea containing caffeine had similar effects to that of water on hydration (823).
  • EpinephrineEpinephrine: In humans, caffeine intake increased epinephrine levels (576; 577; 578; 579; 824). Increases were also noted during exercise (391; 423; 422).
  • Erythropoietin (serumErythropoietin (serum): In humans and animals, theophylline, a methylxanthine and nonselective adenosine antagonist similar to caffeine, reduced erythropoietin production (825; 826). In preterm infants, caffeine demonstrated a similar effect to that of theophylline on serum erythropoietin concentrations (827).
  • EstrogenEstrogen: In epidemiological research, caffeine consumption was positively associated with the estrogen metabolite 2-hydroxyestrone (2-OHE1) (828); individuals with high caffeine consumption had higher levels of 2-OHE1 compared to those with low caffeine intake.
  • Flow-mediated dilation (brachial artery)Flow-mediated dilation (brachial artery): In humans, caffeine improved endothelial function, as evidenced by increased brachial artery flow-mediated dilation (FMD) (533).
  • Fractional exhaled nitric oxide (FeNO)Fractional exhaled nitric oxide (FeNO): In humans, ingestion of a caffeine-containing drink resulted in a modest increase in fractional exhaled nitric oxide (FeNO), a noninvasive marker of eosinophilic airway inflammation (656).
  • Free fatty acidsFree fatty acids: In humans, caffeine increased pre- and postexercise free fatty acid levels (396; 390; 405; 808; 423).
  • Glucagon-like peptide-1 active (GLP-1a)Glucagon-like peptide-1 active (GLP-1a): In humans, consumption of caffeinated coffee was associated with increased glucagon-like peptide-1 active (GLP-1a) following an oral glucose tolerance test (810).
  • Glucosedependent insulinotropic polypeptide (GIP)Glucose-dependent insulinotropic polypeptide (GIP): In humans, consumption of caffeinated coffee was associated with increased glucose-dependent insulinotropic polypeptide (GIP) following an oral glucose tolerance test (810).
  • GlycerolGlycerol: In humans, caffeine ingestion prior to exercise resulted in increased glycerol levels (391).
  • Growth hormoneGrowth hormone: In humans, caffeine intake resulted in elevated growth hormone (579).
  • Heart rateHeart rate: In humans and animals, caffeine caused increases in heart rate or tachycardia (heart rate above 100 beats per minute) (147; 148; 149; 150; 151). In a study on the effects of caffeine administration in premature infants with apnea of prematurity, intravenous administration of caffeine citrate increased heart rate infants tested (812).
  • Heat shock protein-72 (hsp-72)Heat shock protein-72 (hsp-72): In humans, caffeine increased plasma levels of hsp-72 after exercise in the heat, but not salivary hsp-72 (829).
  • HomocysteineHomocysteine: In a review and in humans, caffeine increased blood homocysteine concentrations (539; 830; 831; 832).
  • InsulinInsulin: In animals, acute administration of caffeine increased blood insulin levels; however, chronic daily caffeine injections lowered serum insulin levels (809).
  • Intraocular pressureIntraocular pressure: In individuals with glaucoma, coffee consumption and caffeine intake increased intraocular pressure (280; 281; 282; 283).
  • Iron levelsIron levels: According to secondary sources, caffeine may inhibit iron absorption, which may increase the risk of iron deficiency.
  • LactateLactate: In humans, caffeine ingestion prior to exercise increased lactate levels (402; 391; 392; 422; 423).
  • Lipid profileLipid profile: According to clinical review, meta-analysis and animal research, caffeine increased cholesterol and triglyceride levels (251; 252; 539; 833).
  • Lithium levelsLithium levels: According to human data, caffeine withdrawal produced lithium toxicity in patients maintained on high-baseline lithium blood levels (316). In heavy caffeine-consuming, lithium-maintained patients, abruptly discontinuing daily caffeine consumption resulted in an increase (24%) in lithium blood levels in one study.
  • Liver function testsLiver function tests: In humans, caffeine consumption had a lack of an effect on blood levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP) and gamma-glutamyl transferase (gamma-GT) (815). Regular daily coffee consumption lowered levels of these enzymes dose-dependently (834).
  • MagnesiumMagnesium: In humans, caffeine decreased magnesium excretion, which may be due to a reduction in the renal reabsorption of magnesium (309; 308; 310).
  • Magnetic resonance imaging (MRI)Magnetic resonance imaging (MRI): In humans, the blood oxygenation level dependent (BOLD) signal used in most functional magnetic resonance imaging (fMRI) studies was increased following acute caffeine ingestion (835).
  • Nitric oxideNitric oxide: In patients with asthma, consumption of a standard cup of caffeinated coffee lacked significant effects on exhaled nitric oxide (FENO) measurements compared with control (836).
  • NorepinephrineNorepinephrine: In humans, caffeine intake caused increases in norepinephrine (576; 577; 578; 579). Increases were also noted during exercise (391; 423; 422).
  • Parathyroid hormoneParathyroid hormone: In humans, caffeine intake was not associated with altered parathyroid hormone (PTH) (837).
  • PotassiumPotassium: According to a review and in humans, caffeine, particularly in excessive amounts, may cause reduced potassium levels following exercise due to stimulation of the sodium-potassium pump (311; 312; 313; 314; 315).
  • ProteinProtein: In humans, caffeine increased plasma levels of total protein (829).
  • Pulmonary function testsPulmonary function tests: In humans, caffeine acted as a bronchodilator, as evidenced by improvements in pulmonary function test parameters (forced expiratory volume [FEV], maximum mid-expiratory flow [FEF25-75], forced vital capacity [FVC]) (715; 290; 432; 717; 718).
  • Sex-hormone globulinSex-hormone globulin: In humans, caffeinated coffee was associated with sex hormone-binding globulin levels but not sex hormones (838).
  • Stroke volumeStroke volume: In a study on the effects of caffeine administration in premature infants with apnea of prematurity, intravenous administration of caffeine citrate increased stroke volume in infants tested (812).
  • TemperatureTemperature: In humans, caffeine intake increased tympanic temperature and mean body temperature during physical activity (664).
  • TestosteroneTestosterone: In humans, caffeine ingestion prior to exercise increased testosterone concentrations during exercise in a dose-dependent manner (814).
  • Theophylline levelsTheophylline levels: In humans, caffeine reduced theophylline clearance, increased elimination half-life, and increased serum levels (468).
  • Tidal volumeTidal volume: In humans, caffeine increased tidal volume (the amount of air moved into the lungs during a single breath) during exercise (401).
  • TryptophanTryptophan: In animals, acute caffeine administration raised brain levels of tryptophan (799). In other animal research, caffeine increased hepatic tryptophan pyrrolase activity (the enzyme involved in liver tryptophan breakdown pathways) (800).
  • TyrosineTyrosine: In animals, acute administration of caffeine reduced blood levels of tyrosine (809).
  • UrateUrate: According to secondary sources, caffeine may cause false elevations in serum urate.
  • Vanillylmandelic acid (VMA)Vanillylmandelic acid (VMA): According to secondary sources, caffeine may cause small increases in VMA concentrations and yield false-positive results for the diagnosis of pheochromocytoma or neuroblastoma.
  • Vitamin C levelsVitamin C levels: According to secondary information, caffeine consumption may result in a loss of vitamin C.
  • Vitamin K levelsVitamin K levels: According to secondary information, green tea and coffee, including decaffeinated coffee, contain significant amounts of vitamin K.
  • White blood cellsWhite blood cells: In humans, caffeine ingestion before resistance exercise increased total leukocyte count, neutrophils, and monocytes, but not significantly compared to placebo (52). In other human research, caffeine reduced alterations in circulating leukocyte and neutrophil counts after exercise (49).
  • ZincZinc: According to secondary information, caffeine consumption may result in a loss of zinc.