Caffeine

Common Names: Theobroma cacao (Cacao, Chocolate tree), Cola nitida, Cola acuminata seed (Cola nut), Coffea arabica (Coffee), Paullinia cupana seeds (Guarana), Ilex paraguayensis leaves (Mate), and Camellia sinensis (Tea)

Clinical Name: Caffeine

Summary

Caffeine

overview of interactions:
• food/herbal constituent affected by drug: Beta-adrenergic Blockers

• food/herbal constituent affected by drug: Calcium Channel Blockers, especially Verapamil

• Coffea arabica (Coffee) and Camellia sinensis (Tea) affecting drug performance: Haloperidol

• food/herbal constituent affecting drug performance and toxicity: Lithium

• food affecting drug performance and toxicity: Phenelzine

• food/herb constituent affecting drug performance and toxicity: Theophylline

• herbal constituent affected by drug: Verapamil

Note: See also the "Xanthines" topic in the Neuroendocrine subsection of Herb Groups.

function: Central nervous system stimulant.

dietary sources: Theobroma cacao (Cacao, Chocolate tree), Cola nitida, Cola acuminata seed (Cola nut), Coffea arabica (Coffee), Paullinia cupana seeds (Guarana), Ilex paraguayensis leaves (Mate), and Camellia sinensis (Tea)

side effects: Caffeine induces calcium excretion and regular consumption has been found to be associated with bone loss in some studies. Other potential side effects include anxiety, fatigue, insomnia, increased heart rate and hypertension.



Interactions

food/herbal constituent affected by drug: Beta-adrenergic Blockers

• mechanism: Caffeine is a naturally occurring constituent of many plants used for beverages. Theophylline is a methylxanthine that occurs naturally in tea. Both substances may interfere with the activity of beta-blockers. Furthermore, the combination of these drugs may result in elevated theophylline levels in the body, especially in individuals who smoke.

• report: Hughes and Goldstein reported a case of birth defects following maternal exposure to ergotamine, beta blockers, and caffeine during the first four months of pregnancy. The authors hypothesized that the concomitant use of multiple vasoconstrictive agents during pregnancy produced fetal vasoconstriction, tissue ischaemia and subsequent malformation, resulting in early arrested cerebral maturation and paraplegia.
(Hughes HE, Goldstein DA. J Med Genet. 1988 Jun;25(6):396-399.)

• nutritional concerns: Individuals taking beta blockers might benefit from avoiding caffeine-containing beverages. Individuals being treated for hypertension and heart problems might generally benefit from avoiding consumption of caffeine since it may aggravate these conditions. As indicated by the report above, women who are pregnant or at risk of such should be especially cautious about combining beta-blockers, caffeine and ergotamine.

food/herbal constituent affected by drug: Calcium Channel Blockers, especially Verapamil

• mechanism: Verapamil inhibits the metabolism and/or clearance of caffeine, thereby increasing its stimulant effects.
(Smits P, Thien T, van 't Laar A. Eur J Clin Pharmacol 1986;30(2):171-175; Stockey IH. 1996.)

• nutritional concerns: Individuals taking verapamil might benefit from avoiding caffeine-containing beverages while taking verapamil. Individuals being treated for arrythmias, angina and hypertension might generally benefit from avoiding consumption of caffeine since it may aggravate these conditions.

food/herbal constituent affected by drug: Fluvoxamine

• mechanism: Fluvoxamine inhibits the metabolism and/or clearance of caffeine, thereby increasing its stimulant effects. Fluvoxamine is a very potent inhibitor of the liver enzyme CYP1A2, which is the major P450 catalyzing the biotransformation of caffeine. Fluvoxamine also causes pharmacokinetic interactions with other drugs metabolized by CYP1A2, such as theophylline, imipramine, tacrine and clozapine. Interaction between caffeine and fluvoxamine can lead to lowering of total clearance of caffeine by 80% during fluvoxamine intake.

• research: Jeppesen et al (1996) conducted a randomized, in vivo, cross-over study including eight healthy volunteers looking at the interaction between a daily oral dose of 200 mg caffeine and fluvoxamine 50 mg per day for 4 days and 100 mg per day for 8 days. During fluvoxamine, the median of the total clearance of caffeine decreased and the half-life increased from 5 to 31 h. These findings indicate that intake of caffeine during fluvoxamine treatment may lead to caffeine intoxication. Two years later, Rasmussen evaluated this interaction in vitro in human liver microsomes and confirmed that fluvoxamine was a very potent inhibitor of the metabolism of caffeine in vitro.
(Jeppesen U, et al. Pharmacogenetics 1996 Jun;6(3):213-222; Rasmussen BB, et al. Pharmacol Toxicol 1998 Dec;83(6):240-245.)

• nutritional concerns: Individuals taking fluvoxamine might benefit from avoiding caffeine-containing beverages while taking fluvoxamine. Individuals being treated for anxiety and sleep disorders might generally benefit from avoiding consumption of caffeine since it may aggravate these conditions.

Coffea arabica (Coffee) and Camellia sinensis (Tea) affecting drug performance: Haloperidol

• mechanism: Various reports and in vitro studies have observed that coffee and tea can cause precipitation of haloperidol. Such an interaction, were it to similarly occur in human patients, could potentially reduce absorption of haloperidol and its subsequent therapeutic efficacy. Other animal studies on chlorpromazine, another antipsychotic drug, found that drug's cataleptic effects were abolished when administered with tea, most likely due to its precipitation (in vitro) by non-caffeine constituents. Based on this, and similar, evidence speculation has been raised that the methylxanthines in coffee and tea may act as dopamine agonists.
(Hirsch SR. Lancet. 1979 Nov 24;2(8152):1130-1131; Kulhanek F, et al. Lancet. 1979 Nov 24;2(8152):1130; Cheeseman HJ, Neal MJ. Br J Clin Pharmacol. 1981 Aug;12(2):165-169; Lasswell WL Jr, et al. J Pharm Sci. 1984 Aug;73(8):1056-1058.)

• dietary concerns: Pending definitive research individuals taking haloperidol should avoid consuming coffee and tea within one hour prior to or two hours after taking the drug. Some authors have cautioned that this warning should be extended to include cola drinks.

food/herbal constituent affecting drug performance and toxicity: Lithium

• adverse drug effect: Lithium therapy often produces hand tremor as a side effect. Caffeine can also cause anxiety and tremor.

• report/research: Jefferson reported two cases where women taking lithium experienced increased tremors after they stopped drinking coffee, presumably due to a reduction in renal lithium clearance. One woman had been drinking seventeen cups of coffee per day; her lithium levels showed a 50% increase when she kept taking the lithium but stopped consuming the coffee. She stabilized after her lithium dosage was reduced by 20%. Likewise, Mester et al tracked eleven individuals taking lithium after they stopped consuming an average of four to six cups of coffee per day. They found that the subjects reported a greater incidence of anxiety and depression and demonstrated higher blood levels of lithium within two weeks. Further, lithium levels, as well as ratings on depression and anxiety, returned to their original baseline status two weeks after these subjects returned to their previous coffee consumption patterns.

• dietary concerns: Pending further research, individuals taking lithium should avoid suddenly changing their level of coffee or other sources of caffeine. The reduction of caffeine intake may improve the health and metabolic balance of many individuals suffering from the conditions for which lithium is prescribed, particularly mania. However, the prescribing physician or a pharmacist should be consulted if changes in caffeine consumption patterns are desired or anticipated.
(Jefferson JW. Clin Psychiatry 1988 Feb;49(2):72-73; Mester R, et al. Biol Psychiatry. 1995 Mar 1;37(5):348-50.

food affecting drug performance and toxicity: Phenelzine

• nutritional concerns: Excessive amounts of caffeine or chocolate can also potentiate hypertensive reactions. Also, reports have been published of two cases were reported involving men who were being treated with phenelzine and experienced restlessness, agitation, tremor, and insomnia after drinking large quantities of cola drinks containing aspartame.
(Shader RI, Greenblatt DJ. J Clin Psychopharmacol 1985 Apr;5(2):65.)

food/herb constituent affecting drug performance and toxicity: Theophylline

• mechanism: Theophylline is a methylxanthine that occurs naturally in tea and is chemically similar to caffeine and theobromine, found in cocoa beans. Individuals taking theophylline should avoid consuming large amounts of coffee, colas, cocoa, chocolate, guaraná, tea, and caffeine-containing supplements. These foods may increase the activity and side effects of the medication since they all contain a chemical with effects similar to theophylline.

• nutritional concerns: Individual using theophylline should eliminate or at least minimize their intake of foods and drinks that contain theophylline and caffeine. While this reaction may not be common individual variances in theophylline pharmacokinetics are well known and toxicity reactions can be severe and even life-threatening. Individuals taking theophylline who are concerned with potential interactions between such substances and their medication should consult with their prescribing physician and/or pharmacist.

herbal constituent affected by drug: Verapamil

• mechanism: Verapamil inhibits the metabolism and/or clearance of caffeine, thereby increasing its stimulant effects.
(Stockey IH. 1996.)

• nutritional concerns: Individuals taking verapamil might benefit from avoiding caffeine-containing beverages while taking verapamil. Individuals being treated for arrythmias, angina and hypertension might generally benefit from avoiding consumption of caffeine since it may aggravate these conditions.

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Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.


References

Brinker Francis. Herb Contraindications and Drug Interactions. Second Ed. Sandy, OR: Eclectic Institute, Inc., 1998.

Cheeseman HJ, Neal MJ. Interaction of chlorpromazine with tea and coffee. Br J Clin Pharmacol. 1981 Aug;12(2):165-169.
Abstract: 1 The interaction between phenothiazine neuroleptics with tea and coffee was studied in vitro. 2 Filtered infusions of tea and coffee caused precipitation of all the neuroleptics studied. Tea always caused a heavier precipitate than coffee. 3 The constituent or constituents of tea and coffee responsible for precipitating the neuroleptics was not identified. Solutions of caffeine, caffeine citrate and sodium chloride did not form a precipitate with chlorpromazine but precipitates were formed by sodium salicylate, sodium benzoate and trisodium citrate. 4 The interaction between chlorpromazine (CPZ) and tea was studied quantitatively using radiolabelled drug and it was found that the precipitation of [3H]-CPZ with a given quantity of tea was 'saturable'. The proportion of CPZ precipitated by a 'standard cup of tea' was 80% at low doses of the drug (10-40 mg) whilst at high doses (800 mg), the proportion of the drug precipitated was approximately 20%. 5 The interaction was further studied in vivo by the oral administration of tea and CPZ to rats. The cataleptic effect of CPZ was significantly reduced by the simultaneous administration of tea and this was apparently not due to the caffeine present in tea. 6 The results suggest that a substantial proportion of orally administered neuroleptic may be precipitated as a highly insoluble compound if coffee, or more especially tea, is taken close to drug administration. This interaction might affect the absorption of phenothiazines given orally to patients.

Fligner CL, Opheim KE, Ainardi V. Caffeine and its metabolites in caffeine overdose cause falsely elevated serum theophylline measurements. Vet Hum Toxicol 1984;26 Suppl 2:28.

Hirsch SR. Precipitation of antipsychotic drugs in interaction with coffee or tea. Lancet. 1979 Nov 24;2(8152):1130-1131. (Letter )

Holt GA. Food and Drug Interactions. Chicago: Precept Press, 1998.

Hughes HE, Goldstein DA. Birth defects following maternal exposure to ergotamine, beta blockers, and caffeine. J Med Genet. 1988 Jun;25(6):396-399.
Abstract: Ergotamine exposure during pregnancy has been suggested to cause birth defects which have a vascular disruptive aetiology. The present case provides additional support for the possible adverse fetal effects of exposure to ergotamine, caffeine, and propranolol during the first four months of pregnancy. At birth the infant showed evidence of early arrested cerebral maturation and paraplegia. The nature of these defects suggests a primary vascular disruptive aetiology. We hypothesise that ergotamine, acting either alone or in synergy with propranolol and caffeine, produced fetal vasoconstriction resulting in tissue ischaemia and subsequent malformation. This case raises the possibility that fetal malformation may result from concomitant use of multiple vasoconstrictive agents during pregnancy.

Jefferson JW. Lithium tremor and caffeine intake: two cases of drinking less and shaking more. J Clin Psychiatry 1988 Feb;49(2):72-73.
Abstract: Lithium tremor worsened in two patients when caffeine (coffee) was eliminated from their diets. An associated reduction in renal lithium clearance resulting in increased serum lithium level is thought to be the mechanism.

Jeppesen U, Loft S, Poulsen HE, Brsen K. A fluvoxamine-caffeine interaction study. Pharmacogenetics 1996 Jun;6(3):213-222.
Abstract: The selective serotonin reuptake inhibitor fluvoxamine is a very potent inhibitor of the liver enzyme CYP1A2, which is the major P450 catalysing the biotransformation of caffeine. Thus, a pharmacokinetic study was undertaken with the purpose of documenting a drug-drug interaction between fluvoxamine and caffeine. The study was carried out as a randomized, in vivo, cross-over study including eight healthy volunteers. In Period A of the study, each subject took 200 mg caffeine orally, and in Period B, the subjects took fluvoxamine 50 mg per day for 4 days and 100 mg per day for 8 days. On day 8 in Period B, the subjects again ingested 200 mg caffeine. After caffeine intake, blood and urine were sampled at regular intervals. Caffeine and its three primary demethylated metabolites, paraxanthine, theobromine and theophylline in plasma and the same four compounds plus 11 more metabolites in urine were assayed by HPLC. During fluvoxamine, the median of the total clearance of caffeine decreased from 107 ml min-1 to 21 ml min-1 and the half-life increased from 5 to 31 h. The N3-demethylation clearance of caffeine to paraxanthine decreased from 46 to 9 ml min-1; the N1- and N7-demethylation clearances decreased from 21 to 9 ml min-1 and from 14 to 6 ml min-1, respectively. The results confirm that CYP1A2 is the main enzyme catalysing the biotransformation of caffeine, in particular the N3-demethylation and partly the N1- and N7-demethylation. The results indicate that intake of caffeine during fluvoxamine treatment may lead to caffeine intoxication. Finally, our study provides additional evidence that fluvoxamine can be used to probe CYP1A2 in drug metabolism.

Jung H, Peregrina AA, Rodriguez JM, Moreno-Esparza R. The influence of coffee with milk and tea with milk on the bioavailability of tetracycline. Biopharm Drug Dispos 1997 Jul;18(5):459-463.
Abstract: The effect of milk added to coffee or black tea on the bioavailability of tetracycline was evaluated in 12 healthy volunteers according to a crossover design. Results showed that even a small volume of milk containing extremely small amounts of calcium severely impair the absorption of the drug, so that the presence of this metal ion should be carefully controlled in order to avoid decreasing the available tetracycline.

Kerns II W, Kline J, Ford MD.  Blocker and calcium channel blocker toxicity.  Emerg Med Clinics of NA 1994;12:2:365-390.

Kulhanek F, et al. Kulhanek F, Linde OK, Meisenberg G. Precipitation of antipsychotic drugs in interaction with coffee or tea. Lancet. 1979 Nov 24;2(8152):1130. (Letter)

Lasswell WL Jr, Weber SS, Wilkins JM. In vitro interaction of neuroleptics and tricylic antidepressants with coffee, tea, and gallotannic acid. J Pharm Sci 1984 Aug;73(8):1056-1058.
Abstract: The in vitro interaction of selected drugs with coffee, tea, gallic acid, and gallotannic acid was examined by mixing solutions of drug with each of these four preparations. Results of these experiments indicate that significant precipitation occurs for a variety of agents, including several phenothiazines, amitriptyline, haloperidol, imipramine, and loxapine. The strong complex which is formed between these drugs and tannins is probably the basis of the interaction of these drugs with coffee and tea. Although precipitates did occur with a number of neuroleptics, two members of this drug class, thiothixene and molindone, failed to interact with the solutions used.

Mester R, Toren P, Mizrachi I, Wolmer L, Karni N, Weizman A. Caffeine withdrawal increases lithium blood levels. Biol Psychiatry. 1995 Mar 1;37(5):348-350.

Pronsky Z. Powers and Moore's Food-Medications Interactions. Ninth Edition. Food-Medication Interactions. Pottstown, PA, 1991.

Rasmussen BB, Nielsen TL, Brosen K. Fluvoxamine is a potent inhibitor of the metabolism of caffeine in vitro. Pharmacol Toxicol 1998 Dec;83(6):240-245.
Abstract: The selective serotonin re-uptake inhibitor, fluvoxamine, is a very potent inhibitor of CYP1A2, and accordingly causes pharmacokinetic interactions with drugs metabolised by CYP1A2, such as caffeine, theophylline, imipramine, tacrine and clozapine. Interaction between caffeine and fluvoxamine has been described in vivo, leading to lowering of total clearance of caffeine by 80% during fluvoxamine intake. The main purpose of the present study was to evaluate this interaction in vitro in human liver microsomes. A high-performance liquid chromatography method was developed in order to assay 1,3-dimethylxanthine, 1,7-dimethylxanthine, 3,7-dimethylxanthine and 1,3,7-trimethyluric acid formed from caffeine by human liver microsomes. The limit of detection was 0.06 nmol.mg protein-1.hr-1. As expected, fluvoxamine was a very potent inhibitor of the formation of the N-demethylated caffeine metabolites, displaying Ki values of 0.08-0.28 microM. The formation of 1,7-dimethylxanthine was virtually abolished by 10 microM of fluvoxamine, indicating that the N3-demethylation of caffeine is almost exclusively catalysed by CYP1A2. The CYP3A4 inhibitors, ketoconazole and bromocriptine, inhibited 1,3,7-trimethyluric acid formation with Kis of 0.75 microM and 5 microM, respectively, thus further supporting the involvement of CYP3A4 in the 8-hydroxylation of caffeine. The study shows that fluvoxamine, as expected, is a potent inhibitor of the metabolism of caffeine in vitro.

Robinson C, Weigly E. Basic Nutrition and Diet Therapy. New York: MacMillan, 1984.

Roe DA. Diet and Drug Interactions. New York: Van Nostrand Reinhold, 1989.

Shader RI, Greenblatt DJ. Phenelzine and the dream machine-ramblings and reflections. J Clin Psychopharmacol 1985 Apr;5(2):65. (Editorial)

Smits P, Thien T, van 't Laar A. Influence of slow calcium-channel blockade on the cardiovascular effects of coffee. Eur J Clin Pharmacol 1986;30(2):171-175.

Stockey IH. Drug Interactions. Fourth Edition, London: Pharmaceutical Press, 1996.

Threlkeld DS, ed. Diuretics and Cardiovasculars, Calcium Channel Blocking Agents. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Nov 1992.

Wolf LR. Adrenergic Blocker Toxicity, in Haddad L, Shannon MW, Winchester JF (eds): Clinical Management of Poisoning and Drug Overdose, 3rd ed.  Pennsylvania: WB Sanders Co, 1998:1031-1040.