Drug and Food Interactions with Caffeine

Enzymes are complex proteins that act as catalysts to help other organic molecules to undergo chemical reactions.  Over the last thirty years, scientists have made many discoveries about the role that enzymes play in the metabolism of drugs.  Their findings have revealed surprising ways drugs interact with other drugs—and with foods—to make their effects stronger and longer lasting or weaker and of shorter duration.  Don’t expect your doctor to tell you about the drug and food interactions we discuss in this appendix—few pharmacists and even fewer physicians were ever taught much about them in school. 

The “human polycyclic aromatic hydrocarbon-inducible cytochrome P450(CYP1) family” of enzymes, otherwise called “CYP450” enzymes, was first linked to drug metabolism in the 1970’s, and, since then, the many ways in which CYP450 enzymes affect drug interactions have become one of the exciting topics in the world of pharmacology.  When a medication is metabolized by a CYP450 enzyme, the amount of CYP450 available can determine the speed with which the medication is cleared from the body.  Some medications compete with each other for CYP450 enzymes, while others increase or decrease the production of these enzymes, and, in each case, the rate of clearance of the medications in question is correspondingly increased or decreased. 

In fact, CYP450 enzymes have many functions in addition to metabolizing drugs.  They also metabolize environmental toxins, dietary components, and various endogenous substances (e.g., steroids, prostaglandins) that are produced within the body, and the activity of these substances is also a factor in determining the speed at which various drugs are cleared from the body.  Usually, CYP450 enzymes inactivate a drug or compound, but sometimes they make it more active.

 

__________________________________________________________________________
One Reason Caffeine’s Half-Life Varies So Greatly

As we will see, caffeine is metabolized by the liver enzyme CYP1A2.  However, CYP1A2 exhibits “pronounced interindividual variation in activity.”[i]  The speed with which caffeine is cleared from the body is proportional to the amount of available CYP1A2, and highly variable activity levels of the enzyme means highly variable half-life for caffeine users.  That’s one reason that two cups of coffee in the late afternoon might not keep you awake at night, while one cup in the late morning can disturb your neighbor’s sleep.

_____________________________________________________________

CYP1A2 Enzyme

 Most of the caffeine you ingest is metabolized by a CYP450 liver enzyme called “CYP1A2.”   This means that the body uses CYP1A2 to “demethylate” caffeine molecules, transforming them into other substances, chiefly paraxanthine, which are ultimately excreted in the urine.  CYP1A2 is one of the most abundant CYP liver enzymes and is responsible for the metabolism of several clinically important medications.

As we explain above, there are three ways in which a drug can influence the amount of CYP450 that is available to metabolize other drugs:  It can use some of the enzymes; it can inhibit the production of the enzymes; or it can stimulate the production of the enzymes.  

When caffeine and another drug are each metabolized by CYP1A2, they compete for the enzyme.  As a result, each is said to partially block the “enzymatic metabolism” of the other, and the speed with which they are excreted from the body decreases.  When another drug interferes with the production of CYP1A2, the speed with which caffeine is excreted is also reduced.  Finally, when a drug increases the production of CYP1A2, the speed at which caffeine is metabolized will also be increased.

It was recently discovered that CYP1A2 is the major enzyme used by the body to metabolize not only caffeine but many drugs that are commonly used as medications.[ii]   Other drugs metabolized by this enzyme include theophylline, warfarin, and several antidepressants and antipsychotics.  As we have explained, when caffeine is introduced, there is less of the enzyme available to metabolize these drugs.  What this means is that each acts as a metabolic inhibitor—and sometimes as a very potent metabolic inhibitor—of the other, slowing down the speed with which the body can “break down” or eliminate the drugs.   The result is that blood level of these drugs, or of caffeine, or of both increases.  For example, a woman who was a heavy coffee drinker who was also taking clozapine (an anti-schizophrenic medication) was found to have about 2 ½ times higher blood levels of the drug when she took caffeine.  Because schizophrenic patients commonly consume remarkably high doses of caffeine, such interactions could conceivably constitute a relatively common problem for patients taking that medication.

CAFFEINE MUGS GALORE!!!!

Alternatively, other drugs can inhibit the production of CYP1A2 and in this way dramatically slow the metabolism of caffeine and inhibit the clearance of caffeine from the body.  Several antibiotics and antidepressants are potent inhibitors of several CYP450 enzymes, including CYP1A2.  For example, the selective serotonin reuptake inhibitors Prozac (fluoxetine), Paxil (paroxetine), and  Luvox (fluvoxamine), commonly used to treat depression, social anxiety, and obsessive eating disorders, are inhibitors of the CYP1A2,[iii] and therefore interfere with the body’s ability to catalyze the biotransformation of caffeine.  Luvox is a particularly potent inhibitor of the enzyme and people taking it can “exhibit unexpected toxicity or intolerance to caffeine as plasma levels of caffeine rise.”[iv]  Research has shown that when Luvox is being used in treatment, the half-life of a caffeine dose between 100mg and 200mg increases 500%,  that is, from 5 hours to over 30 hours![v],[vi]  If large amounts of caffeine are consumed over a period of several days, such an enormous extension of caffeine’s activity could lead to blood levels associated with undesirable side effects, including sustained sleep disturbances, anxiety, and even, in extreme cases, in which unusually large amounts of caffeine had been consumed, caffeine intoxication. 

The consequences of these drug interactions are highly variable.  Caffeine may cause therapeutic failure in patients receiving lithium (an antipsychotic), may cause toxic reactions in patients receiving clozapine (another antipsychotic), may augment the efficacy of aspirin and acetainophen (Tylenol), and may have no significant consequences, despite metabolic interactions, on the effects of mexiletine (an antiarrhythmic).[vii]  For this reason, some scientists have suggested that the FDA should require that drugs interacting with caffeine be labeled with an advisory about these interactions.[viii]

Finally, certain substances other than drugs can activate the production of CYP1A2 and thus increase its activity.  The polycyclic hydrocarbons found in cigarette smoke, charbroiled foods, and so-called “cruciferous” vegetables, such as broccoli and cauliflower, are capable of inducing this enzyme, that is, of increasing its production.[ix]  If you smoke cigarettes, the amount of CYP1A2 available in your body to metabolize caffeine increases, and the speed with which you metabolize caffeine increases correspondingly.

CAFFEINE APPAREL & OTHER CAFFEINE GEAR

Luvox and “Time Release” Caffeine

Although these interactions can create problems, if they are understood and utilized strategically, they might actually offer some opportunities to caffeine users to improve caffeine’s effects.  Caffeine does not affect the metabolism of the antidepressant Luvox.  However, Luvox dramatically slows the metabolism of caffeine.  As a result, if Luvox users take a low dose of caffeine, say 100 mg, once or twice a day, the extended half life would effectively give them a “time release” caffeine.  Because caffeine has powerful anti-depressant effects, this extended activity could help alleviate their condition.  Half of the caffeine from a caffeine pill taken at noon would still be active at 7 AM the next morning, which would mean that the person could wake up cheerful and in good spirits, without the symptoms of depression—even before he’s taken any more caffeine!  As we’ve observed, the uses of caffeine as a treatment for clinical depression must be investigated further, but existing data strongly suggests that even a small amount of caffeine can pick a depressed person out of the doldrums for an entire day.

In sum, the medications you are taking, the foods you are eating, even the cigarettes you are smoking, can change the way caffeine is metabolized by your body.  And caffeine can also change the way certain other drugs are metabolized.  The charts below summarize some of the primary interactions between caffeine and medications and other common substances[BAW1] .

Medications Whose Rate of Metabolism is Slowed by Caffeine and that Slow the Metabolism of Caffeine. This is a list of drugs whose metabolism is partially or entirely dependent on CYP(1A2), which means that they will be metabolized more slowly—and remain active in the body longer—when caffeine is being used.  It also means that they will slow the rate at which caffeine is metabolized, extending the time during which it will continue to exert its effects.

Class of Drug Generic Name
Antiadgrogens Flutamide
Antidepressants  Amitriptyline Clomipramine Fluvoxamine Mianserin Imipramine
Antipsychotics Clozapine Haloperidol Olanzapine
Cardiovascular Drugs and Anticoagulants Lidocaine Mexiletine Propafenone Propranolol Triamterene Verapamil Warfarin
Cholinesterase Inhibitors Tacrine
Local Anesthetic Ropivacaine 
Nonsteroidal Anti-inflammatory Drugs Acetaminophen Phenacetin Methotrexate
Quinolones Pefloxacin

 (Source: Adapted from Juan A. Carrillo and Julio Benitez, “Clinically Significant Pharmacoinetic Interactions Between Caffeine and Medications,” Clinical Pharmacokinetics, 2000 Aug; 39(2); 127-153 )                   

Medications that Affect the Rate of Metabolism of Caffeine.  Here are some examples of medications and the amounts by which they facilitate or inhibit the ability of the body to metabolize caffeine by affecting the production of CYP1A2.  Some of these medications are not affected by caffeine, but they all affect the rate at which caffeine is metabolized[BAW2] .  A recent journal article by Dr. Juan Carrilo warned that “pharmacokinetic interactions at the CYP1A2 enzyme level may cause toxic effects during concomitant administration of caffeine and certain drugs used for cardiovascular, CNS, gastrointesticnal, infectious, respiratory and skin disorders.”[x]  The author of the article advises physicians that, unless a lack of interaction has been established,  “dietary caffeine intake should be considered when planning, or assessing response to, drug therapy.”  Women should note that oral contraceptives decrease caffeine clearance by 40%, which means that caffeine’s effects will be considerably prolonged in women taking them.  Athletes should also be aware that medications that slow caffeine clearance can affect urine caffeine concentrations and might cause a competitor to exceed the current regulatory limit even with an intake of as little as 400 mg of caffeine.[xi] 

EXAMPLES OF DRUGS INCREASING OR DECREASING PRODUCTIONOF CYP1A2

Type of Drug Name of Drug Change in speed of caffeine clearance (+ means speeds clearance of  caffeine; – means slows clearance of caffeine)
Antimycotic    
  Fluconazole -25%
  Ketoconazole -11%
  Terbinafine -21%
Cardiovascular drugs    
  Diltiazem -22%
  Mexiletine -50%
  Verapamil -20%
  Propafenone Slows clearance
  Propranolol Slows clearance
  Triamterene Slows clearance
  Warfarin Slows clearance
  Lansoprazole +10%
  Omeprazole +40%
CNS drugs Clozapine Slows clearance
  Fluvoxamine -80%
  Olanzapine Slows clearance
  Antiserotonergic Slows clearance
  Ondansetron Slows clearance
Oral contraceptives All brands -40%
Psoralens    
  Methoxsalen -70%
  5-methoxypsoralen -31%
Quinolones    
  Ciprofloxacin -33%
  Enoxacin -80%
  Grepafloxacin -50%
  Norfloxacin -35%
  Pefloxacin -47%
Other    
  Cimetidine -31%
  Idrocilamide Slows clearance
  Methotrexate Slows clearance
  Phenylpropanolamine Slows clearance

(Source: Adapted from Juan A. Carrillo and Julio Benitez, “Clinically Significant Pharmacoinetic Interactions Between Caffeine and Medications,” Clinical Pharmacokinetics, 2000 Aug; 39(2); 127-153)

 

Miscellaneous Factors Affecting the Speed of Caffeine Metabolism.  The following factors have been found to affect CYP1A2 activity and therefore to increase or decrease the amount of time it takes for caffeine to be cleared from the body.  When a factor increases the speed of caffeine metabolism, that means that it enables the body to eliminate caffeine from your blood stream more quickly, and that it will cause caffeine to affect you for a shorter time.  When a factor decreases the speed of caffeine metabolism, it causes caffeine to remains at active levels in your bloodstream for longer and causes caffeine to affect you for a longer time.   For example, narigenin, the chemical that makes grapefruit juice bitter, by inhibiting the production of CYP1A2, slows the clearance of caffeine from the body and prolongs its half-life by over 30%![xii]

Increases Speed of Caffeine Metabolism

(Makes caffeine’s effects abate more quickly)

Decreases Speed of Caffeine Metabolism

(Makes caffeine’s effects last longer)

Cruciferous vegetables (broccoli, cauliflower, cabbages, radishes, etc.)

Grapefruit juice

Coffee

Alcohol

Grilled meat

Pregnancy

Tobacco smoke

Liver disease

Lean people

Obese people

Younger people

Older people

 

 

(Source: Adapted from Juan A. Carrillo and Julio Benitez, “Clinically Significant Pharmacoinetic Interactions Between Caffeine and Medications,” Clinical Pharmacokinetics, 2000 Aug; 39(2); 127-153)


 

[i] JA Carrillo and J Benitez, “CYP1A2 activity, gender, and smoking as variables influencing the toxicity of caffeine,” Bri J Clin Pharmacology 1996; 41(6); 605-608,

[ii] “CYP1a2 is the major enzyme responsible for the metabolism of many drugs and estrogens.”FDA white paper “Molecular Epidemiology,” Fred F. Kadlubar, Ph.D. http://www.fda.gov/nctr/science/96-97%20Research%20Plans/organizations/molepid.htm  “Theoretically, estrogen should also inhibit caffeine metabolism.”—Graham SURVEY p 794.

[iii] Jeppesen U, Gram LF, Vistisen K, Loft s, Poulsen HE, Brosen K. Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. Eur J Clin Pharmacol 1996; 51(1):73-78

[iv] Robert M. Julien, A Primer of Drug Action, New York: WH Freeman & Co, 2001, p 147.

[v] Jeppesen, U, et al, A fluvoxamine-caffeine interaction study, Pharmacogenetics 1996 Jun;6(3)213-222.

[vi] Rasmussen BB, et al, Pharmacol Toxicol 1998 Dec;83(6):240-245.

[vii] Juan A. Carrillo and Julio Benitez, “Clinically Significant Pharmacoinetic Interactions Between Caffeine and Medications,” Clinical Pharmacokinetics, 2000 Aug; 39(2); 127-153.

[viii] Juan A. Carrillo and Julio Benitez, “Clinically Significant Pharmacoinetic Interactions Between Caffeine and Medications,” Clinical Pharmacokinetics, 2000 Aug; 39(2); 127-153.

[ix] On-Line Continuing Education for Pharmacists, National Community Pharmacists Association, educational series sponsored by Pfizer, by Daniel S. Streeman, Parm.D. “Cytochrome P450 Enzymes,” ACPE Program Number 207-000-99-001-H01, December 1998.

[x] Carrillo Juan A., Julio Benitez, “Clinically significant pharmacokinetic interactions between dietary caffeine and Medications,” Clinical Pharmacology, 29, no. 2 (2000): 127-163.

[xi] Birkett, DJ, Iners, JO, “Caffeine renal clearance and urine caffeine concentrations during steady state dosing: implications for monitoring caffeine intake during sports events,” British Journal of Clinical Pharmacology, 31(4):405-8, 1991.

[xii]Uwe Fuhr, et al, “Inhibitory effect of grapefruit juice and its bitter principal, naringenin on CYP1A2 dependent metabolism of caffeine in man,” British Journal of Clinical Pharmacology, (1993), 35, 431-436.

 ADDITIONAL NOTES:

  • WARNING: Don’t expect your doctor to tell you about the interactions of caffeine and the enzyme system that cause interactions with other drugs and with foods. 
  • We think that the FDA should require a boxed warning for drugs like Luvox regarding possible adverse interactions with caffeine.
  • Cytochrome P4501A2 is otherwise known as CYP1A2.
  •  “The goal of drug metabolism is to make the drug more water soluble so that it can be excreted by the kidneys.”
  •  CYP1a2 inducibility is governed by the CYP1A2 gene.

 Here are the generic names of some medications that may inhibit the metabolism of caffeine:

Allopurinol
Cimetidine
Ciprofloxacin
Diltiazem
Disulfiram
Enoxacin
Erythromycin
Etintidine
Furosemide
Idrocilamide
Mexiletine
Nifedipine
Norfloxacin
Ofloxacin
Pefloxacin
Pipemidic acid
Propranolol
Roxithromycin
Thiabendazole
Ticlopidine
Troleandomycin
Verapamil
Viloxazine

 

5 Responses to Drug and Food Interactions with Caffeine

  1. Justin says:

    Lainna: Caffeine is usually removed from your system by 24 hours, but it is below active concentrations by four hours. The symptoms you describe (migraines and vomiting) may be induced by caffeine’s upregulation of adrenaline and increases in blood pressure and reduced digestive capacity.

    You may have high blood pressure inherently which exacerbates the effect, that’s a possibility. But otherwise you may also be allergic to it, in that your system is hyper-sensitive to adrenaline.

    (Not a doctor, just a pharmacology student)

    • Caffeine is not below “active concentrations” after four hours. Unlike the way other drugs work, the half-life of caffeine actually varies with the dose! That means that, the more caffeine you take, the longer the half-life is. Also, everyone has a different sensitivity to caffeine, so some people will respond to levels of caffeine that don’t affect others.

      Caffeine probably lowers blood pressure and, without question, offers a tremendous protection again a wide range of cardiovascular pathologies. Finally, caffeine can help end a migraine– in fact that was its first known use in medicine– and it does not induce vomiting.

  2. dumbadovsky says:

    stop taking caffeine.

  3. Lainna says:

    I have had a drastic reaction to caffiene for about 3 years now. If I even take 1 sip of coffee, let alone a whole cup (or an energy drink, caffiene pill, etc) the following day (about 24 hours later) I have a wicked migraine and I throw up. Doctors can’t explain it. They act like I’m crazy because the caffiene should already be out of my system by the time I experience the nausea and migraine. Do you have any answers?