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.
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.
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.

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]

Type of Drug Name of Drug Change in speed of caffeine clearance (+ means speeds clearance of  caffeine; – means slows clearance of caffeine)
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%
Methoxsalen -70%
5-methoxypsoralen -31%
Ciprofloxacin -33%
Enoxacin -80%
Grepafloxacin -50%
Norfloxacin -35%
Pefloxacin -47%
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



Grilled meat


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.

  • 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:

Pipemidic acid

16 Responses

  1. 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?

    1. Lainna
      Estrogen can compete here so if you are extremely estrogen dominant you may be competing for methylation. Or you may have a polymorphism in the CY1A2 gene. 23andme will show your SNPs for CYp450 in their raw data report if you send them a saliva sample (they no longer give you a health report for this so you have to look it up in the raw data). As you age polymorphisms can be turned on (or off) in the body depending on a lot of factors which could explain why caffeine may have been tolerated better previously. If you find you have mutations in the CYP450 genome (or even other mutations like MTHFR, CBS, MAO, COMT and so on) check out the work of Dr Ben Lynch and Dr Amy Yasko who have lots of info about blocks and problems in the methylation cycle due to gene variations which maybe causing your symtoms (and by the way, could be causing other issues at the sametime).

  2. 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)

    1. 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.

      1. Dear Mr Weinberg
        The half-life of say 6 hours means is that half is still working, and one quarter is till going at 6 hours after that.
        AND the principal metabolite of caffeine is paraxanthine, which is equally psychoactive in the same way as caffeine. It has its own half-life…I think 1-2 hours or so.
        Neuropharmacology. 2013 Apr;67:476-84. doi: 10.1016/j.neuropharm.2012.11.029. Epub 2012 Dec 19.
        Psychostimulant pharmacological profile of paraxanthine, the main metabolite of caffeine in humans.
        Sleep. 2010 Jul 1; 33(7): 930–942.
        PMCID: PMC2894435
        Effects of Paraxanthine and Caffeine on Sleep, Locomotor Activity, and Body Temperature in Orexin/Ataxin-3 Transgenic Narcoleptic Mice
        This why some people will not drink coffee after midday. Even with no other meds.
        Triple espresso please, if it is not a workday next day.

        1. If anyone is interested in what caffeine will do for him or to him, the only way to find out is to try it at different times and in different doses. Some people have trouble sleeping at night if they drink a cup of tea in the morning. Other people can have a big cup of coffee at 11PM and fall asleep in a half hour! The half-life doesn’t really tell the story.
          Bonnie can’t drink coffee after late afternoon or she will be awake at bedtime. I can drink it as late as I like and it really doesn’t bother my sleep. The effects also vary with what other drugs or even what foods you are consuming with it.

  3. I love my coffee (1 cup) in the morning , but I am on Paxil and Trazodone and I can tell something is different after a few days of drinking the caffeine. I can’t even sit down and watch tv. I have to be moving . My husband says I act like Im on crack. I have Cystic Fibrosis and have a lot of anxiety from my my breathing troubles. If I don’t have some caffeine though I stay sleepy all day.

  4. This was a great article but you should take out the statement about doctors not advising patients about potential medication interactions. This is incorrect information. We absolutely learn and are examined on this information throughout our education and our continuing careers.. Also, caffeine is a major risk factor for high blood pressure and migraines all by itself due to it increasing levels of adrenaline. It can also therefore aggravate cardiovascular pathology, as well as anxiety disorders.

    1. You are mixed up. Caffeine’s first medical use, apart from keeping people on morphine from nodding out, was to reduce migraine pain. Also, caffeine actually lowers blood pressure, even though naïve users experience a slight temporary increase in blood pressure. Besides, a slight high blood pressure increase is only bad if it causes harm. Many super large studies have proven that caffeine use extends life expectancy and does so primarily because of it reduction of cardiovascular pathologies. You need to study caffeine a bit more!

    2. Just because you do something doesn’t mean no one does it. How about instead of reacting defensively, you actually listen to people’s concerns and take action to do something about it?
      I once had a very bad experience with a doctor not warning me of drug-caffeine interactions. When I was prescribed one of the medications known to interact with caffeine, drastically slowing its metabolism, it came with a generic warning label that had a very mildly-worded warning to “avoid excessive amounts of caffeine”…since I only drink tea, not coffee, and don’t drink an excessive amount, I thought nothing of it. I didn’t know what was wrong when I drank a single cup of tea and started feeling severely lightheaded, weak heartbeat, severe anxiety, and it didn’t go away and I was unable to sleep. Turns out the drug in many people increases blood concentrations of caffeine by a factor of 3-4. I was angry, especially given how mildly-worded the drug’s label was — I would recommend people to completely avoid caffeine when on that medication.
      My experience with numerous doctors in the U.S. is that most doctors seem eager to prescribe medications, often carelessly. I can’t even count how many times I’ve been prescribed something that I never filled, “just in case”.
      Now I’m uninsured, and I’m absolutely sure that part of the reason health care costs are rising so fast is that doctors are so eager to prescribe drugs left and right, when they’re not medically necessary and even in some cases when they’re harmful.
      I want doctors and healthcare professionals to listen to my concerns and be like: “Oh yeah, you’re right, that’s a real problem. Wow, that really sucks that you had to go through that unpleasant experience. I’m going to keep that in mind when interacting with future patients. I’m going to talk to my colleagues about these sorts of things. I’m going to lend my voice towards addressing these sorts of problems.”
      It’s frustrating to me to see that doctors have high status in society, and many of them have very high salaries as well, and, to me, so many of them don’t seem to be doing their jobs and it seems like people like me, who don’t get paid for any of this, and who are often taken less seriously because we don’t have medical degrees, are the ones who are actually picking up the slack and working to address these problems.

      1. Health care costs go up and up too high only because there is no market competition in health care. It is really very simple! Doctors have a monopoly on delivering health care and they charge whatever they decide to charge. You have no alternative but to consult a member of the AMA, because the government won’t allow anyone else to treat you or give you a prescription. End of story.
        Children need someone to guide and supervise them, in health care and many other things. Adult free citizens should be free to consult anyone they want for treatment and to use any treatment that they think is worth the risk. The FDA is a sinister and authoritarian and tyrannical agency, and it should be abolished.

  5. ok so i think my comment was deleted or didn’t show up.. but I will post it again so I can maybe I can know the answer.
    Does this article seems to contradict itself because it says, “Caffeine does not affect the metabolism of the antidepressant Luvox. However, Luvox dramatically slows the metabolism of caffeine.”
    But they put Luvox under the list of “Medications Whose Rate of Metabolism is Slowed by Caffeine and that Slow the Metabolism of Caffeine.”
    So Im just wondering…….caffeine does interacts with luvox and luvox interacts with caffeine? Im thinking it would It makes sense since I guess one would interact with the other.

    1. You may be correct that I made a mistake. There are thousands of facts related to caffeine that I have tried to learn and it is certainly possible that an error has slipped in. I am grateful that you pointed this out, and, when I have time, I will look into your comment and try to correct my statements.

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