Caffeine: How It Works in the Human Body

Caffeine is the most widely used psychoactive substance in the world, and most of what is written about its effects on the body is written without a source. This article covers what happens after you drink it: how it is absorbed, what it does at the receptor, how your liver clears it, why two people react differently to the same cup, and how much is considered safe.

What is in the cup before you drink it — the chemistry, how much caffeine is in the bean, and how much reaches the cup by brewing method — is covered in the companion article on caffeine as a compound.

This article provides educational information about caffeine. It is not medical advice, and nothing in it is a recommendation about what you should drink. If you are pregnant or breastfeeding, have a heart condition or high blood pressure, take medication that interacts with caffeine, or have been advised to limit it, follow the guidance of your own clinician.

A Correction, First

This encyclopedia previously opened this article by calling caffeine the compound that made coffee the world's second-most-traded commodity. That statement is false. It is probably the most widely repeated false statistic in coffee writing, it appears everywhere from trade journalism to the preamble of Puerto Rican legislation, and it has no basis. Coffee is a significant agricultural export. It is not second to oil in world trade by any measure this encyclopedia could locate.

It has been removed. It was the first line of a page promising what the peer-reviewed research actually says.

Absorption and Onset

caffeine molecule chemical structure diagram on white background. Photo: Jynto / Wikimedia Commons, CC0.

Caffeine is absorbed rapidly and almost completely from the gut. Standard pharmacological references give onset of action at roughly 45 minutes to an hour, and a duration of action of about 3 to 4 hours — which is not the same as the time it takes to clear, as the next section explains.

It is metabolised primarily by the liver enzyme CYP1A2, with minor contributions from other cytochrome enzymes. Its main metabolite is paraxanthine, which accounts for the large majority of the breakdown, followed by theobromine and theophylline. Excretion is essentially entirely in urine.

Adenosine: Caffeine Blocks the Brake

Caffeine is a competitive antagonist at adenosine receptors, principally the A1 and A2A subtypes.

Adenosine accumulates in the brain across the waking day. When it binds to those receptors, the result is part of what you experience as tiredness. Caffeine is close enough in shape to occupy the same receptors without activating them.

Caffeine does not give you more fuel. It blocks the brake.

The consequence is the part people feel without understanding. Adenosine keeps accumulating the whole time the receptors are blocked. When the caffeine clears, all of it is waiting.

Watch: James Hoffmann on Caffeine: Health, Dose, Decaffeination & More — The Curious Bartender. An interview; the channel is not James Hoffmann's own.

The Half-Life Is Not One Number

This encyclopedia has published two different half-life ranges on two different pages — 1.5 to 9.5 hours on one, 3 to 9 hours on the other — neither with a source. The honest position is that no single figure is correct.

Standard pharmacological references give an elimination half-life in adults of roughly 3 to 7 hours. Published averages cluster around 5 to 6 hours. The spread between individuals is larger than the spread between published averages, and the reasons are known:

Factor	Effect on clearance
Smoking	Induces CYP1A2 and roughly doubles the rate of clearance
Oestrogen-containing oral contraceptives	Impairs clearance; a measured study found a mean half-life of about 7.9 hours against about 5.4 in controls
Pregnancy	Slows clearance substantially, most markedly in the third trimester
CYP1A2 genotype	Shifts clearance in either direction

The practical consequence is about timing rather than dose. A 200 mg coffee at nine in the morning, on a five-hour half-life, still leaves roughly 100 mg in circulation at two in the afternoon and roughly 50 mg at seven in the evening. Caffeine does not leave in one clean exit; it tapers, and the slower your clearance, the further the tail runs into the night.

Why People Differ

CYP1A2 accounts for approximately 95 per cent of caffeine metabolism. A common variant at position 734 defines the CYP1A21F allele, which reduces how far the enzyme can be induced. Carriers are described as slow metabolisers; people homozygous for CYP1A21A are described as rapid metabolisers.

This encyclopedia previously stated that roughly 40 per cent of people are fast metabolisers, 45 per cent average and 15 per cent slow. Those three figures had no source, no such standard three-way distribution is established, and they have been removed. The same figures were removed from another article in this encyclopedia earlier this month.

It also stated that research has consistently linked heavy coffee consumption in slow metabolisers to increased cardiovascular risk. That word is not supportable, and this is health content, so the actual evidence is given instead.

The study behind the claim is Cornelis and colleagues, published in JAMA in 2006: a case-control study of 2,014 people with a first non-fatal myocardial infarction and 2,014 matched controls in Costa Rica, all self-described Hispanic Americans. Fifty-four per cent of controls carried the slow allele. Compared with less than one cup a day, after adjustment:

Intake	Slow metabolisers	Rapid metabolisers
1 cup a day	0.99 (0.69–1.44)	0.75 (0.51–1.12)
2 to 3 cups a day	1.36 (1.01–1.83)	0.78 (0.56–1.09)
4 or more cups a day	1.64 (1.14–2.34)	0.99 (0.66–1.48)

Odds ratios with 95 per cent confidence intervals. Gene–coffee interaction P = 0.04.

That is one case-control study of survivors of a non-fatal event, and its own authors note they cannot exclude an effect on survival. The literature that followed it is mixed rather than consistent. No cardiology body recommends genotype testing to decide how much coffee to drink.

This encyclopedia also previously advised readers to infer their own metaboliser status from jitteriness. No validated method for that has been located, and the advice has been removed.

Blood Pressure and the Heart

A painted anatomical teaching model of the human heart on a stand. Photo: Ekko / Wikimedia Commons, public domain.

Caffeine produces transient increases in blood pressure and heart rate, through the same adenosine blockade described above. That is the acute effect, and it is the one people feel.

The European Food Safety Authority concluded in 2015 that single doses up to 200 mg — about 3 mg per kilogram of body weight for a 70 kg adult — are unlikely to produce clinically relevant changes in blood pressure in healthy adults. Habitual and non-habitual drinkers respond differently to the same dose.

This encyclopedia previously gave a figure of 3 to 5 mmHg systolic for the hour following a 200 mg dose. The figure sits inside the published range but carried no source, and it has been removed.

On longer-term cardiovascular outcomes, the large observational evidence comes from cohorts including the Nurses' Health Study and the Health Professionals Follow-up Study, both run from Harvard, and the European Prospective Investigation into Cancer and Nutrition, which is coordinated by the International Agency for Research on Cancer rather than by Harvard. These are observational studies. They show association, not cause, and confounding by smoking and other factors is a real and acknowledged limitation.

Tolerance, Dependence and Withdrawal

Regular use produces tolerance: the body adapts, and the same dose does less. Stopping produces withdrawal — headache, fatigue, difficulty concentrating, low mood — typically beginning within a day and resolving within a week or so.

Two DSM-5 entries are frequently confused, and both are stated here correctly:

• Caffeine withdrawal is a recognised diagnosis in DSM-5.
• Caffeine use disorder is not. It appears as a condition for further study.

That distinction is the difference between a clinician being able to diagnose something and a proposal awaiting evidence.

Pregnancy and Breastfeeding

The American College of Obstetricians and Gynecologists recommends a maximum of 200 milligrams of caffeine a day during pregnancy. The European Food Safety Authority reaches the same figure, for pregnancy and for breastfeeding.

On breastfeeding specifically, EFSA concluded that caffeine consumed by lactating women at up to 200 mg a day does not give rise to safety concerns for the breastfed infant, on a calculation that the infant's own intake would not exceed 0.3 mg per kilogram of body weight. Measured milk-to-serum concentration ratios fall between about 0.52 and 0.81.

This encyclopedia previously stated that only about one per cent of the mother's dose passes into breast milk. That figure could not be traced and has been replaced with the EFSA calculation above.

Decaffeinated Coffee and Your Dose

Close-up of green unroasted coffee beans, the form in which coffee is decaffeinated before roasting. Photo: Michael Allen Smith@INeedCoffee from Seattle, USA / Wikimedia Commons, CC BY-SA 2.0.

Decaffeinated coffee is not caffeine-free, and for someone who clears caffeine slowly that is worth knowing. What decaffeination is and how much caffeine remains is covered in the companion article on caffeine as a compound.

How Much Is Safe

A white laminate desk with a laptop, a glass of orange juice, a cappuccino in a glass, a teal mug, sticky notes and a succulent, with two hands reaching for a plate holding a croissant and a chocolate doughnut. Photo: Shixart1985 / Wikimedia Commons, CC BY 2.0.

Body	Figure	Applies to
European Food Safety Authority, 2015	Up to 400 mg a day, habitual	Healthy non-pregnant adults
European Food Safety Authority, 2015	Up to 200 mg in a single dose	Adults
European Food Safety Authority, 2015	Up to 200 mg a day	Pregnancy and breastfeeding
American College of Obstetricians and Gynecologists	Up to 200 mg a day	Pregnancy
American Academy of Pediatrics	No more than 100 mg a day	Ages 12 to 18

EFSA concluded that the information available was insufficient to derive a safe caffeine intake for children under 12.

None of these figures is a target. They are ceilings below which no safety concern has been identified, which is not the same as a recommendation to reach them.

Key Facts

• Caffeine is absorbed rapidly; onset roughly 45 minutes to an hour.
• Metabolised primarily by CYP1A2, which handles approximately 95 per cent of it. Main metabolite paraxanthine. Excreted in urine.
• Elimination half-life in adults roughly 3 to 7 hours, with large individual variation.
• Smoking roughly doubles clearance. Oestrogen-containing oral contraceptives, pregnancy and genotype all slow it.
• Caffeine blocks adenosine A1 and A2A receptors. It supplies no energy.
• Caffeine withdrawal is a DSM-5 diagnosis; caffeine use disorder is a condition for further study.
• 400 mg a day for healthy adults; 200 mg a day in pregnancy and breastfeeding; 100 mg a day for ages 12 to 18.
• Coffee is not the world's second-most-traded commodity.

Frequently Asked Questions

How long does caffeine stay in my system? Longer than most people think. Individual half-lives range from about 3 to 7 hours in adults, and further in pregnancy.

Why does coffee affect my friend differently? Mostly the liver. CYP1A2 activity varies with genotype, smoking, hormonal contraception and pregnancy, and the difference between a fast and a slow clearer is large.

Can I tell whether I'm a slow metaboliser? Not reliably. This encyclopedia previously suggested inferring it from jitteriness; no validated method for that has been located.

Is caffeine addictive? Caffeine withdrawal is a recognised DSM-5 diagnosis. Caffeine use disorder is listed only as a condition for further study.

How much is safe in pregnancy? Both ACOG and EFSA give 200 mg a day. Ask your own clinician about your circumstances.

Does caffeine raise my blood pressure? Transiently, yes. EFSA concluded that single doses up to 200 mg are unlikely to produce clinically relevant changes in healthy adults. If you have hypertension, this is a question for your clinician rather than for an encyclopedia.

Sources

• Standard pharmacological references for caffeine — onset of action of 45 minutes to an hour, duration of action of 3 to 4 hours, elimination half-life in adults of 3 to 7 hours, full-term infants around 8 hours, metabolism primarily by CYP1A2 with minor contributions from CYP2E1, CYP3A4, CYP2C8 and CYP2C9, metabolites paraxanthine 84 per cent, theobromine 12 per cent and theophylline 4 per cent, and excretion entirely in urine.
• EFSA Panel on Dietetic Products, Nutrition and Allergies, "Scientific Opinion on the safety of caffeine", EFSA Journal 2015;13(5):4102 — 400 mg daily and 200 mg single dose for adults; 200 mg daily in pregnancy and lactation; the 3 mg/kg equivalence; the conclusion on blood pressure; the conclusion that 200 mg a day by lactating women does not give rise to safety concerns for the breastfed infant, on a calculation of infant intake not exceeding 0.3 mg/kg body weight; and the insufficiency of data to derive a safe intake for children.
• Measured milk-to-serum caffeine concentration ratios of 0.52 to 0.81, as cited in the EFSA assessment literature.
• Studies of impaired caffeine clearance under chronic use of low-dose oestrogen-containing oral contraceptives, and of caffeine disposition during and after pregnancy, both in the EFSA opinion's bibliography — the prolonged half-life of about 7.9 hours against about 5.4 hours in controls, and the slowing of clearance in pregnancy.
• Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H, "Coffee, CYP1A2 Genotype, and Risk of Myocardial Infarction", JAMA 2006;295(10):1135–1141 — the CYP1A2*1F and *1A alleles; 2,014 cases and 2,014 matched controls in Costa Rica; the 54 per cent carrier frequency; every odds ratio in the table; and the authors' own caution about survival effects.
• American College of Obstetricians and Gynecologists — the 200 mg daily maximum in pregnancy.
• American Academy of Pediatrics — no more than 100 mg a day for ages 12 to 18.
• Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition — caffeine withdrawal as a recognised diagnosis, and caffeine use disorder as a condition for further study.
• The Nurses' Health Study and the Health Professionals Follow-up Study, run from Harvard, and the European Prospective Investigation into Cancer and Nutrition, coordinated by the International Agency for Research on Cancer — the observational cohort evidence on long-term cardiovascular outcomes.

Claims this encyclopedia could not source

• That coffee is the world's second-most-traded commodity. False, not merely unsourced. It was the bolded first line of this article.
• A population distribution of caffeine metaboliser types. The figures previously carried here — 40 per cent fast, 45 per cent average, 15 per cent slow — have no located source and no such standard distribution is established.
• A single elimination half-life figure. Published ranges differ between references, and this encyclopedia has itself published two conflicting ranges. The commonly cited adult range is given instead.
• That research has consistently linked heavy coffee consumption in slow metabolisers to increased cardiovascular risk. One case-control study supports an association; the literature that followed is mixed.
• Any method of inferring your own metaboliser status from symptoms. No validated method located.
• A specific millimetre-of-mercury figure for the acute pressor effect of a 200 mg dose. Published ranges vary; no single sourced figure located.
• That about one per cent of a mother's caffeine dose passes into breast milk. Not traced. The EFSA calculation is given instead.
• That a single coffee bean contains roughly 6 milligrams of caffeine. Plausible as an arabica average; no source located.
• Any claim that coffee from a particular origin or altitude produces a smoother or different caffeine effect. Caffeine is one molecule and is chemically identical whatever grew it.

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