Caffeine

1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione

Overview

Caffeine belongs to Stimulants.

Key safety note: Caffeine is the most widely consumed psychoactive substance and is generally safe at dietary intakes.[4][3][7]
Effects
Subjective effects vary. What a substance feels like depends on dose, individual physiology, mindset, and setting. The points below describe commonly reported effects, not guaranteed, uniform, or desirable outcomes.
  • Increased alertness and wakefulness, reduced fatigue and drowsiness, and improved reaction time, attention and concentration.
  • A mild mood lift, and, especially at higher doses, jitteriness, anxiety, restlessness, tremor and insomnia.
  • Peripheral effects: raised heart rate and blood pressure, increased gastric acid and (acutely) diuresis. Tolerance to several of these develops with regular use.
  • Abrupt cessation after regular use causes withdrawal, headache, tiredness, irritability and difficulty concentrating, typically within 12–24 h.
Dosing & duration
Harm-reduction note: These are commonly cited reference ranges, not a recommendation or a “safe” dose. Potency, purity, body chemistry, tolerance, and drug combinations vary widely. Start low, go slow, wait for full effects before redosing, and never assume an unknown product matches these figures. Missing data is not evidence of safety.

Oral (beverages, foods, tablets). Consumed almost entirely orally in beverages, foods and tablets. Health authorities regard up to ~400 mg/day as low-risk for most adults and ~200 mg/day in pregnancy. Single moderate doses are ~40–200 mg. These are reference intakes, not a recommendation: sensitivity varies several-fold between people.

Dose ranges

Typical serving

Coffee ≈80–100 mg/cup · espresso ≈60–80 mg/shot · tea ≈30–50 mg · energy drink ≈80 mg · cola ≈35 mg

Low-risk daily ceiling

≤400 mg/day (adults), ≤200 mg/day in pregnancy

Ergogenic (athletic) dose

≈3–6 mg/kg (~200–400 mg) before exercise

Duration

onset

≈15–45 min

total

Peak 30–120 min, effects ~3–5 h

Chemical & Physical Properties
FormulaC8H10N4O2
Molar mass194.19 g/mol
StateSolid
Melting point236.2 °C
Boiling point178 °C (sublimes)
Density1.23 g/cm³ at 18 °C (NTP, 1992)
Vapor pressure1×10⁻⁸ mmHg
pKa14
LogP-0.07
Solubility10 to 50 mg/mL at 23 °C (NTP, 1992), 2.17 g/100mL, Solubility in water is increased by alkali benzoates, cinnamates, citrates or salicylates
Refractive indexNot reported
Identifiers & Synonyms
CAS58-08-2
CAS (enantiomer)
PubChem CID2519
InChIKeyRYYVLZVUVIJVGH-UHFFFAOYSA-N
InChIInChI=1S/C8H10N4O2/c1-10-4-9-6-5(10)7(13)12(3)8(14)11(6)2/h4H,1-3H3
SMILESCN1C=NC2=C1C(=O)N(C(=O)N2C)C

Synonyms

  • 1,3,7-Trimethylxanthine
  • Guaranine
  • Theine
  • Caffeine
Pharmacodynamics & Biochemistry

Caffeine (1,3,7-trimethylxanthine) is the world's most widely used psychoactive drug. Its stimulant action comes almost entirely from non-selective antagonism of adenosine receptors. It blocks the A1, A2A, A2B and A3 subtypes, but at dietary intakes only A1 and A2A are meaningfully occupied (Ki ≈8–20 µM, matching the tens-of-µM plasma levels a few cups of coffee produce). Adenosine normally accumulates during waking and promotes sleep and sedation. By occupying its receptors caffeine releases that brake, raising arousal, alertness and neuronal firing. The alerting effect is driven largely by A2A blockade. A2A receptors sit in the sleep-promoting ventrolateral preoptic area and, in the striatum, form heteromers with dopamine D2 receptors. Antagonising them disinhibits downstream dopaminergic and histaminergic arousal circuits. This indirect enhancement of dopamine signalling, caffeine binds no dopamine receptor or transporter itself, underlies both the wakefulness and the mild reinforcing, habit-forming quality of caffeine. The textbook secondary actions: phosphodiesterase inhibition (raising cAMP) and ryanodine-receptor-mediated intracellular calcium release: are real but occur only at toxic, supraphysiological concentrations far above normal consumption. They contribute to overdose toxicity, not to the everyday cup-of-coffee effect. At dietary doses adenosine antagonism is essentially the whole story. Caffeine is metabolised in the liver by CYP1A2 to paraxanthine (~84%), theobromine and theophylline, which are themselves active. Regular use up-regulates adenosine receptors, producing tolerance to the alerting effect and a withdrawal syndrome (headache, fatigue, low mood) on abrupt cessation. CYP1A2 activity varies several-fold between people, induced by smoking, inhibited by drugs such as fluvoxamine, so both clearance and sensitivity differ widely.

Biological targets

  • Adenosine A1
  • Adenosine A2A

Binding & functional measurements

TargetMeasurementSpecies
A2A receptorpKi 5.1Human
Pharmacokinetics
BioavailabilityOral ≈100%
Tmax≈30–60 min
Half-life≈3–5 h (prolonged in pregnancy and with CYP1A2 inhibitors)
VdNot reported
Protein bindingNot reported
MetabolismHepatic CYP1A2 to paraxanthine, theobromine, theophylline
ExcretionRenal (metabolites)
Toxicology & Safety
Harm-reduction note: Toxicity and risk depend on dose, route, purity, combinations, setting, and individual health factors. Missing harms should never be interpreted as evidence of safety.

Not reported

Caffeine is the most widely consumed psychoactive substance and is generally safe at dietary intakes. Health authorities put a low-risk ceiling around ≤400 mg/day for adults and ≤200 mg/day in pregnancy. Above that it causes 'caffeinism', anxiety, restlessness, insomnia, tremor, palpitations and diuresis, and can precipitate or worsen anxiety and cardiac arrhythmia. Acute overdose (roughly >1–2 g) brings vomiting, agitation, tachyarrhythmia, hypokalaemia and seizures. The estimated lethal dose is ~150–200 mg/kg (~10 g in an adult), but concentrated or pure caffeine powders and tablets have caused deaths from as little as a teaspoon, which prompted FDA action. A genuine, DSM-5-recognised dependence with withdrawal (headache, fatigue, irritability) develops even at ordinary intakes. Risk is higher in children, pregnancy, and people with impaired CYP1A2 metabolism or cardiac/anxiety disorders.[4][3][7]

Legal Status
Legal note: Legal status can change over time and may vary by country, region, formulation, analogue status, prescription context, and enforcement practice. Always confirm with current official sources before relying on this section.
Interactions & Contraindications

Drug interactions

CYP1A2 inhibitors (fluvoxamine, ciprofloxacin) Fluvoxamine especially (clearance down >90%), plus ciprofloxacin and some antiarrhythmics, markedly raise caffeine levels and prolong its half-life.[2][3]
Stimulants (amphetamines, cocaine) Additive stimulation and cardiovascular strain with ephedrine, other sympathomimetics and stimulants.[2][3]
CYP1A2 substrate drugs (clozapine, olanzapine, theophylline) Caffeine can raise clozapine and theophylline levels.[2][3]

Contraindications

Cardiovascular disease, hypertension or arrhythmia serious cardiac arrhythmia or uncontrolled hypertension (high doses).[3]
Personal or family history of psychosis, schizophrenia or bipolar disorder severe anxiety or panic disorder.[3]
Pregnancy or breastfeeding limit intake (≤200 mg/day).[3][7]
Kidney or liver impairment impaired hepatic (CYP1A2) metabolism, with caution in children and adolescents.[3]
Usage & Context
  • A dietary stimulant in coffee, tea, cola, energy drinks and chocolate, by far the most common use, taken for alertness and reduced fatigue.
  • Therapeutic uses: apnoea of prematurity in neonates (caffeine citrate), an analgesic adjuvant (added to paracetamol, aspirin or ibuprofen), and an ergogenic aid for athletic performance.
  • An over-the-counter alertness aid (tablets) and a common additive in weight-loss and 'pre-workout' supplements.
Sources & Evidence

Further Information