Caffeine

Category: stimulant

Aliases: 1,3,7-trimethylxanthine

Pharmacological Mechanism

Non-selective adenosine receptor signaling A1/A2A antagonist; PDE inhibition at high doses.

Half-Life (t½)

PO: 5h

Dosing Guidelines

PO: Typical 100 (Range: 50–400)

Target Organ Systems

nervous

Interactions

L-Theanine (synergistic): Classic nootropic pair — theanine smooths caffeine without blunting alertness.
Adenosine (caution): Caffeine is an adenosine receptor antagonist — blunts IV adenosine clinical potency. Hold ≥24 h before cardiac stress testing.
EGCG (synergistic): Classic fat-oxidation stack (COMT inhibition by EGCG + catecholamine release by caffeine).
Theobromine (synergistic): Both share CYP1A2 metabolism. Cocoa's combined caffeine + theobromine content drives the milder stimulant profile vs. pure caffeine.
Theophylline (caution): Caffeine competitively inhibits CYP1A2 (Ki ≈ 80 µM, Tassaneeyakul 1992) — slows theophylline clearance; concurrent dosing risks additive tachycardia.
Yohimbine (caution): Combined sympathetic stimulation — additive tachycardia/anxiety. Popular in pre-workout but higher cardiovascular risk.
Dipyridamole (caution): Caffeine antagonises adenosine at A2A → reduces dipyridamole stress-test sensitivity. Hold caffeine 24 h prior.

Notes

Tolerance develops within 1-2 weeks of daily use. orexin arousal axis — A2A is the higher-affinity arousal receptor (lower ec50) — caffeine occupies it well below the typical 100 mg dose's Cmax.

Pathways It Modulates

Adenosine receptor signaling (inhibitor) — A1 + A2A (non-selective antagonist)
Caffeine A1-adenosine cardiac ectopy (inhibitor) — adenosine A1 receptor (cardiac nodal tissue)
cAMP / PKA second-messenger signaling (inhibitor) — PDE (non-selective) + adenosine A1/A2A antagonism
Circadian clock (inhibitor) — adenosine A1/A2A (phase-delays clock; via cAMP/CREB)
Orexin / wakefulness arousal axis (activator) — orexin disinhibition (via A1/A2A antagonism on orexin neurons)
Purinergic signaling (inhibitor) — P1 (adenosine) antagonist — indirect P2 system modulation

Chemical Identifiers

PubChem CID: 2519
Formula: C8H10N4O2
Molecular weight: 194.19 g/mol
InChIKey: RYYVLZVUVIJVGH-UHFFFAOYSA-N
SMILES: CN1C=NC2=C1C(=O)N(C(=O)N2C)C