Caffeine | Supplementopedia

Overview

Caffeine (1,3‑dimethylxanthine) is a naturally occurring xanthine alkaloid that acts primarily as a central nervous‑system stimulant. It is widely consumed in beverages and as a dietary supplement to promote alertness, improve mental performance, and reduce perceived fatigue.

Benefits

Cognitive Function: Enhances cognitive function, particularly attention, reaction time, and vigilance, with meta‑analyses showing 3–15 % improvements in simple‑reaction and psychomotor tasks (e.g., 200 mg dose).
Physical Performance: Modestly boosts physical performance, especially endurance‑type activities, by increasing maximal oxygen uptake (VO₂max) and reducing perceived exertion, likely via heightened catecholamine release.
Metabolic Rate: Stimulates metabolic rate, raising resting metabolic rate by ~3–5 % and modestly augmenting lipolysis during exercise.
Neuroprotective Effects: In neurodegenerative contexts, long-term moderate intake (≈200 mg/day) is associated with a lower incidence of Parkinson’s disease, possibly through neuroprotective adenosine‑receptor antagonism.
Mood and Cancer Risk: Improves mood and reduces the risk of certain types of cancer (e.g., liver cancer) in epidemiologic studies, though causality remains under investigation.

How It Works

Adenosine Receptor Antagonism: Caffeine's primary action is competitive antagonism at adenosine receptors (A₁, A₂A, A₂B, A₃), preventing adenosine’s inhibitory neuromodulation.
Neuronal Firing and Dopamine Release: Adenosine antagonism increases neuronal firing and dopamine release in the prefrontal cortex and basal ganglia.
cAMP Accumulation and Catecholamine Signaling: This blockade triggers downstream cAMP accumulation via inhibition of phosphodiesterase (PDE) at high concentrations, amplifying catecholamine signaling.
Physiological Effects: The resultant rise in epinephrine/norepinephrine elevates heart rate, bronchodilation, and lipolysis.
Cortical Arousal and Sleep Reduction: In the brain, adenosine blockade enhances cortical arousal and reduces sleep‑inducing neurotransmission (e.g., GABA).
Muscular Effects: At the muscular level, caffeine augments calcium release from the sarcoplasmic reticulum, improving contractile force.
Combined Actions: The combination of central and peripheral actions accounts for the observed improvements in cognition, endurance, and metabolic rate.

Dosage

Typical Dosage: Typical caffeine supplement doses range from 50 mg (≈½ cup coffee) to 400 mg (≈four cups) per day for healthy adults.
Acute Cognitive Enhancement: For acute cognitive enhancement, 100–200 mg taken 30–60 min before the task yields optimal results.
Endurance Performance: For endurance performance, 3–6 mg kg⁻¹ body weight (≈200–400 mg for a 70 kg adult) ingested 30–90 min prior to exercise is recommended.
Weight Management: In weight‑management formulations, 100–200 mg divided into two doses (morning and early afternoon) helps sustain metabolic elevation without disrupting sleep.
Special Considerations:
- Athletes may use higher acute doses (up to 9 mg kg⁻¹) under supervision.
- Older adults or those with low body mass should limit intake to ≤200 mg/day.
- Avoid dosing within 6 h of bedtime to prevent insomnia.

Safety & Side Effects

General Safety: Caffeine is generally safe up to 400 mg/day for most adults.
Common Side Effects: Common side effects include insomnia, jitteriness, gastrointestinal upset, and tachycardia.
High Dose Risks: Higher doses (≥600 mg) may cause anxiety, arrhythmias, or hypertension.
Contraindications: Contraindications include pregnancy (limit to ≤200 mg/day), uncontrolled hypertension, arrhythmias, anxiety disorders, and certain psychiatric conditions.
Drug Interactions: Caffeine interacts with CYP1A2 substrates (e.g., clozapine, theophylline) and may potentiate the effects of antidepressants, anticoagulants, and certain antihypertensives.
Sensitivity and Special Populations: Individuals with caffeine‑sensitivity, cardiac disease, or pediatric populations should use lower doses (≤100 mg) or avoid supplementation.
Withdrawal: Withdrawal can occur after regular >200 mg/day use, presenting as headache, fatigue, and irritability; gradual tapering mitigates symptoms.

Chemistry

Molecular Formula: C₈H₁₀N₄O₂ (molar mass = 194.19 g mol⁻¹).
IUPAC Name: 1,3,7‑trimethylpurine‑2,6‑dione.
Structure: The structure consists of a fused heterocyclic purine core with three methyl groups at N‑1, N‑3, and N‑7, and carbonyl groups at C‑2 and C‑6, conferring a planar, aromatic configuration.
Acidity/Basicity: It is a weak base (pKa ≈ 0.6 for the imidazole nitrogen).
Solubility: Highly soluble in water (≈21 g L⁻¹ at 25 °C) and organic solvents (e.g., ethanol).
Stability: The compound is stable at neutral pH but undergoes oxidation to theobromine and theophylline under oxidative conditions.

Sources & Quality

Natural Sources: Caffeine is extracted from coffee beans (Coffea spp.), tea leaves (Camellia sinensis), cacao beans (Theobroma cacao), and guarana seeds (Paullinia cupana).
Extraction Method: Commercially, it is obtained by solvent (water/ethanol) extraction followed by spray‑drying to produce a fine white powder.
Synthetic Production: Synthetic caffeine via the Mannich reaction (using urea, chloroacetone, and methylating agents) produces a chemically identical product, often used for pharmaceutical grade consistency.
Quality Considerations: Quality considerations include purity (>99 % for pharmaceutical‑grade), absence of heavy metals or pesticide residues, and certification (e.g., USP, NSF) to assure safety and potency in supplements.