Caffeine
1,3,7-Trimethylxanthine
Also known as: Caffeine, 1, 3, 7-Trimethylxanthine, Guaranine, Methyltheobromine, Theine
Evidence Strength: STRONG
This ingredient receives a unclassified risk score due to safety concerns identified by health authorities in EU. Scientific evidence indicates caffeine acts primarily by antagonizing adenosine receptors, particularly A1 and A2A subtypes,…. Reported adverse effects include insomnia and nervousness.
Safety Profile
Common Adverse Effects
- Insomnia
- nervousness
- restlessness
- stomach upset
- increased heart rate
Serious Adverse Effects
- Tachycardia
- arrhythmia
- hypertension
- seizures
- anxiety disorders
Contraindications
- Anxiety disorders
- insomnia
- hypertension
- heart arrhythmias
- People taking Ciprofloxacin
- pregnancy
Interactions
| Drug / Nutrient | Interaction Mechanism | Warning |
|---|---|---|
| Ciprofloxacin | inhibits metabolism — may increase caffeine levels. Theophylline: additive effects — monitor for toxicity. Oral contraceptives: slow caffeine clearance — may enhance effects. | Monitor |
Evidence and Scientific Findings
Ingredient Overview
Biological and Chemical Classification
- Chemical Class
- Xanthine alkaloid
- Biological Class
- Central nervous system stimulant
- Natural Source
- Coffea arabica seeds, Camellia sinensis leaves
- Scientific Name
- 1,3,7-Trimethylxanthine
- Chemical Formula
- C8H10N4O2
- CAS Number
- 58-08-2
Mechanism of Action
Clinical Evidence of Effectiveness
| Indication | Evidence Level | Summary |
|---|---|---|
| General | Moderate | Numerous studies have demonstrated caffeine's efficacy in improving cognitive performance, particularly in tasks requiring sustained attention. It has also been shown to enhance physical performance by increasing endurance and reducing perceived exertion. However, the effects can vary significantly among individuals due to genetic differences in caffeine metabolism. |
Pharmacokinetics
Recommended Dosage
| Condition / Use | Typical Dose |
|---|---|
| Alertness | 100-200 mg as needed. Physical performance: 3-6 mg/kg body weight before exercise. Weight loss: 100-400 mg per day. |
Dosage ranges are based on clinical studies and commonly used supplement formulations. Individual requirements may vary.
SETI — Scientific Evidence Transparency Index
Executive Summary — Ingredient Assessment
- 10 studies reviewed
- 2 high-quality studies (meta-analysis or RCT)
- Main clinical benefit observed: Caffeine, scientifically known as 1,3,7-Trimethylxanthine, is a natural stimulant most commonly found in coffee, tea, and various energy…
- Evidence consistency: High consistency across studies (100%)
- Caffeine consumption is generally safe for most adults at moderate doses, but excessive intake can lead to serious cardiovascular and neurological effects. Pregnant women should limit caffeine intake due to potential risks to fetal development. Individuals with anxiety disorders or heart conditions should use caffeine cautiously.
- USA/FDA — Approved
Current scientific evidence suggests potential clinical benefits for Caffeine; however, some safety concerns have been reported in the literature. Additional large-scale randomized clinical trials are needed to confirm long-term safety and effectiveness.
Total SETI Score
Moderate risk| Evidence quality | 23/40 |
| Evidence consistency | 20/20 |
| Safety signals | 0/20 |
| Study recency | 10/10 |
| Evidence transparency | 10/10 |
Evidence Summary
- 10 studies reviewed
- 2 high-quality studies (meta-analysis or systematic review)
- 0 studies identified benefits or no safety concern (GREEN)
- 10 studies reported limited or advisory safety evidence (YELLOW)
Evidence Policy
Only peer-reviewed scientific literature indexed in PubMed or comparable databases is included in this evaluation. Commercial websites, blogs, and marketing materials are excluded. All references include direct traceable links to source documents.
Last updated: 06 მარ 2026, 12:00
Evidence Distribution
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Observational / other LOW evidence YELLOWUnraveling the complexities of caffeine: metabolism, genetics, evolution, and health. ↗Liu X et al.. Unraveling the complexities of caffeine: metabolism, genetics, evolution, and health.. Hereditas. 2026. PMID:41622288.PMID 41622288 ↗Journal HereditasYear 2026Study type Observational / otherEvidence strength LOW evidencePubMed link https://pubmed.ncbi.nlm.nih.gov/41622288/
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Systematic review HIGH evidence YELLOWInfluence of the CYP1A2 genotype on the exercise performance of physically active individuals under caffeine supplementation: a systematic review. ↗Messenburger GP et al.. Influence of the CYP1A2 genotype on the exercise performance of physically active individuals under caffeine supplementation: a systematic review.. Nutr Res. 2025. PMID:41207073.PMID 41207073 ↗Journal Nutr ResYear 2025Study type Systematic reviewEvidence strength HIGH evidencePubMed link https://pubmed.ncbi.nlm.nih.gov/41207073/
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Meta-analysis HIGH evidence YELLOWEffects of Acute Caffeine Ingestion on Physical Performance and Skill Execution in Volleyball Players: A Systematic Review and Meta-Analysis. ↗Negaresh R et al.. Effects of Acute Caffeine Ingestion on Physical Performance and Skill Execution in Volleyball Players: A Systematic Review and Meta-Analysis.. Int J Exerc Sci. 2025. PMID:41079003.PMID 41079003 ↗Journal Int J Exerc SciYear 2025Study type Meta-analysisEvidence strength HIGH evidencePubMed link https://pubmed.ncbi.nlm.nih.gov/41079003/
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Observational / other LOW evidence YELLOWSynthesis, characterization, and evaluation of the cytotoxic effects of caffeine nanoparticles on K562 cancer cell line. ↗Amirizadeh A et al.. Synthesis, characterization, and evaluation of the cytotoxic effects of caffeine nanoparticles on K562 cancer cell line.. Med Oncol. 2025. PMID:40450083.PMID 40450083 ↗Journal Med OncolYear 2025Study type Observational / otherEvidence strength LOW evidencePubMed link https://pubmed.ncbi.nlm.nih.gov/40450083/
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Case report LOW evidence YELLOWDeath Due to Caffeine and Methamphetamine Toxicity: A Case Report. ↗Kim DG et al.. Death Due to Caffeine and Methamphetamine Toxicity: A Case Report.. Cureus. 2024. PMID:39258035.PMID 39258035 ↗Journal CureusYear 2024Study type Case reportEvidence strength LOW evidencePubMed link https://pubmed.ncbi.nlm.nih.gov/39258035/
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Observational / other LOW evidence YELLOWTRPA1, TRPV1, and Caffeine: Pain and Analgesia. ↗Puthumana EA et al.. TRPA1, TRPV1, and Caffeine: Pain and Analgesia.. Int J Mol Sci. 2024. PMID:39063144.PMID 39063144 ↗Journal Int J Mol SciYear 2024Study type Observational / otherEvidence strength LOW evidencePubMed link https://pubmed.ncbi.nlm.nih.gov/39063144/
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Observational / other LOW evidence YELLOWRecording of hippocampal activity on the effect of convulsant doses of caffeine. ↗Eiru00f3-Quirino L et al.. Recording of hippocampal activity on the effect of convulsant doses of caffeine.. Biomed Pharmacother. 2024. PMID:39032287.PMID 39032287 ↗Journal Biomed PharmacotherYear 2024Study type Observational / otherEvidence strength LOW evidencePubMed link https://pubmed.ncbi.nlm.nih.gov/39032287/
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Observational / other LOW evidence YELLOWAssociation between caffeine metabolites in urine and muscle strength in young and older adults: A cross-sectional study from NHANES 2011-2012. ↗Batista-da-Silva B et al.. Association between caffeine metabolites in urine and muscle strength in young and older adults: A cross-sectional study from NHANES 2011-2012.. Clin Nutr. 2024. PMID:38759491.PMID 38759491 ↗Journal Clin NutrYear 2024Study type Observational / otherEvidence strength LOW evidencePubMed link https://pubmed.ncbi.nlm.nih.gov/38759491/
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Observational / other LOW evidence YELLOWMethionine Supplementation Alleviates the Germ Cell Apoptosis Increased by Maternal Caffeine Intake in a C. elegans Model. ↗Min H et al.. Methionine Supplementation Alleviates the Germ Cell Apoptosis Increased by Maternal Caffeine Intake in a C. elegans Model.. Nutrients. 2024. PMID:38542805.PMID 38542805 ↗Journal NutrientsYear 2024Study type Observational / otherEvidence strength LOW evidencePubMed link https://pubmed.ncbi.nlm.nih.gov/38542805/
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Observational / other LOW evidence YELLOWVitamin B12 Supplementation Improves Oocyte Development by Modulating Mitochondria and Yolk Protein in a Caffeine-Ingested Caenorhabditis elegans Model. ↗Min H et al.. Vitamin B12 Supplementation Improves Oocyte Development by Modulating Mitochondria and Yolk Protein in a Caffeine-Ingested Caenorhabditis elegans Model.. Antioxidants (Basel). 2023. PMID:38247478.PMID 38247478 ↗Journal Antioxidants (Basel)Year 2023Study type Observational / otherEvidence strength LOW evidencePubMed link https://pubmed.ncbi.nlm.nih.gov/38247478/
Score Transparency
0 of 10 approved references (score saturates at 10). More peer-reviewed studies = stronger evidence base.
Method: Q = number of approved references ÷ 10 (capped at 1.0)
Limited — mostly case reports or animal studies
Method: L = mean study-level weight across approved references. Level 1 (meta-analysis / systematic review) = 1.0; Level 2 (RCT) = 0.8; Level 3 (cohort/case-control) = 0.6; Level 4 (case report) = 0.4; Level 5 (animal / in-vitro) = 0.2.
Mixed or neutral — roughly equal benefit and risk signals
Method: D = (sum of risk-scored references − sum of benefit-scored references) ÷ total evidence score, then scaled from [−1, 1] to [0, 1]. 0.0 = pure benefit; 0.5 = neutral; 1.0 = pure risk.
Multiple active safety or regulatory signals
Method: S = 0.5 (neutral baseline) + sum of active signal severity deltas ÷ 10. Severity deltas: Critical = +2.0, High = +1.5, Moderate = +1.0, Low = +0.5. Capped at 1.0.
Final GIRI Score for Caffeine. Risk level thresholds: Low 0–3.0 · Moderate 3.0–5.5 · High 5.5–7.5 · Critical 7.5–10.
Full methodology & data sources
The GIRI Score is computed entirely from structured data — no editorial scoring or subjective weighting is applied at any step.
- References: Only approved references are counted. Each reference is assigned an evidence level (L1–L5) and a direction (risk / neutral / benefit) by the reference manager or AI classifier.
- Safety Signals: Sourced from regulatory agencies (FDA, EMA, Health Canada, TGA, and others) and pharmacovigilance databases. Only active signals count toward the score.
- Formula version: GIRI Score v3.7.0 — Q × L × D × S × 10.
- Limitations: The score reflects published evidence and recorded signals as of the last update date. It is not a clinical risk assessment and should not replace advice from a qualified healthcare professional.
Risk Level Classification
Based on available regulatory signals and scientific evidence, this ingredient presents a moderate safety concern. Caution is advised, particularly at high doses or in sensitive populations.
0–3.0
3.0–5.5
5.5–7.5
7.5–10
The score pin shows exactly where this ingredient falls on the fixed risk scale.
What drove the Moderate classification for Caffeine
A score of 4.0 places this ingredient in the Moderate band. Thresholds: Low 0–3.0 · Moderate 3.0–5.5 · High 5.5–7.5 · Critical 7.5–10.
0 approved references.
Limited — mostly case reports or animal studies (Level 4–5).
Neutral or mixed — benefit and risk signals roughly balanced.
2 active signals (highest severity: Critical). Each active signal raises S above the neutral baseline of 0.5.
1 jurisdiction has active restrictions or advisories. Regulatory signals are recorded as Safety Signals and raise the S component.
How are the Low / Moderate / High / Critical thresholds defined?
The four risk levels are fixed score bands. A score is assigned to exactly one level based on where it falls:
| Level | Score | Meaning |
|---|---|---|
| LOW | 0.0 – 2.9 | Sparse or predominantly beneficial evidence. No active safety alerts. |
| MODERATE | 3.0 – 5.4 | Mixed signals — some risk alongside benefit. Caution at high doses or in sensitive groups. |
| HIGH | 5.5 – 7.4 | Multiple studies or regulatory alerts documenting adverse effects. Professional oversight recommended. |
| CRITICAL | 7.5 – 10 | Regulatory restrictions in one or more major jurisdictions. Serious documented harm. Avoid without specialist supervision. |
Thresholds are fixed constants (GIRI_Score_Utils::LEVEL_THRESHOLDS). They do not change per ingredient and are never subject to editorial adjustment.