Definition and research guide
This page combines a MeSH definition, publication statistics and selected research abstracts. It is a starting point for reading the literature, not a medical textbook or a systematic evidence review.
Content available: 4 complete abstracts (788 words), 10 references. Full article text is not stored or reproduced here; follow the PMID, DOI or PMC links to read the original sources and their access terms.
Definition
A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine's most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes smooth muscle, stimulates cardiac muscle, stimulates diuresis, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling.
Definition: NLM Medical Subject Headings (MeSH) scope note (Public domain (U.S. National Library of Medicine); attribution requested). View the MeSH record.
Also known as: 1,3,7-Trimethylxanthine; No Doz; Caffedrine; Coffeinum N; Coffeinum Purrum; Dexitac; Durvitan; Percoffedrinol N.
Where it fits in the MeSH classification
- Broader topics
- Xanthines
Related concepts
- Smooth Muscle
- Myocardium
- Diuresis
- Phosphodiesterases
- Adenosine Receptors
Research landscape
PubMed indexes 27,085 records tagged with the MeSH heading “Caffeine” (counts retrieved 2026-10-31). 3,788 of them (14.0%) were published from 2020 onward, and the busiest period so far is through 1999 with 12,694 records.
Reviews account for 2,083 records (7.7%) and meta-analyses for 270. Randomized controlled trials number 1,897 (7.0%) as a share of all records on the topic.
Show the data
| Period | Records |
|---|---|
| through 1999 | 12,694 |
| 2000-2009 | 5,041 |
| 2010-2019 | 5,562 |
| 2020 onward | 3,788 |
Publication-type chart data
| Type | Records | Share |
|---|---|---|
| Reviews | 2,083 | 7.7% |
| Meta-analyses | 270 | 1.0% |
| Randomized controlled trials | 1,897 | 7.0% |
Method: PubMed query "Caffeine"[MeSH Terms] with publication-type and date filters, retrieved 2026-10-31.
Reading the evidence in drugs and chemicals
Studies of a chemical or drug can answer very different questions: what it is and how it behaves in cells and animals, how the body handles it, and whether it changes outcomes in people. Laboratory and animal findings often do not carry over to patients, and observational studies of exposures are confounded by who uses a substance and why. Nothing on this page is a recommendation to use, avoid, start or stop any substance or medicine; talk to a qualified clinician or pharmacist about your own situation. Check the dose, the species, the comparison group and whether a patient-relevant outcome was measured.
Evidence from open-access studies
These open-access studies come from PubMed’s best-match results for this heading (papers whose main topic it is), ranked here by citation count, with one recent addition. Each abstract is reproduced in full under its recorded open licence so that you can read the authors’ own words. They illustrate the literature; they are not a systematic summary of it. Citation counts measure attention, not reliability or clinical benefit.
| Study / authors | Year | Source label / design | Europe PMC citations | Licence / source |
|---|---|---|---|---|
| Association of Coffee Consumption and Prediagnostic Caffeine Metabolites With Incident Parkinson Disease in a Population-Based Cohort | 2024 | Research article Design not recorded in structured metadata | 32 | cc by PMID 38513162 · DOI · PMC11175631 |
| Dose and timing effects of caffeine on subsequent sleep: a randomized clinical crossover trial | 2025 | Randomized controlled trial Design not recorded in structured metadata | 30 | cc by PMID 39377163 · DOI · PMC11985402 |
| Caffeine for apnea and prevention of neurodevelopmental impairment in preterm infants: systematic review and meta-analysis | 2024 | Meta-analysis Design not recorded in structured metadata | 28 | cc by PMID 38553606 · DOI · PMC11161406 |
| Caffeine inhibits nonhomologous end joining by impairing ligase IV/XRCC4 function | 2026 | Research article Design not recorded in structured metadata | 1 | cc by PMID 41773020 · DOI · PMC12956356 |
Association of Coffee Consumption and Prediagnostic Caffeine Metabolites With Incident Parkinson Disease in a Population-Based Cohort [1]
Abstract reading summary — source excerpts
- Opening excerpt
- Background and objectivesInverse associations between caffeine intake and Parkinson disease (PD) have been frequently implicated in human studies.
- Closing excerpt
- DiscussionThis study demonstrates that the neuroprotection of coffee on PD is attributed to caffeine and its metabolites by detailed quantification of plasma caffeine and its metabolites years before diagnosis.
- Interpretation limits
- Verbatim excerpts from the authors’ abstract; the closing excerpt may describe a finding, limitation or recommendation. Design, population, effect size and uncertainty have not been independently extracted or appraised. Read the complete abstract and linked paper before interpreting the findings.
Read complete abstract (282 words)
Background and objectivesInverse associations between caffeine intake and Parkinson disease (PD) have been frequently implicated in human studies. However, no studies have quantified biomarkers of caffeine intake years before PD onset and investigated whether and which caffeine metabolites are related to PD.MethodsAssociations between self-reported total coffee consumption and future PD risk were examined in the EPIC4PD study, a prospective population-based cohort including 6 European countries. Cases with PD were identified through medical records and reviewed by expert neurologists. Hazard ratios (HRs) and 95% CIs for coffee consumption and PD incidence were estimated using Cox proportional hazards models. A case-control study nested within the EPIC4PD was conducted, recruiting cases with incident PD and matching each case with a control by age, sex, study center, and fasting status at blood collection. Caffeine metabolites were quantified by high-resolution mass spectrometry in baseline collected plasma samples. Using conditional logistic regression models, odds ratios (ORs) and 95% CIs were estimated for caffeine metabolites and PD risk.ResultsIn the EPIC4PD cohort (comprising 184,024 individuals), the multivariable-adjusted HR comparing the highest coffee intake with nonconsumers was 0.63 (95% CI 0.46-0.88, p = 0.006). In the nested case-control study, which included 351 cases with incident PD and 351 matched controls, prediagnostic caffeine and its primary metabolites, paraxanthine and theophylline, were inversely associated with PD risk. The ORs were 0.80 (95% CI 0.67-0.95, p = 0.009), 0.82 (95% CI 0.69-0.96, p = 0.015), and 0.78 (95% CI 0.65-0.93, p = 0.005), respectively. Adjusting for smoking and alcohol consumption did not substantially change these results.DiscussionThis study demonstrates that the neuroprotection of coffee on PD is attributed to caffeine and its metabolites by detailed quantification of plasma caffeine and its metabolites years before diagnosis.
Abstract reproduced from the open-access article under the recorded cc by licence; © the authors. PMID 38513162 · DOI · PMC11175631
Dose and timing effects of caffeine on subsequent sleep: a randomized clinical crossover trial [2]
Abstract reading summary — source excerpts
- Opening excerpt
- Study objectivesTo investigate the effect of a typical dose of caffeine and a high dose of caffeine consumed in the morning, afternoon, and evening on subsequent sleep.
- Closing excerpt
- ACTRN=12621001625864.
- Interpretation limits
- Verbatim excerpts from the authors’ abstract; the closing excerpt may describe a finding, limitation or recommendation. Design, population, effect size and uncertainty have not been independently extracted or appraised. Read the complete abstract and linked paper before interpreting the findings.
Read complete abstract (159 words)
Study objectivesTo investigate the effect of a typical dose of caffeine and a high dose of caffeine consumed in the morning, afternoon, and evening on subsequent sleep.MethodsUsing a placebo-controlled, double-blind, randomized crossover design, 23 males (25.3 ± 5.0 years) with a moderate habitual caffeine intake (ResultsNo significant effect on objective or subjective sleep occurred with the 100 mg dose of caffeine compared with the placebo (p > .05), but significant effects occurred with the 400 mg dose (p ConclusionsA 100 mg dose of caffeine can be consumed up to 4 hours prior to bedtime, but 400 mg may negatively impact sleep when consumed as one dose within 12 hours of bedtime, with the adverse influence on sleep increasing the closer consumption occurs to bedtime. The discrepancy between objective and subjective sleep quality suggests that individuals may have difficulty accurately perceiving the influence of caffeine on sleep quality.Clinical trial registrationAustralian and New Zealand Clinical Trials Registry, registration number: ACTRN12621001625864, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12621001625864.
Abstract reproduced from the open-access article under the recorded cc by licence; © the authors. PMID 39377163 · DOI · PMC11985402
Caffeine for apnea and prevention of neurodevelopmental impairment in preterm infants: systematic review and meta-analysis [3]
Abstract reading summary — source excerpts
- Opening excerpt
- This systematic review and meta-analysis evaluated the evidence for dose and effectiveness of caffeine in preterm infants.
- Closing excerpt
- The optimal dose remains unknown; further long-term studies, are needed.
- Interpretation limits
- Verbatim excerpts from the authors’ abstract; the closing excerpt may describe a finding, limitation or recommendation. Design, population, effect size and uncertainty have not been independently extracted or appraised. Read the complete abstract and linked paper before interpreting the findings.
Read complete abstract (153 words)
This systematic review and meta-analysis evaluated the evidence for dose and effectiveness of caffeine in preterm infants. MEDLINE, EMBASE, CINHAL Plus, CENTRAL, and trial databases were searched to July 2022 for trials randomizing preterm infants to caffeine vs. placebo/no treatment, or low (≤10 mg·kg-1) vs. high dose (>10 mg·kg-1 caffeine citrate equivalent). Two researchers extracted data and assessed risk of bias using RoB; GRADE evaluation was completed by all authors. Meta-analysis of 15 studies (3530 infants) was performed in REVMAN across four epochs: neonatal/infant (birth-1 year), early childhood (1-5 years), middle childhood (6-11 years) and adolescence (12-19 years). Caffeine reduced apnea (RR 0.59; 95%CI 0.46,0.75; very low certainty) and bronchopulmonary dysplasia (0.77; 0.69,0.86; moderate certainty), with higher doses more effective. Caffeine had no effect on neurocognitive impairment in early childhood but possible benefit on motor function in middle childhood (0.72; 0.57,0.91; moderate certainty). The optimal dose remains unknown; further long-term studies, are needed.
Abstract reproduced from the open-access article under the recorded cc by licence; © the authors. PMID 38553606 · DOI · PMC11161406
Caffeine inhibits nonhomologous end joining by impairing ligase IV/XRCC4 function [4]
Abstract reading summary — source excerpts
- Opening excerpt
- DNA double-strand breaks (DSBs), the most lethal DNA lesions, are repaired primarily by homologous recombination (HR) or nonhomologous end joining (NHEJ).
- Closing excerpt
- Thus, caffeine suppresses NHEJ by directly inhibiting ligase IV/XRCC4-mediated DNA end joining.
- Interpretation limits
- Verbatim excerpts from the authors’ abstract; the closing excerpt may describe a finding, limitation or recommendation. Design, population, effect size and uncertainty have not been independently extracted or appraised. Read the complete abstract and linked paper before interpreting the findings.
Read complete abstract (194 words)
DNA double-strand breaks (DSBs), the most lethal DNA lesions, are repaired primarily by homologous recombination (HR) or nonhomologous end joining (NHEJ). Caffeine is known to inhibit HR by displacing Rad51 from single-stranded DNA, but its impact on NHEJ was unclear. Here, we show that caffeine inhibits NHEJ in a concentration-dependent manner using biochemical and cellular assays. Increased 53BP1 and γ-H2AX foci upon caffeine exposure indicate inhibition of chromosomal NHEJ, leading to accumulation of DSBs. γ-H2AX immunofluorescence, neutral comet, and TUNEL assays revealed persistent DNA breaks and reduced repair. Mechanistically, in silico, biophysical, and biochemical analyses demonstrate that caffeine directly binds to XRCC4, disrupting its interaction with DNA ligase IV and thereby inhibiting repair. Biolayer interferometry confirmed caffeine-XRCC4 binding, with mutation of Thr133 reducing caffeine affinity and impairing XRCC4 recruitment to γ-H2AX-marked DSBs. Disruption of the predicted caffeine interaction site in XRCC4 (T133A) partially restored end joining in the presence of caffeine. Clonogenic survival assays showed decreased survival after caffeine treatment, more prominently in wild-type than in ligase IV-deficient cells. Immunodepletion and reconstitution experiments confirmed that caffeine specifically targets the ligase IV/XRCC4 complex. Thus, caffeine suppresses NHEJ by directly inhibiting ligase IV/XRCC4-mediated DNA end joining.
Abstract reproduced from the open-access article under the recorded cc by licence; © the authors. PMID 41773020 · DOI · PMC12956356
Key reviews and meta-analyses
The most cited review-type papers among PubMed’s best-match results for this heading, listed with bibliographic details only. Follow the links for the full text and access terms.
- Research article Coffee consumption and health: umbrella review of meta-analyses of multiple health outcomes [5]
- Research article International society of sports nutrition position stand: caffeine and exercise performance [6]
- Research article Interindividual Differences in Caffeine Metabolism and Factors Driving Caffeine Consumption [7]
- Research article Coffee, Caffeine, and Health Outcomes: An Umbrella Review [8]
- Research article Coffee, Caffeine, and Health [9]
- Research article Effects of caffeine ingestion on rating of perceived exertion during and after exercise: a meta-analysis [10]
References
- Zhao Y, Lai Y, Konijnenberg H, Huerta JM, Vinagre-Aragon A, Sabin JA, et al.. Association of Coffee Consumption and Prediagnostic Caffeine Metabolites With Incident Parkinson Disease in a Population-Based Cohort. . 2024. PMID 38513162 · DOI · PMC11175631
- Gardiner CL, Weakley J, Burke LM, Fernandez F, Johnston RD, Leota J, et al.. Dose and timing effects of caffeine on subsequent sleep: a randomized clinical crossover trial. . 2025. PMID 39377163 · DOI · PMC11985402
- Oliphant EA, Hanning SM, McKinlay CJD, Alsweiler JM. Caffeine for apnea and prevention of neurodevelopmental impairment in preterm infants: systematic review and meta-analysis. . 2024. PMID 38553606 · DOI · PMC11161406
- Kumari S, Sathees D, Rai PK, Sahu LR, Raghavan SC. Caffeine inhibits nonhomologous end joining by impairing ligase IV/XRCC4 function. . 2026. PMID 41773020 · DOI · PMC12956356
- Poole R, Kennedy OJ, Roderick P, Fallowfield JA, Hayes PC, Parkes J. Coffee consumption and health: umbrella review of meta-analyses of multiple health outcomes. BMJ. 2017. PMID 29167102 · DOI · PMC5696634
- Guest NS, VanDusseldorp TA, Nelson MT, Grgic J, Schoenfeld BJ, Jenkins NDM, et al.. International society of sports nutrition position stand: caffeine and exercise performance. J Int Soc Sports Nutr. 2021. PMID 33388079 · DOI · PMC7777221
- Nehlig A. Interindividual Differences in Caffeine Metabolism and Factors Driving Caffeine Consumption. Pharmacol Rev. 2018. PMID 29514871 · DOI
- Grosso G, Godos J, Galvano F, Giovannucci EL. Coffee, Caffeine, and Health Outcomes: An Umbrella Review. Annu Rev Nutr. 2017. PMID 28826374 · DOI
- van Dam RM, Hu FB, Willett WC. Coffee, Caffeine, and Health. N Engl J Med. 2020. PMID 32706535 · DOI
- Doherty M, Smith PM. Effects of caffeine ingestion on rating of perceived exertion during and after exercise: a meta-analysis. Scand J Med Sci Sports. 2005. PMID 15773860 · DOI
About this article
- Sources
- NLM Medical Subject Headings (definition, synonyms); NCBI PubMed (counts, identifiers); Europe PMC (open-access abstracts and citation counts).
- Verification
- Every reference was resolved against PubMed on 2026-10-31; title, year and DOI matched.
- Review state
- automated source verified; no human expert review has been recorded yet.
- Version
- 1, last updated 2026-10-31.
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Evidence strength
EvidenceHelix's computed view of the study designs behind this topic: how common meta-analyses, randomized trials and reviews are, how recent the literature is, and a plain-language reading. It describes the design mix of the literature. It is not a quality appraisal of any study, and it is not medical advice.