Cited by 631Coffee research and impactsAlkaloids: synthesis and pharmacologyAdenosine and Purinergic Signaling

The DOI matches its Crossref record; 190 of the 190 references it cites were found in a registry or an index; none of the 134 sources its claims cite is checked for support yet.

Caffeine: Cognitive and Physical Performance Enhancer or Psychoactive Drug?

Open access
Cappelletti, Simone, Daria, Piacentino, Sani, Gabriele, Aromatario, Mariarosaria·2015·Current Neuropharmacology

Abstract

Caffeine use is increasing worldwide. The underlying motivations are mainly concentration and memory enhancement and physical performance improvement. Coffee and caffeine-containing products affect the cardiovascular system, with their positive inotropic and chronotropic effects, and the central nervous system, with their locomotor activity stimulation and anxiogenic-like effects. Thus, it is of interest to examine whether these effects could be detrimental for health. Furthermore, caffeine abuse and dependence are becoming more and more common and can lead to caffeine intoxication, which puts individuals at risk for premature and unnatural death. The present review summarizes the main findings concerning caffeine's mechanisms of action (focusing on adenosine antagonism, intracellular calcium mobilization, and phosphodiesterases inhibition), use, abuse, dependence, intoxication, and lethal effects. It also suggests that the concepts of toxic and lethal doses are relative, since doses below the toxic and/or lethal range may play a causal role in intoxication or death. This could be due to caffeine's interaction with other substances or to the individuals' preexisting metabolism alterations or diseases.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes caffeine’s pharmacokinetics, mechanisms of action, cardiovascular and central nervous system effects, and its potential for abuse, dependence, intoxication, and lethal toxicity. It argues that toxic and lethal doses are relative, because interactions, preexisting disease, and genetic/metabolic differences can make even sub-toxic doses harmful.

Key findings

  • Caffeine’s main mechanism is competitive adenosine receptor antagonism, especially A1 and A2A, which can occur at low dietary doses; intracellular calcium mobilization and phosphodiesterase inhibition require higher doses unlikely from usual dietary sources.
  • Caffeine half-life in humans ranges from 2 to 12 hours; CYP1A2 accounts for about 95% of caffeine clearance, and caffeine is demethylated mostly to paraxanthine (84%), theobromine (12%), and theophylline (4%).
  • Acute toxic caffeine levels are not well established, but for adults are approximately 10 g/day, comparable to about 100 cups of coffee; life-threatening overdoses usually involve caffeine-containing medications, with blood concentrations in excess of 80 mg/l, and lethal cases often involve supplements or other substances.
  • Human studies provide scarce evidence that caffeine induces arrhythmias in healthy or predisposed subjects, though heavy coffee intake (10 cups/day) was associated with increased sudden cardiac death risk in 117 patients with coronary artery disease (odds ratio=55.7); cognitive benefits remain debated and may reflect relief from withdrawal rather than enhancement.

Methods

  • Conceptual review including retrospective, prospective, and cross-sectional studies examining caffeine’s mechanisms of action, use, abuse, dependence, intoxication, and death.
  • Electronic search of Pubmed, INFORMA healthcare, EMBASE, and PsycINFO from database inception to July 20, 2014, without language restriction; search terms combined caffeine with pharmacokinetics, pharmacodynamics, heart, brain, abuse, dependence, intoxication, or death.
  • The database search selected 29,421 potentially relevant titles, and 20 additional potentially eligible articles were identified by hand-searching reference lists; no unpublished studies were found, and no evidence of language bias or significant publication bias was reported.

Limitations

  • The paper states that tolerance research is limited because most studies compare caffeine-naïve individuals with habitual users or habitual users before/after abstinence; since 80% of the population reports regular caffeine use, nonusers are a selected, atypical subpopulation, and few studies compare repeated caffeine administration with placebo.
  • The paper states that caffeine dependence studies are mainly observational and have difficulty verifying exact caffeine products and amounts, and that many caffeine consumers simultaneously use nicotine or alcohol, which may have overlapping effects.
  • Evident from the text: this is a conceptual review rather than a systematic review or meta-analysis, and although it reports search counts and bias comments, it does not present a formal study-selection flow, quality appraisal, or quantitative synthesis.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.2174/1570159x13666141210215655

Cites

190 of 190 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

86 Not checked yet · 48 No basis given · 37 Own interpretation · 1 Own result

Verify all 134 references — free account

Show all 84 claims

  • It may state two separate claims as one. 57
  • Probably not a substantial claim. 53
88 of 88
  • The paper relies on this without support.

    Caffeine use is increasing worldwide.

    “Caffeine use is increasing worldwide.”
  • The paper relies on this without support.

    Caffeine abuse and dependence are becoming more and more common.

    “Furthermore, caffeine abuse and dependence are becoming more and more common and can lead to caffeine intoxication, which puts individuals at risk for premature and unnatural death.”
  • The paper relies on this without support.

    Caffeine abuse and dependence can lead to caffeine intoxication.

    “Furthermore, caffeine abuse and dependence are becoming more and more common and can lead to caffeine intoxication, which puts individuals at risk for premature and unnatural death.”
  • The paper relies on this without support.

    Caffeine intoxication puts individuals at risk for premature and unnatural death.

    “Furthermore, caffeine abuse and dependence are becoming more and more common and can lead to caffeine intoxication, which puts individuals at risk for premature and unnatural death.”
  • The paper relies on this without support.

    The majority of studies compare caffeine-naive individuals to habitual caffeine users, or habitual users before and after caffeine abstinence.

    “The majority of studies compare caffeine “naïve” individuals to habitual caffeine users, or habitual users before and after caffeine abstinence.”
  • The paper relies on this without support.

    80% of the population report regular use of caffeine.

    “As 80% of the population report regular use of caffeine, nonusers are much selected, atypical subpopulation.”
  • The paper relies on this without support.

    Very few studies compare individuals subjected to repeated caffeine administration versus controls taking placebo.

    “Furthermore, very few studies compare individuals subjected to repeated caffeine administration vs. controls taking placebo.”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

2 of 2

Citations

Cites

Show all 189 references

Research works printed but not linked: 5

  1. [17]Arnaud M.J. Garattini S. Metabolism of caffeine and other components of coffee Caffeine, coffee and health 1993 New York Raven Press 43 95
  2. [21]Daly J. Garattini S. Mechanism of action of caffeine. Caffeine, Coffee, and Health. 1993 New York Raven Press 97 149
  3. [163]American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorderss 2013 Fifth Edition (DSM-5) Arlington APA
  4. [170]Moffatt A.C. Osselton M.D. Widdop B. Galichet L.Y. Clarke’s Analysis of Drugs and Poisons in Pharmaceuticals, Body Fluids and Postmortem Material. 2011 4th ed London Pharmaceutical Press 36
  5. [174]Bryant J. Suicide by ingestion of caffeine. Arch. Pathol. Lab. Med. 1981 105 12 685 686 6895464

Cited by

Sorted by citations

Items 601–627 of 627

Metadata

Authors
Cappelletti, S., Daria, P., Sani, G., & Aromatario, M.
Affiliations
Sapienza University of Rome (IT)
Corresponding author
Aromatario, Mariarosaria
Venue
Current Neuropharmacology
Published
2015-04-13
Volume
13
Issue
1
Pages
71-88
ISSN
1570-159X (ISSN-L)
OpenAlex
W2314874570
Cited by
631
References
189
Citations by year
2026: 58 · 2025: 81 · 2024: 86 · 2023: 93 · 2022: 76 · 2021: 71 · 2020: 49 · 2019: 49 · 2018: 35 · 2017: 19 · 2016: 11 · 2015: 3
FWCI
1.41
Type
journal article
Language
en
Open access
Locations
  • Current Neuropharmacology (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, other-oa)
Funders
National Collegiate Athletic Association
Topics
  • Health Sciences › Medicine › Pharmacology (medical) › Coffee research and impacts
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Alkaloids: synthesis and pharmacology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
Keywords
caffeine, cognitive enhancement, physical performance, adenosine antagonism, calcium mobilization, phosphodiesterase inhibition, caffeine toxicity, caffeine dependence, cardiovascular effects, central nervous system stimulation, anxiogenic effects, lethal dose, drug interactions, caffeine metabolism
MeSH terms
Central Nervous System Stimulants, Caffeine, Drug Utilization, Humans, Nootropic Agents, Substance-Related Disorders, Athletic Performance

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review