Evidence map›Paper›PMID 25679525›Full record

ArticlePloS one2015

Menthol attenuates respiratory irritation and elevates blood cotinine in cigarette smoke exposed mice.

Michael A Ha, Gregory J Smith, Joseph A Cichocki, Lu Fan, Yi-Shiuan Liu, Ana I Caceres, Sven Eric Jordt, John B Morris

Open access · goldAbstract read
In one paragraph

Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.

0numbers the graph read from it
0cells of the map it votes in
55citing papers in PubMed
4.4field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

55 citing papers in PubMed, 72 citations in OpenAlex.

  1. Trial
  2. Trial
  3. Article
  4. Commentary Paper on Cooling Flavors in Cigarette and Non-Cigarette Tobacco Products.Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco · 2026
    Article
  5. Influence of e-cigarettes and their constituents on cardiac rhythm and arrhythmias.American journal of physiology. Heart and circulatory physiology · 2026
    Review
  6. Review
  7. Chemosensory tobacco product toxicology part 2: toxicological testing, assays, and state of the science.Toxicological sciences : an official journal of the Society of Toxicology · 2025
    Review
  8. Article
  9. Article
  10. Article
  11. Review
  12. Article
  13. Review
  14. Article
  15. Article
  16. Article
  17. Comparison of Carcinogen Biomarkers in Smokers of Menthol and Nonmenthol Cigarettes: The 2015-2016 National Health and Nutrition Examination Survey Special Sample.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2022
    Article
  18. Synthetic Cooling Agents in US-marketed E-cigarette Refill Liquids and Popular Disposable E-cigarettes: Chemical Analysis and Risk Assessment.Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco · 2022
    Article
  19. Review
  20. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 3 institutions in 1 country.

Michael A HaToxicology Program, Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, United States of America.
Gregory J SmithToxicology Program, Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, United States of America.
Joseph A CichockiToxicology Program, Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, United States of America.
Lu FanDepartment of Psychiatry, Yale School of Medicine, New Haven, Connecticut, United States of America.
Yi-Shiuan LiuDepartment of Pharmacology, Yale School of Medicine, New Haven, Connecticut, United States of America.
Ana I CaceresDepartment of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, United States of America.
Sven Eric JordtDepartment of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, United States of America.
John B MorrisToxicology Program, Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, United States of America.
University of Connecticut · USDuke University · USYale University · US

Funding

Yale Tobacco Center of Regulatory ScienceP50DA036151 · NIDA · YALE UNIVERSITY · PI KRISHNAN-SARIN, SUCHITRA, O'MALLEY, STEPHANIE S · 2013 to 2017
$20.6M
TRPA1 Channels Sensory Neurons Environmental IrritantsR01ES015056 · NIEHS · YALE UNIVERSITY · PI JORDT, SVEN-ERIC · 2006 to 2012
$2.8M
Counter-Irritation by Menthol: Molecular Targets and Role in Airway DiseaseR01HL105635 · NHLBI · YALE UNIVERSITY · PI JORDT, SVEN-ERIC, MORRIS, JOHN B · 2011 to 2014
$2.4M
NHLBI NIH HHS R01 HL105635NHLBI NIH HHS R01HL105635NHLBI NIH HHS R01HL105635-S1NIEHS NIH HHS R01 ES015056NIEHS NIH HHS R01ES015056
6 · The paper itself

Abstract

Addition of menthol to cigarettes may be associated with increased initiation of smoking. The potential mechanisms underlying this association are not known. Menthol, likely due to its effects on cold-sensing peripheral sensory neurons, is known to inhibit the sensation of irritation elicited by respiratory irritants. However, it remains unclear whether menthol modulates cigarette smoke irritancy and nicotine absorption during initial exposures to cigarettes, thereby facilitating smoking initiation. Using plethysmography in a C57Bl/6J mouse model, we examined the effects of L-menthol, the menthol isomer added to cigarettes, on the respiratory sensory irritation response to primary smoke irritants (acrolein and cyclohexanone) and smoke of Kentucky reference 2R4 cigarettes. We also studied L-menthol's effect on blood levels of the nicotine metabolite, cotinine, immediately after exposure to cigarette smoke. L-menthol suppressed the irritation response to acrolein with an apparent IC₅₀ of 4 ppm. Suppression was observed even at acrolein levels well above those necessary to produce a maximal response. Cigarette smoke, at exposure levels of 10 mg/m³ or higher, caused an immediate and marked sensory irritation response in mice. This response was significantly suppressed by L-menthol even at smoke concentrations as high as 300 mg/m³. Counterirritation by L-menthol was abolished by treatment with a selective inhibitor of Transient Receptor Potential Melastatin 8 (TRPM8), the neuronal cold/menthol receptor. Inclusion of menthol in the cigarette smoke resulted in roughly a 1.5-fold increase in plasma cotinine levels over those observed in mice exposed to smoke without added menthol. These findings document that, L-menthol, through TRPM8, is a strong suppressor of respiratory irritation responses, even during highly noxious exposures to cigarette smoke or smoke irritants, and increases blood cotinine. Therefore, L-menthol, as a cigarette additive, may promote smoking initiation and nicotine addiction.

Indexed as

AcroleinAnimalsCotinineFemaleIrritantsMentholMiceRespirationSmokingTRPM Cation ChannelsAcroleinCotinineIrritantsMentholTRPM8 protein, mouseTRPM Cation Channels

Identifiers

PMID25679525
PMCPMC4334501
OpenAlexW2047108864

What OpenQuestion holds

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LicenceCC BY
Read underepoch 390

Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.