Menthol is a common additive in tobacco products and reduces the aversiveness of nicotine. While numerous studies have examined the effects of menthol in cigarettes on nicotine exposure and other addiction-related outcomes, no clinical study to date has investigated the influence of menthol on nicotine pharmacokinetics (PK) and abuse liability in smokeless tobacco (ST).
Aims:
The current study investigated the effects of varying levels of menthol in ST on nicotine PK, pharmacodynamics (i.e., heart rate and blood pressure), hypothetical purchasing, subjective effects (e.g., withdrawal, craving, and liking), and nicotine extraction from ST.
Methods:
Twenty-eight male participants completed five sessions of prescribed ST use in a within-subjects, crossover design that included participants’ usual-brand ST products and study ST products in which nicotine concentration was held constant and menthol levels were systematically varied: non-menthol, 1 mg of menthol per g of ST, 3 mg/g menthol, and 5 mg/g menthol.
Results:
No significant differences in nicotine or cotinine PK, heart rate, hypothetical purchasing, or nicotine extraction were observed between products. Subjective ratings of “cooling” significantly differed between the non-menthol and mentholated study products, and higher ratings of cooling were associated with greater positive subjective effects.
Conclusions:
These results suggest that menthol content up to 5 mg/g is unlikely to significantly impact nicotine absorption and may have a limited impact on the subjective experience of using ST.
AhijevychKGarrettBE (2004) Menthol pharmacology and its potential impact on cigarette smoking behavior. Nicotine Tob Res6: S17–S28.
2.
AhijevychKGarrettBE (2010) The role of menthol in cigarettes as a reinforcer of smoking behavior. Nicotine Tob Res12: S110–116.
3.
AliFRMSeamanELDiazMC, et al. (2024) Trends in unit sales of cooling flavoured e-cigarettes, USA, 2017–2021. Tob Control33: 147–153.
4.
AlsharariSDKingJRNordmanJC, et al. (2015) Effects of menthol on nicotine pharmacokinetic, pharmacology and dependence in mice. PLoS One10: e0137070.
5.
BagdasDCamBGulZ, et al. (2020) Impact of menthol on oral nicotine consumption in female and male sprague dawley rats. Nicotine Tob Res22: 196–203.
6.
BenowitzNLDainsKMDempseyD, et al. (2011) Racial differences in the relationship between number of cigarettes smoked and nicotine and carcinogen exposure. Nicotine Tob Res13: 772–783.
BlankMDSamsCWeaverMF, et al. (2008) Nicotine delivery, cardiovascular profile, and subjective effects of an oral tobacco product for smokers. Nicotine Tob Res10: 417–421.
9.
BuchhalterARAcostaMCEvansSE, et al. (2005) Tobacco abstinence symptom suppression: The role played by the smoking-related stimuli that are delivered by denicotinized cigarettes. Addiction100: 550–559.
10.
CassidyRNLongVTideyJW, et al. (2020) Validation of an E-cigarette purchase task in advanced generation device users. Nicotine Tob Res22: 1851–1859.
11.
Centers for Disease Control and Prevention (2010) State-specific prevalence of cigarette smoking and smokeless tobacco use among adults—United States, 2009. MMWR Morb Mortal Wkly Rep59: 1400–1406.
12.
ChenCIsabelleLMPickworthWB, et al. (2010) Levels of mint and wintergreen flavorants: Smokeless tobacco products versus confectionery products. Food Chem Toxicol48: 755–763.
13.
CobbCOLopezAASouleEK, et al. (2019) Influence of electronic cigarette liquid flavors and nicotine concentration on subjective measures of abuse liability in young adult cigarette smokers. Drug Alcohol Depend203: 27–34.
14.
CohnAMAlexanderACEhlkeSJ (2022) Affirming the abuse liability and addiction potential of menthol: Differences in subjective appeal to smoking menthol versus non-menthol cigarettes across African American and White young adult smokers. Nicotine Tob Res24: 20–27.
15.
CohnAMGanzODennhardtAA, et al. (2020) Menthol cigarette smoking is associated with greater subjective reward, satisfaction, and “throat hit,” but not greater behavioral economic demand. Addict Behav101: 106108.
16.
DelnevoCDHrywnaMMiller LoEJ, et al. (2021) Examining market trends in smokeless tobacco sales in the United States: 2011–2019. Nicotine Tob Res23: 1420–1424.
17.
DiazMCDonovanEMSchilloBA, et al. (2021) Menthol e-cigarette sales rise following 2020 FDA guidance. Tob Control30: 700–703.
18.
DigardHProctorCKulasekaranA, et al. (2013) Determination of nicotine absorption from multiple tobacco products and nicotine gum. Nicotine Tob Res15: 255–261.
19.
DimovaHSchroederMJPickworthWB, et al. (2024) The effects of changes in cigarette menthol content on acute nicotine pharmacology and smoking topography. Nicotine Tob Res27: 676–683.
20.
DolanSMcDonaldJClausE, et al. (2024) A method for amending loose smokeless tobacco with menthol for administration in clinical studies. Nicotine Tob Res26: 1244–1247.
21.
EbbertJOPattenCASchroederDR (2006) The Fagerstrom test for nicotine dependence-smokeless tobacco (FTND-ST). Addict Behav31: 1716–1721.
22.
FaganPMoolchanETHartAJr, et al. (2010) Nicotine dependence and quitting behaviors among menthol and non-menthol smokers with similar consumptive patterns. Addiction105: 55–74.
23.
FaganPPokhrelPHerzogTA, et al. (2015) Nicotine metabolism in young adult daily menthol and nonmenthol smokers. Nicotine Tob Res18: 437–446.
24.
FanLBalakrishnaSJabbaSV, et al. (2016) Menthol decreases oral nicotine aversion in C57BL/6 mice through a TRPM8-dependent mechanism. Tob Control25: ii50–ii54.
25.
FantRVHenningfieldJENelsonRA, et al. (1999) Pharmacokinetics and pharmacodynamics of moist snuff in humans. Tob Control8: 387–392.
26.
Gonzalez-RozAJacksonJMurphyC, et al. (2019) Behavioral economic tobacco demand in relation to cigarette consumption and nicotine dependence: A meta-analysis of cross-sectional relationships. Addiction114: 1926–1940.
27.
GriffithsRRBigelowGEAtorNA (2003) Principles of initial experimental drug abuse liability assessment in humans. Drug Alcohol Depend70: S41–S54.
28.
HaMASmithGJCichockiJA, et al. (2015) Menthol attenuates respiratory irritation and elevates blood cotinine in cigarette smoke exposed mice. PLoS One10: e0117128.
29.
HarrisonEBiswasLAvusulaR, et al. (2017) Effects of menthol and its interaction with nicotine-conditioned cue on nicotine-seeking behavior in rats. Psychopharmacology (Berl)234: 3443–3453.
30.
HatsukamiDKKeenanRMAntonDJ (1988) Topographical features of smokeless tobacco use. Psychopharmacology (Berl)96: 428–429.
31.
HeathertonTFKozlowskiLTFreckerRC, et al. (1991) The Fagerstrom test for nicotine dependence: A revision of the Fagerstrom Tolerance Questionnaire. Br J Addict86: 1119–1127.
32.
HenningfieldJERadziusAConeEJ (1995) Estimation of available nicotine content of six smokeless tobacco products. Tob Control4: 57–61.
33.
HughesJRHatsukamiD (1986) Signs and symptoms of tobacco withdrawal. Arch Gen Psychiatry43: 289–294.
34.
JaoNCVeluz-WilkinsAKSmithMJ, et al. (2017) Does menthol cigarette use moderate the effect of nicotine metabolism on short-term smoking cessation?Exp Clin Psychopharmacol25: 216–222.
35.
KoffarnusMNFranckCTSteinJS, et al. (2015) A modified exponential behavioral economic demand model to better describe consumption data. Exp Clin Psychopharmacol23: 504–512.
36.
KuiperNMGammonDLoomisB, et al. (2018) Trends in sales of flavored and menthol tobacco products in the United States during 2011–2015. Nicotine Tob Res20: 698–706.
37.
LawrenceDCadmanBHoffmanAC (2011) Sensory properties of menthol and smoking topography. Tob Induc Dis9: S3.
38.
LeasECBenmarhniaTStrongDR, et al. (2022) Use of menthol cigarettes, smoking frequency, and nicotine dependence among US youth. JAMA Netw Open5: e2217144.
39.
LemmondsCAHechtSSJensenJA, et al. (2005) Smokeless tobacco topography and toxin exposure. Nicotine Tob Res7: 469–474.
40.
LunellELunellM (2005) Steady-state nicotine plasma levels following use of four different types of Swedish snus compared with 2-mg Nicorette chewing gum: A crossover study. Nicotine Tob Res7: 397–403.
41.
ManteyDSChido-AmajuoyiOGOmega-NjemnobiO, et al. (2021) Cigarette smoking frequency, quantity, dependence, and quit intentions during adolescence: Comparison of menthol and non-menthol smokers (National Youth Tobacco Survey 2017–2020). Addict Behav121: 106986.
42.
MeadELDuffyVOnckenC, et al. (2019) E-cigarette palatability in smokers as a function of flavorings, nicotine content and propylthiouracil (PROP) taster phenotype. Addict Behav91: 37–44.
43.
MillsSDHaoYRibislKM, et al. (2021) The relationship between menthol cigarette use, smoking cessation, and relapse: Findings from waves 1 to 4 of the population assessment of tobacco and health study. Nicotine Tob Res23: 966–975.
44.
MuscatJELiuHPStellmanSD, et al. (2012) Menthol smoking in relation to time to first cigarette and cotinine: Results from a community-based study. Regul Toxicol Pharmacol63: 166–170.
45.
MushtaqNBeebeLAVeselySK, et al. (2014) A multiple motive/multi-dimensional approach to measure smokeless tobacco dependence. Addict Behav39: 622–629.
46.
NighborTMeredithSSalazarE, et al. (2023) A comparison of use topography and nicotine pharmacokinetics among loose and portioned smokeless tobacco users. Nicotine Tob Res25: 624–630.
47.
NkosiLOdaniSAgakuIT (2022) 20-year trends in tobacco sales and self-reported tobacco use in the United States, 2000–2020. Prev Chronic Dis19: E45.
48.
NonnemakerJFeirmanSPMacMonegleA, et al. (2019) Examining the role of menthol cigarettes in progression to established smoking among youth. Addict Behav98: 106045.
49.
OliverAJJensenJAVogelRI, et al. (2013) Flavored and nonflavored smokeless tobacco products: rate, pattern of use, and effects. Nicotine Tob Res15: 88–92.
50.
OmaiyeEELuoWMcWhirterKJ, et al. (2022) Flavour chemicals, synthetic coolants and pulegone in popular mint-flavored and menthol-flavored e-cigarettes. Tob Control31: e3–e9.
51.
OnckenCALittMDMcLaughlinLD, et al. (2015) Nicotine concentrations with electronic cigarette use: Effects of sex and flavor. Nicotine Tob Res17: 473–478.
52.
PangRDGoldensonNIKirkpatrickM, et al. (2020) Sex differences in the appeal of flavored e-cigarettes among young adult e-cigarette users. Psychol Addict Behav34: 303–307.
53.
PerkinsKAGerlachDVenderJ, et al. (2001) Sex differences in the subjective and reinforcing effects of visual and olfactory cigarette smoke stimuli. Nicotine Tob Res3: 141–150.
54.
PerkinsKAKarelitzJLKunkleN (2018) Evaluation of menthol per se on acute perceptions and behavioral choice of cigarettes differing in nicotine content. J Psychopharmacol32: 324–331.
55.
PickworthWBRosenberryZRGoldW, et al. (2014) Nicotine absorption from smokeless tobacco modified to adjust pH. J Addict Res Ther5: 1000184.
56.
RathJMVillantiACWilliamsVF, et al. (2016) Correlates of current menthol cigarette and flavored other tobacco product use among U.S. young adults. Addict Behav62: 35–41.
57.
SquierCAMantzMJWertzPW (2010) Effect of menthol on the penetration of tobacco carcinogens and nicotine across porcine oral mucosa ex vivo. Nicotine Tob Res12: 763–767.
58.
SteinJSKoffarnusMNSniderSE, et al. (2015) Identification and management of nonsystematic purchase task data: Toward best practice. Exp Clin Psychopharmacol23: 377–386.
59.
StricklandJCVsevolozhskayaOAStoopsWW (2021) E-cigarette demand: Impact of commodity definitions and test-retest reliability. Nicotine Tob Res23: 557–565.
60.
TomarSLHenningfieldJE (1997) Review of the evidence that pH is a determinant of nicotine dosage from oral use of smokeless tobacco. Tob Control6: 219–225.
61.
ValentineGWDeVitoEEJatlowPI, et al. (2018) Acute effects of inhaled menthol on the rewarding effects of intravenous nicotine in smokers. J Psychopharmacol32: 986–994.
62.
VillantiACJohnsonALGlasserAM, et al. (2019) Association of flavored tobacco use with tobacco initiation and subsequent use among U.S. youth and adults, 2013–2015. JAMA Netw Open2: e1913804.
63.
VillantiACMoweryPDDelnevoCD, et al. (2016) Changes in the prevalence and correlates of menthol cigarette use in the USA, 2004–2014. Tob Control25: ii14–ii20.
64.
WatkinsSLPieperFChaffeeBW, et al. (2022) Flavored tobacco product use among young adults by race and ethnicity: Evidence from the population assessment of tobacco and health study. J Adolesc Health71: 226–232.
65.
WatsonDClarkLATellegenA (1988) Development and validation of brief measures of positive and negative affect: The PANAS scales. J Pers Soc Psychol54: 1063–1070.
66.
WilhelmJMishinaEVirayL, et al. (2022) The pH of smokeless tobacco determines nicotine buccal absorption: Results of a randomized crossover trial. Clin Pharmacol Ther111: 1066–1074.
67.
ZvorskyINighborTDKurtiAN, et al. (2019) Sensitivity of hypothetical purchase task indices when studying substance use: A systematic literature review. Prev Med128: 105789.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
