Menthol Sensory Properties and Possible Effects on Topography

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1 Menthol Sensory Properties and Possible Effects on Topography Deirdre Lawrence Ph.D., M.P.H. FDA Center for Tobacco Products on detail from National Cancer Institute (NCI) / NIH Tobacco Products Scientific Advisory Committee (TPSAC) March 30-31, 2010

2 What is Topography? Puffing behavior Quantifiable Number of puffs per cigarette Puff volume (ml: mean & total) Puff duration (seconds) Puff flow (ml/sec) Inter-puff interval (seconds) Photo provided by Dr. Karen Ahijevych

3 CReSS Lab 1 CReSS Pocket 2 SPA-D Photo provided by Dr. Pamela Clark 2010

4 Topography Photo provided by Dr. Pamela Clark

5 Overview What are menthol s sensory properties? Do these properties contribute to the smoking experience? Does menthol alter topography? 5

6 Published Literature 343 articles in the NCI Bibliography of Literature on Menthol and Tobacco (2009) + 23 recent additions Not directly relevant Reviews (mostly relied on primary sources) 26 articles Note: Red and * denotes tobacco industry-funded study 6

7 Sensory Qualities and Smoking Topography Reviews have been published on menthol s pharmacology and sensory qualities 1,2,3,4* Small number of published smoking topography studies comparing menthol & nonmenthol smokers. Variability: Differences in study design and protocols Differences in ad lib (as desired) smoking versus rapid-smoking procedures Only one study varied menthol content 5 1. Eccles 1994; 2. Ahijevych & Garrett 2004; 3. Harris 2006; 4 Heck 2010*; 5. Miller et al

8 Sensory Properties of Menthol

9 Sensory Properties: Flavor Natural menthol is primarily found in peppermint and cornmint Menthol stimulates olfactory and taste receptors 1 Mint-like flavor and smell 1. Harris 2005; 2. Hymowitz 1995 Menthol smokers (n=473) 2 : 60% would pay more money for a menthol cigarette than for a nonmenthol cigarette Taste was one of the 3 main reasons for smoking menthol cigarettes 9

10 Sensory Properties: Cooling & Warming When applied to skin or mucosal surface causes a sensation of coolness or warmth 1 Affects thermoreceptors---transient receptor potential (TRP) receptors 2 Activates TRPM8 ( cold activated ) receptors Activates TRPM3 ( warm activated ) receptors May also activate TRPM8 pain receptors causing a painful sensation. 1. Eccles 1994; 2. Harris,

11 Cooling & Warming (cont.) Inhalation of menthol produces cooling sensation 1 Menthol inhalation stimulates trigeminal cold receptors, resulting in cool sensation without a change in physiological temperature Menthol can increase sensation of cold in oral cavity, but can either enhance or attenuate feelings of warmth 1. Eccles

12 Sensory Properties: Respiration Menthol often used as a nasal decongestant and gives users sensation of increased airflow and respiratory ease, without physical decongestant activity 1,2,3 Menthol inhibited ventilation in in vivo 4 experiments & increase breath hold time in humans 5 Menthol acts as a cough suppressant 6,7 In animal models menthol has been demonstrated to: Promote mucus clearance 3 Produce bronchodilation (in vitro and in vivo) 8 1. Eccles 1990; 2. Eccles and Jones 1983; 3. Nishino et al. 1997; 4. Harris 2006; 5. Sloan et al. 1993; 6. Houghton et al.1998; 7 Laude et al 1994; 8 Wright et al

13 Sensory Properties: Analgesia Menthol has both analgesic and local anesthetic effects Analgesic effects likely due to 1 Activation of TRPM8 Inhibition of pain-sensitive TRP1 Activation of κ-opioid system (when given orally to rodents) 2 Menthol is an irritant; however desensitization develops with repeated exposure 3 Menthol reduces nicotine s irritant properties through cooling and cross-desensitization 3 1. Harris 2006; 2. Galeotti 2002; 3. Dessirier et al

14 Sensory Properties: Perceived Strength Menthol can produce varying degrees of irritation and temperature sensations 1 Trigeminal nerve endings in mouth and throat Seems directly related to menthol s cooling effect Menthol may be added to increase perceived strength and smoke-like sensations in low-yield cigarettes 2 Menthol content was greater in ultralight or light menthol cigs compared with regular or medium/mild menthol cigs (48-brands) 3 Menthol smokers believe menthol cigarettes are more soothing to the throat than nonmenthol 4 1. Eccles 1994; 2. Wayne and Connolly 2004; 3. Celebucki et al. 2005; 4. Hymowitz

15 Tobacco Documents-Based Research on Menthol & Topography

16 Tobacco Industry Documents-Based Research: Changing Menthol Levels Publicly available tobacco industry docs showed different properties associated with different levels of menthol 1 : Low-content menthol cigarettes to mask the taste of tobacco/reduce throat scratch Higher menthol cigarettes for increased impact and menthol flavor 1. Kreslake et al

17 Tobacco Industry Documents-Based Research: Consumer Preference Publicly available tobacco industry docs showed smoking status was associated with overall liking of menthol concentrations 1 Heavy smokers (>20 cpd) preferred higher levels of menthol (0.80%) Moderate smokers ( 20 cpd) preferred moderate concentrations (0.52%) 1. Kreslake, et al

18 Tobacco Industry Documents-Based Research: Properties & Function 1 Cooling Property Anesthetic (Analgesic) Impact Function Mask irritation of smoke Enable initiation and increased uptake Substitute perceived smoke effect Counter- or anti-irritant; Reduce pain sensations Mask irritation of smoke; enable initiation & increased uptake Increased bite or strength Substitute for nicotine in low-tar cigarette Sensory Increase smoothness; Reduce harshness Enable deeper inhalation and uptake Smoke soothing Wayne & Connolly 2004 (modification of Table 4)

19 Interim Summary

20 Sensory Properties of Menthol Convergent data on sensory properties of menthol Flavor, cooling, analgesia, sensation of ease of respiration Could result in larger puff volumes, increased frequency, deeper inhalation, greater intensity of smoking Increased breath hold time may alter inhalation patterns 20

21 Role of Menthol s Sensory Qualities on Topography

22 Does Mentholation Result in Larger Puff Volumes and Increased Frequency? Study n Participants Methods 1993 Caskey et al. 28 Men only Three rapid-smoking; 1994 Jarvik et al. 20 Jarvik ad lib (smoke as desired) 1994 Miller et al. 12 Commercially available 1995 McCarthy et al. 29 cigarettes 1996 Ahijevych et al. 37 Women only Smoke ad lib Smoked preferred brand 1999 Ahijevych & Parsley 95 of commercially available cigarettes 22

23 Menthol s Effect on Puff Volume Compared to Nonmenthol Cigarettes Decreased volume 1994 Jarvik et al McCarthy et al. No significant effect 1995 Miller et al Ahijevych et al. Increased volume 1999 Ahijevych & Parsley 23

24 Menthol s Effect on Puffs per Cigarette Compared to Nonmenthol Cigarettes Fewer Puffs 1994 Jarvik et al McCarthy et al. No Significant Effect 1993 Caskey et al Miller et al Ahijevych et al. 24

25 Other Topography Measures Jarvik et al. 1 (men, n=20) Decreased puff volume, fewer puffs AND puff flow rate significantly lower during menthol cigarette smoking BUT no significant differences in peak puff flow and puff duration Ahijevych and Parsley 2 (women, n=95) Significantly larger puff volume among menthol smokers BUT no significant differences in mean puff duration, inter-puff interval or total puff duration between cigarette types 1. Jarvik et al 1994; 2. Ahijevych & Parsley

26 Self-Reported Topography Prospective cohort (n=29,037) menthol and nonmenthol smokers reported similar puff frequencies, depths of inhalation and length of cigarettes smoked 1 No difference in ratings of harshness between menthol and nonmenthol smokers 2 Menthol smokers (n=473) gave ease of inhalation as one of the 3 main reasons for smoking menthol cigarettes 3 1. Sydney 1989; 2 Jarvik 1994; 3. Hymowitz

27 Limitations of Topography Studies Small sample sizes Majority of the comparative studies (5/6) under 40 participants Largest was 95 participants Small studies do not account for inter- and intra-individual differences in smoking behavior Gender-specific: 2 women-only; 4 men-only External validity: 3 studies drew participants from drug and alcohol treatment center 27

28 Summary Sensory properties of menthol Well-documented: taste, cooling/warming, respiratory, analgesic/anesthetic Component of perceived strength Studies do not give consistent topography results: Puff volume: 4 - depressive or no effect; 1 increase (women) Puff frequency: 2 - fewer puffs; 3 - no significant effect No effect found with variation in menthol content Self-reported assessments not consistent 28

29 Clarifying Questions? References are listed in subsequent slides

30 References Ahijevych, K. and B. E. Garrett (2004). Menthol pharmacology and its potential impact on cigarette smoking behavior. Nicotine Tob Res 6 Suppl 1: S17-28 Ahijevych, K., J. Gillespie, et al. (1996). Menthol and nonmenthol cigarettes and smoke exposure in black and white women. Pharmacol Biochem Behav 53(2): Ahijevych, K. and L. A. Parsley (1999). Smoke constituent exposure and stage of change in black and white women cigarette smokers. Addict Behav 24(1): Caskey, N. H., M. E. Jarvik, et al. (1993). Rapid smoking of menthol and nonmenthol cigarettes by black and white smokers. Pharmacol Biochem Behav 46(2): Celebucki, C. C., G. F. Wayne, et al. (2005). Characterization of measured menthol in 48 U.S. cigarette sub-brands. Nicotine Tob Res 7(4): Dessirier, J. M., M. O Mahony, et al. (2001). Oral irritant properties of menthol: sensitizing and desensitizing effects of repeated application and cross-desensitization to nicotine. Physiol Behav 73(1-2): Eccles, R. (1994). Menthol and related cooling compounds. J Pharm Pharmacol 46(8): Eccles, R., M. S. Jawad, et al. (1990). The effects of oral administration of (-)-menthol on nasal resistance to airflow and nasal sensation of airflow in subjects suffering from nasal congestion associated with the common cold. J Pharm Pharmacol 42(9): Galeotti, N., L. Di Cesare Mannelli, et al. (2002). Menthol: a natural analgesic compound. Neurosci Lett 322(3):

31 References Harris, B. (2006). Menthol: A review of its thermoreceptor interactions and their therapeutic applications. Int J Aromather 16(3-4): Heck, J.D. (2010). A review and assessment of menthol employed as a cigarette flavoring ingredient. Food Chem Toxicol 48:S1-S38. Houghton, T. M. and C. S. Beardsmore (1998). The effect of menthol on nasal airflow, perception of nasal patency, and cough receptor sensitivity in children aged 10 and 11 years. Thorax 53(Suppl.4): A9. Hymowitz, N., C. Mouton, and H. Edkholdt. (1995). Menthol cigarette smoking in African Americans and Whites. Tob Control 4: Jarvik, M. E., D. P. Tashkin, et al. (1994). Mentholated cigarettes decrease puff volume of smoke and increase carbon monoxide absorption. Physiol Behav 56(3): Kreslake, J. M., G. F. Wayne, et al. (2008). The menthol smoker: tobacco industry research on consumer sensory perception of menthol cigarettes and its role in smoking behavior. Nicotine Tob Res 10(4): Kreslake, J. M., G. F. Wayne, et al. (2008). Tobacco industry control of menthol in cigarettes and targeting of adolescents and young adults. Am J Public Health 98(9): Kuhn, F. J. P., C. Kuhn, et al. (2009). Inhibition of TRPM8 by icilin distinct from desensiti-zation induced by menthol and menthol derivatives. J Biol Chem 284(7):

32 References Laude, E. A., A. H. Morice, et al. (1994). The antitussive effects of menthol, camphor and cineole in conscious guinea-pigs. Pulm Pharmacol 7(3): McCarthy, W. J., N. H. Caskey, et al. (1995). Menthol vs nonmenthol cigarettes: effects on smoking behavior. Am J Public Health 85(1): Miller, G. E., M. E. Jarvik, et al. (1994). Cigarette mentholation increases smokers exhaled carbon monoxide levels. Exp Clin Psychopharm 2(2): Nil, R. and K. Battig (1989). Separate effects of cigarette smoke yield and smoke taste on smoking behavior. Psychopharmacology (Berl) 99(1): Nishino, T., Y. Tagaito, et al. (1997). Nasal inhalation of l-menthol reduces respiratory discomfort associated with loaded breathing. Am J Respir Crit Care Med 156(1): Sidney, S., I. Tekawa, et al. (1989). Mentholated cigarette use among multiphasic examinees, Am J Public Health 79(10): Sloan, A., S. C. De Cort, et al. (1993). Prolongation of breath-hold time following treatment with an L-menthol lozenge in healthy man. J Physiol 473: 53P. Wayne, G.F. and G. N. Connolly (2004). Application, function, and effects of menthol in cigarettes: a survey of tobacco industry documents. Nicotine Tob Res 6 Suppl 1: S Wright, C. E., E. A. Laude, et al. (1997). Capsaicin and neurokinin A-induced bronchoc-onstriction in the anaesthetised guinea-pig: evidence for a direct action of menthol on isolated bronchial smooth muscle. Br J Pharmacol 121(8):

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