Nicotine & Tobacco Research Volume 6, Supplement 1 (February 2004) S17–S28

Menthol pharmacology and its potential impact on cigarette smoking behavior1
Karen Ahijevych, Bridgette E. Garrett
[Received 1 November 2002; accepted 30 June 2003]

Menthol is the only tobacco additive promoted and advertised by the tobacco industry. Although a considerable body of research has examined the effects of menthol when it is administered alone and unburned, the effects of menthol when burned in cigarette smoke are more complex because it is administered in a matrix of more than 4,000 substances. Therefore, it is difficult to isolate potential pharmacological and toxic effects of menthol when it is administered in a smoke mixture. Menthol properties include cooling and local anesthesia, as well as effects on drug absorption and metabolism, bronchodilation and respiration changes, and electrophysiology. Subjective effects of smoothness and less harshness have been identified as reasons for menthol cigarette smoking, but findings have been inconclusive regarding the effect of menthol on carbon monoxide exposure and smoking topography parameters. Gaps in the research literature and future research areas include the following: (a) What is the role of menthol in tobacco reinforcement and addiction? (b) In the absence of nicotine, is menthol reinforcing? (c) Are the pharmacological and physiological effects of menthol mediated by a menthol-specific receptor or some other central nervous system–mediated action? (d) What are the influences of menthol and menthol metabolism on the metabolic activation and detoxification of carcinogens in tobacco smoke? and (e) Do differences exist in cigarette smoking topography in relation to the interaction of ethnicity, gender, and menthol cigarette preference? Answers to these questions will help to elucidate the function of menthol in cigarettes and its impact on smoking behavior.

Introduction
Tobacco addiction often is what influences the progression of tobacco use and prevents smokers from quitting, thus leading to increased morbidity and mortality from cigarette smoking. Tobacco use causes more than 440,000 deaths each year in the United States (Centers for Disease Control and Prevention [CDC], 2002a). In 2000, smoking prevalence rates

Karen Ahijevych, Ph.D., College of Nursing and College of Medicine and Public Health, The Ohio State University, Columbus, OH; Bridgette E. Garrett, Ph.D., Office on Smoking and Health, Centers for Disease Control and Prevention, Atlanta, GA. 1 This paper is based on four presentations at the First Conference on Menthol Cigarettes: Setting the Research Agenda, held in Atlanta, Georgia, March 21–23, 2002, sponsored by the Centers for Disease Control and Prevention, the National Cancer Institute, the American Legacy Foundation, the Battelle Centers for Public Health Research and Evaluation, the Robert Wood Johnson Foundation, the Onyx Group, and the Tobacco-Related Disease Research Program. Presenters included Jack Henningfield, Neal Benowitz, Karen Ahijevych, and Bridgette Garrett. Correspondence: Karen Ahijevych, Ph.D., Ohio State University, 1585 Neil Avenue, Columbus, Ohio 43210 USA. Tel: z1 (614) 2924699; Fax: z1 (614) 292-7976; E-mail: ahijevych.1@osu.edu

were similar by race and ethnicity (Whites~24.1%, Blacks~23.2%; CDC, 2002b). However, the majority of Black smokers prefer mentholated cigarettes as evidenced by 76% of Black smokers choosing menthol brands, compared with 23% of White smokers (U.S. Department of Health and Human Services [USDHHS], 1989). More recent data show similar menthol preference rates with 69% of Black smokers and 23% of White smokers reporting menthol cigarette use (Giovino et al., 2004). In addition, the percentage of ever-smokers who had quit was highest for Whites (51%) and lowest for Blacks (37.3%) (CDC, 2002b). Therefore, it is important to examine menthol as one potential factor involved in maintaining smoking behavior. Menthol may make cigarettes more reinforcing, increase the strength of tobacco addiction, or promote maintenance of cigarette smoking behavior. A number of findings suggest that menthol is involved in tobacco addiction. Black smokers prefer mentholated cigarettes, which are typically higher in tar and nicotine (Federal Trade Commission [FTC], 2000). Also, these cigarettes may deliver more tar and

ISSN 1462-2203 print/ISSN 1469-994X online # 2004 Society for Research on Nicotine and Tobacco DOI: 10.1080/14622200310001649469

1998. but menthol also may aid in the delivery of nicotine and increase the sensory impact of cigarettes (USDHHS.and (z)-neoisomenthol (Eccles. For example. Because menthol is a volatile compound. which could be due to low air dilution of mainstream smoke (Kozlowski et al. Best (1993) reported a range of 2. or it can be applied to the cigarette packaging foil (www. the primary nicotine metabolite. Delivery may not necessarily translate into the actual dose consumed by the smoker because dose consumed would depend on the amount of menthol absorbed from the inhaled smoke and how the smoker smokes the cigarette. and (2). Because menthol is classified as generally regarded as safe by the Flavoring Extract Manufacturers Association and is approved for food use by the Food and Drug Administration (FDA) (Opdyke. Menthol (C10H20O). In our laboratory. A better understanding of menthol application and delivery will help unravel the complexities of how menthol functions in tobacco. mentholated cigarette smokers were found to have significantly shorter times to the first cigarette of the day (19 minutes vs.34 mg menthol on average (Ahijevych. which are less volatile and have a longer lasting cooling effect (Perfetti. Many synthetic forms of menthol have been developed. Clark & Gautam..and (z)-isomenthol. 37 minutes). and higher cotinine levels (239 ng/ml vs. it has been reported that candy lozenges (Altoids. Black smokers have higher levels of cotinine. & Chan. Information on menthol delivery is limited.. 1990).. Kool. Menthol content varies by product. Jacob. the major constituent of peppermint oil.34–2. Wagenknecht et al.S.5 mg menthol per cigarette (Cantrell. . cyclohexanol-5-methyl-2-(1methylethyl).S18 MENTHOL PHARMACOLOGY AND ITS IMPACT nicotine. Structure of menthol. and mint tea (Good Earth Peppermint Herb Tea) contains 9. As reported by the tobacco industry. The other isomers of menthol have a similar odor but do not have the same cooling actions of (2)-menthol (Eccles. Elmsford. The fact that menthol cigarettes are higher in nicotine and tar than nonmenthol cigarettes (FTC. is a monocyclic terpene alcohol that naturally occurs in plants of the Mentha species (i. 1993).. 2000). we found that Newport menthol cigarettes contained 2. Menthol has three asymmetric carbon atoms in its cyclohexane ring (Figure 1) and therefore occurs as four pairs of optical isomers: (2). 2000). Rowsell.. (2). Kloska. cornmint oil). 1993). (2).g. In comparison with mentholated cigarettes. 1999). These menthol analogs could have an impact on the menthol application and delivery process. Majchrzak. Spring. Salem) has not been reported by the tobacco industry. 1978). a widely used measure of nicotine dependence. Hems. Mentha arvensis.and (z)-menthol. 1976). 1998). Dai. 1994). Data from tobacco industry documents show that most major U.e. (2)-Menthol is the isomer that occurs most widely in nature and produces the characteristic peppermint odor and cooling sensation when applied to the skin and mucus membranes (Watson. when compared with Whites and Mexican American smokers (Caraballo et al. 1994. 1990). Menthol can be applied to cigarettes in a number of ways: It can be applied directly to the tobacco or introduced into the cigarette filter. 2000) should be considered as a possible confounding factor in future research efforts.com/mentholappliedetc. New York) contain approximately 10 mg menthol.7 mg menthol/240 ml (Gelal et al. 1998). 1990).S. Newport. The specific method of application used in major U. 1999. the physiological and pharmacological effects of this compound as an additive in tobacco have gained little attention. Pomerleau.and (z)-neomenthol. & Malakuti.0¡1. 2002) as measured by gas chromatography–mass spectrometry (GC-MS) assay modified from Gelal. Cigarettes with menthol applied to the filter deliver menthol more efficiently than those with menthol applied to the tobacco (Curran. In addition. menthol is added to cigarettes to alleviate harshness and enhance taste and smoothness of cigarette smoke (Perfetti. 1972). but menthol is the only one widely advertised by the tobacco industry. Furthermore. These findings demonstrate the need for more research on the possible relationship between menthol and tobacco addiction. a significant correlation between cotinine and nicotine dependence has been reported (Pomerleau. & Figure 1. As purported by the tobacco industry. Some investigators have found that menthol cigarette use increases cotinine levels regardless of the smoker’s ethnicity (Ahijevych & Parsley. peppermint oil.htm). the application method influences the extent of its delivery to cigarette smoke. and Benowitz (1999). Yu.94 mg menthol per cigarette depending on the age of the cigarette. menthol brands deliver approximately 0. 1999). freeservers. 1996). Mentha piperita.goodhealth.. approximately 600 substances are used as cigarette ingredients (Tobacco Reporter. menthol brands (e. 189 ng/ ml) in a study with menthol and nonmenthol smoker groups with a balanced representation of Black and White women (Ahijevych & Parsley.

¨ Until recently. 1988. 2002. 1986. Cooling and local anesthesia Menthol produces a sensation of coolness in several parts of the body (Green. Swandulla. Braun. 1992 Kaplan-Frischoff & Touitou. aroma. 1992). For example. Factors that could affect menthol’s function in tobacco are regulation and distribution of this receptor. tar. 2002). it has a number of other documented physiological effects (Table 1). Physiological impact and pharmacology of menthol Menthol is used widely in a number of pharmaceutical and commercial products including tobacco. Whether these effects of menthol are apparent after inhalation of menthol from smoke is not known. 1991. In contrast. 1992). unpublished data Eccles.. 1939 Melikian et al.. Schafer et al.. Schafer. Watson et al. effects on bronchodilation and respiration. 1997. Sant’Ambrogio. Schafer. 1983. References Green. Kunta et al. effects on drug absorption. 1994. 1999 Benowitz et al. As described in more detail in the section on electrophysiology. Kobayashi et al. Sellers & Tyndale. and cooling characteristics. 2003 . Anderson. Research gaps and future research needs are discussed.NICOTINE & TOBACCO RESEARCH S19 This paper reviews what is already known about the pharmacology of menthol as a nontobacco additive and the possible impact of menthol cigarettes on smokers and smoking behavior. & Julius. Madyastha & Srivatsan. Neuhausser. 1991. Sant’Ambrogio. 1978)... ¨ 1986 Macht. Shojaei et al. & Sant’Ambrogio. Sellers. In addition to the cooling effects of menthol. 1997. 1968. a plasma membrane enzyme involved in signal transduction. ¨ Braun. ¨ 1986. 1992. Summary of physiological effects from published literature. menthol in high concentrations has both irritant and local anesthetic effects (Green 1986. 1998. and other harmful tobacco constituents Increase nerve activity Stimulant and depressant effects on the central nervous system Increase carcinogen production or metabolic activation and exposure Possible smoking implications Permit greater inhalation Increase nicotine intake Physiological effects Cooling and anesthetic Drug absorption Drug metabolism Increase addiction potential Respiration Increase addiction and toxicity potential Enhance tobacco reinforcement Enhance tobacco reinforcement and addiction Increase carcinogenic effects Electrophysiological Central nervous system Toxicity Eccles. 1951. and electrophysiological.. 1986. several TRP channels are regulated by receptors that couple to phospholipase C (McKemy et al.and menthol-sensitive receptor (CMR1) is a member of the TRP (transient receptor potential) family of excitatory ion channels. 2002. thus increasing neural discharge by increasing the afferent activity of cold sensors (Schafer. & Lux.. thus producing antinociceptive effects (Green 1986. & Sant’Ambrogio. These effects may explain how menthol functions in tobacco and its physiological impact on smoking behavior (see Table 1). indicating that menthol elicits a sensation of cool by serving as a chemical agonist of a thermally responsive receptor. 1990 Possible physiological impact Counteract harshness Increase absorption and lung permeability of smoke constituents Decrease nicotine and cotinine metabolism Permit increased lung exposure to nicotine. whereas menthol is thought to produce its local anesthetic effects by blockade of nociceptors on these same surfaces. 2002). below. The cooling effects of menthol are attributed to its stimulation of cold receptors in the skin and mucosal surfaces (Hensel & Zotterman. Whether CMR1 or other menthol-binding sites are expressed in higher brain Table 1. The compound is used in nontobacco mentholated products because of its minty flavor. 1982. menthol has been reported to produce its cooling and local anesthetic effects by inhibiting the efflux of calcium from cold receptors. Orani. including local anesthetic effects. Anderson. New evidence shows that the molecular site of action of menthol is an excitatory ion channel expressed by small-diameter neurons in trigeminal and dorsal root ganglia (McKemy. the exact physiological impact of menthol on smoking behavior remains to be understood. 1992). Furthermore. central nervous system.. This channel has been cloned and is activated by both cold and menthol. This cold. Watson et al. 1994. and metabolism effects. menthol had not been shown to have a receptor site of action by which it produced its sensory effects. & Isenberg. 1986). Zhang et al. & Hensel. 1978) when administered in low to moderate concentrations (Green 1986. Schmeltz and Schlotzhauer. but the reasons for its use in tobacco are not clear.

1999) permeability of drugs. The effects of menthol on drug absorption may stimulate greater pulmonary absorption and diffusibility of smoke constituents. minty.fda. More research on menthol receptor sites will be useful in determining the mechanisms of action of menthol when present in tobacco smoke. and menthol chewing gum on salivation in human subjects. 1994. Menthol. refreshing.gov/cder/guidance/3616fnl. and no evidence was found to support nasal decongestion by menthol. Sasaki. This increased sensation of airflow has been demonstrated repeatedly in the literature. (1986) evaluated the ´ ¨m effects of nicotine. & Sezaki. it was difficult to ascertain whether the effects of the mixture were due to menthol. Matsuzawa. placebo. 1996). & Shibasaki. 1997. . it is plausible that menthol. menthol alters perception of breathing patterns. Smokers also say that mentholated cigarettes reduce irritating effects. Kunta. have a soothing effect on the lungs. Jarvik. McCarthy. Jawad. descriptors that smokers use to explain why they smoke mentholated cigarettes are taste.and neurokinin A–induced bronchoconstriction in guinea pigs. USDHHS.. and are less harsh and smoother. In a follow-up study by Eccles. Menthol enhances transdermal drug diffusibility by affecting the intracellular lipids or proteins. However. when inhaled. 1994). Laude. 1996. 1994). Sugibayashi. In addition. ´ ¨ 1986). 1991). Nakamura. allowing the inhaler to feel that he or she is breathing freely. & Khosravan. Several reports demonstrate the bronchodilating effects of menthol. 1998). & Rosenblatt. More research is needed on the doseresponse relationship between menthol and nicotine absorption. Hashida. Brotherton. Kojima. Khan. and more taste (Wiseman & McMillan. and increasing the partitioning of drugs into the stratum corneum (Kaplan-Frischoff & Touitou. Duner-Engstro et al. then mintflavored nicotine gum would be expected to deliver nicotine in greater amounts. increases the diffusibility and permeability of drugs across the lungs as well (Clark & Gautam. plasma levels of nicotine do not differ between FDA-approved regular. because a mixture of aromatic vapors was used. McCarthy et al. Kobayashi. The mechanism by which menthol influences transbuccal absorption is less clear but appears to enhance the partitioning of drugs across the transcellular pathway (Shojaei et al. The menthol gum produced a significantly higher amount of stimulated saliva compared with the placebo or nicotine gum. Lundberg. thus aiding in the overall absorption of drugs (Clark & Gautam. menthol was shown to attenuate capsaicin. Consistent with the documented cooling effects of menthol. 1997). Other reported respiratory effects of menthol include the surfactant qualities of menthol as demonstrated via in vitro studies on synthetic surfactant film. & Reddy. Tashkin. menthol relaxed both acetylcholine and potassium chloride preconstricted bronchi (Wright. Morimoto. & Kimura. may increase dissolution of drugs in the mouth. 1997) and transbuccal (Shojaei. 1998). This effect of menthol is thought to occur via the actions of menthol on cold receptors (Eccles. menthol has been shown to increase salivary flow (Duner-Engstrom. The majority of subjects reported an increased sensation of nasal airflow. 1988. total resistance to airflow was measured in 31 subjects before and after a 5-minute exposure to a menthol vapor. increases the transdermal (Kaplan-Frischoff & Touitou. Because the FDA requires that both formulations be bioequivalent with respect to their nicotine dosing (www. Because menthol has been shown to increase transdermal and transbuccal absorption of drugs. by increasing salivary flow. flavor. In addition. 1994. The first study identified that the acute inhalation of aromatic vapors (including menthol) improved pulmonary function in volunteers with respiratory tract infections (Cohen & Dressler. A dual mechanism of action for the bronchodilating effects of menthol was proposed. Caskey. Respiration The respiratory effects of menthol have been reviewed extensively elsewhere (Eccles.htm).S20 MENTHOL PHARMACOLOGY AND ITS IMPACT areas also could have important implications on the function of menthol in tobacco. Okamoto.. If menthol were capable of increasing nicotine absorption across the oral mucosa. Often used as a nasal decongestant. this information does not prove a lack of an effect of menthol on nicotine absorption. whereby menthol lowered surface tension (Zanker. the oral administration of an 11-mg menthol lozenge to subjects suffering from nasal congestion caused a subjective sensation of improved airflow without any change in nasal airway resistance. Drug absorption Menthol. Grattan. In a study by Eccles & Jones (1983). & Morice. & Fredholm. as well as other terpenes. Khan. although menthol inhalation had no measurable effect on nasal resistance to airflow. 1995. Goskonda.and mint-flavored nicotine gums. demonstrating the absorption-enhancing effects of this compound. 1997. The potential physiological impact that the cooling and local anesthetic effects of menthol could have on menthol cigarette smoking is that it may alleviate the perception of harshness and permit greater inhalation of cigarette smoke. However. Mori. via inhibition of smooth muscle contraction and inhibition of sensory afferents. which might be due to the effects of menthol on calcium conductance. Larsson. and Morris (1990). In a more recent study. 1999). 1982). Lim.

Hinni. Menthol also has been shown to significantly increase breath-hold time. Central nervous system effects Menthol is recognized mainly for its local effects. Menthol exerts its effect on cold receptors by acting in the same manner as EDTA by interfering with the movement of calcium across the cell membrane. Finally. in the presence of menthol and other essential oils (eucalyptus and pine needle oil). In this study. Breath holding has been shown to increase the onset of central nervous system effects and increase the deposition of tar in the lungs of marijuana smokers (Matthias. with a mainstream compositional value of 98. respiration. This isolated effect of menthol may. the central nervous system effects of menthol cigarettes have not been documented and are highly speculative because it is difficult to isolate the effects of menthol in a cigarette smoke mixture. Electrophysiology studies show that the calcium-chelating agent EDTA can increase electrical discharge from cold receptors by decreasing external calcium concentrations and slowing the efflux of calcium from the cold receptor (Eccles. & Martin. indicating that menthol caused receptor depolarization and increased nervous discharge by inhibiting the efflux of calcium from the cold receptor (Schafer et al. aids in the release of neurotransmitters. Wilkins. Brommer. hairlike processes projecting from epithelial cells such as in the bronchi. It is well known that changes in the calcium concentration around thermoreceptors cause changes in the sensation of temperature (Eccles. and nasal discharge) in rats after smoke exposure from mentholated and nonmentholated cigarettes. Lorillard Tobacco Company conducted a 13-week inhalation study designed to compare biological responses (i.. benzo[a]pyrene. In a study conducted by Philip Morris. Cilia. 1939). This study identified the pyrolysis products of menthol at two different temperatures. involuntary breath holding may increase uptake of inhaled tobacco smoke constituents from the alveoli of the lungs into the bloodstream. A study by Sloan. Blumel. pyrolysis of menthol at the higher temperature resulted in the formation of pyrene. the menthol was unchanged in mainstream smoke. & Chavis. This effect of menthol is due to its electrophysiological effects on calcium conductance. serum cotinine. however. 1994). Similarly. Marques-Magallanes. In one study. Calcium is essential for nerve impulse conduction because it Toxicity Little is known about the toxicity profile of menthol. 1994). DeCort.e. 1987) and menthol may reduce this capability to clear lung airways. Tashkin. cold and warm receptors) on free nerve endings (Eccles. It could be postulated that the stimulant and depressant effects of menthol on the central nervous system could affect smoking behavior by enhancing the reinforcing and addictive effects of cigarettes. 1980). 1986). 1994). the latter being the burning temperature of tobacco. However. especially when it is burned in conjunction with tobacco. 1986). Electrophysiological effects on calcium conductance One of the main effects of menthol is its ability to produce a sensation of coolness and warmth by stimulating thermoreceptors (i. cilia beat frequency is significantly reduced in vitro (Riechelmann.. For example. tobacco industry studies found no carcinogen formation after the pyrolysis of menthol. However. little pyrolysis and combustion of menthol occurred during a cigarette puffing procedure (Jenkins. and central nervous system effects also have been attributed to the effects of menthol on calcium conductance. carboxyhemoglobin.e. No significant differences were found in these parameters between the two types of . the animals first became excited and this initial stimulation was followed by a depression of activity. and benz[a]anthracene. then menthol may affect smoking behavior by enhancing the reinforcing effects of tobacco. benzo[a]pyrene (Schmeltz & Schlotzhauer. 1997). the pyrolysis of menthol produced a potent carcinogen. 1970). Newman. This effect of menthol was ¨ blocked by intravenous infusion of a calcium solution. and then coma. & Probst. serum nicotine. 1968). & Simmons. unconsciousness. The respiratory effects of menthol could potentially permit increased lung exposure to nicotine and toxic smoke constituents including smoke carcinogens. After pyrolysis at the lower temperature.NICOTINE & TOBACCO RESEARCH S21 Tolle.. Cigarette smoke (Kitamura.9%. studies show that intravenous infusion of menthol causes an increase in the electrical discharge of cat nasal and lingual cold receptors (Schafer et al. In this study. 1997). Other effects of menthol such ¨ as bronchodilation. when high doses of menthol were administered orally to animals.. and Eccles (1993) found significantly prolonged breath holding as an involuntary response to menthol inhalation. If menthol affects calcium conductance in nerve cells containing neurotransmitters involved in drug reinforcement. propel mucus and dust particles from the pulmonary tree. be altered in the presence of other cigarette smoke constituents. 600‡C and 860‡C. In contrast to the above findings by Schmeltz and Schlotzhauer. menthol also produces effects in the central nervous system as demonstrated by its ability to produce both stimulant and depressant behavior in mice (Macht. most of the menthol (78%) was unchanged.

Blood samples were obtained at 0. The last two tobacco industry studies described suggest that the combustion of menthol does not produce carcinogens or other significant toxic effects. 45. This cross-over design study was balanced across 22 participants (Pritchard. 20. 10. 1997).7 mg menthol/240 ml). 1999). disposition kinetics of menthol were examined in a cross-over placebocontrolled design that compared oral menthol in a capsule and a placebo capsule. Menthol metabolism The interaction of menthol and other terpenes with microsomal enzymes in the liver has important pharmacological implications. 1999). and little evidence of the central pharmacological effects of menthol was obtained as determined by EEG measurements. . electroencephalogram [EEG] and heart rate) and subjective effects of menthol denicotinized cigarettes. such as menthol. these same enzymes are induced by repeated terpene administration. 5. forming menthol glucuronide. and research high and low nicotine yield cigarettes (Pickworth. In other words. 60. Nicotine delivery. In one study. Berlin. Tolerance developed to this effect as further treatment of menthol for up to 7 days reduced enzyme levels considerably (17% and 35% for cytochrome P-450 and NADPH-cytochrome c reductase. a human laboratory repeated-measures design study with 36 participants compared menthol and nonmenthol cigarettes across three levels: commercial average nicotine yield cigarettes. Houlihan. they are consistent with data from the National Cancer Institute (1979) that found no evidence of menthol carcinogenicity in rats and mice. This effect increased menthol metabolism and decreased blood levels of menthol. In the first and second phases. as demonstrated in a study that examined the psychophysiological (i. In a study by Madyastha and Srivatsan (1988). 2002). No significant differences were found in tumor development between the treated and control animals. 1999. Results indicated a higher heart rate postcigarette in commercial and high nicotine yield cigarettes. 2002). This bioassay of D. Systolic and diastolic blood pressure response was significantly lower in low nicotine yield cigarettes regardless of menthol composition. are capable of accelerating their own metabolism by increasing the metabolic activity of the enzymes responsible for their metabolism. which is excreted in the urine (Eccles. However. & Murty. Subsequently. indicating that menthol does not alter the biological effects attributable to smoke exposure in rats (Gaworski et al. menthol was administered orally and the dose used was much higher than the dose that could potentially be consumed by a pack-a-day smoker (approximately 10 mg.S22 MENTHOL PHARMACOLOGY AND ITS IMPACT cigarettes. half of the group received 10 mg (64 mmol) menthol in a mint lozenge and the remaining six subjects drank mint tea (9.. To our knowledge. The negative findings from the industry studies on menthol toxicity are not consistent with those from the Schmeltz and Schlotzhauer study.. nicotine was found to have a significant effect on heart rate. These findings indicate that the repeated administration of a high dose of menthol initially produced an induction of drug-metabolizing enzymes. as well as mint tea and a mint lozenge (Gelal et al. Kaffenberger & Doyle.0¡1. the Schmeltz and Schlotzhauer study is the only one that has demonstrated the formation of a carcinogen when menthol is pyrolyzed. and decrease its effect on enzyme induction. 30. respectively) from the initial increase.e. Cantrell. determined subjective ratings of strength (Pickworth et al. not menthol flavoring. Guy. 12 nonsmoker subjects received 100 mg L-menthol capsule (641 mmol) or a placebo capsule in random order. Carbon monoxide change postcigarette was similar across all cigarette types. These two studies indicate no evidence of cardiovascular effects of menthol. Thus. Because tolerance develops rapidly to this effect of menthol. but no main effect was found for menthol. No significant subjective effects were found for menthol.. In this study. repeated oral administration of L-menthol (800 mg/kg/day) to rats for 3 days resulted in an increase of both liver microsomal cytochrome P-450 content and NADPH-cytochrome c reductase activity by almost 80%... Consistent with these findings. Thus. Menthol is metabolized primarily in the liver. after repeated administration. chronic treatment with a terpene.Lmenthol for possible carcinogenicity was conducted by administering menthol in the feed of rats and mice over several weeks. 1990). and paradoxically. the effects of menthol on enzyme induction administered under the present conditions were less pronounced over time. can accelerate its own metabolism. Human studies have measured menthol exposure following oral administration of menthol in capsules and in the form of mint candy and mint tea (Gelal et al. These enzymes are responsible for the metabolism of terpenes. Moolchan. 1990). 1994). & Robinson. it may have important implications only in the pharmacological effects of other drugs that are metabolized by these enzyme systems during their initial use. terpenes. Further research is warranted to determine if pyrolysis of menthol increases the carcinogenic effects of cigarette smoking. and 90 minutes after dosing to assay for menthol and menthol Cardiovascular and subjective effects Both menthol and nonmenthol cigarettes produce significant increases in heart rate. lower its blood levels. As a result.

60 mmol/l occurred 3–15 minutes after completion of the second cigarette..36¡0. & Browning. Thus. Sellers posited that menthol might competitively inhibit glucuronidation of cotinine and nicotine and possibly cytochrome P-4502A6 activity for cotinine and nicotine metabolism. Tyndale. Weed.. These preliminary findings suggest a short half-life.. This finding suggests that menthol may be able to inhibit the metabolism of cotinine more extensively than nicotine. Herrera.17 mmol/l) with a dose-response effect with number of cigarettes per day (Ahijevych et al. Menthol content of a cigarette was an average 2.74 mmol/l after a lozenge or tea. 10. Menthol glucuronide pharmacokinetics comparing oral and cigarette smoke menthol exposure (mean¡SD). Table 2). Peak plasma concentration (mmol/l) 16. Average peak plasma menthol glucuronide concentrations were 16. 2. 1999). see Table 2). During the 3-week study. It is difficult to extrapolate from studies of oral administration of menthol to menthol delivered in a complex matrix of more than 4. Six Black women smoked two cigarettes of their usual menthol brand consecutively during the protocol.68 mg) Source.7 minutes.000 substances during cigarette smoking. Oral menthol administration may be pharmacologically different from menthol administered through inhalation from a burning cigarette. 15. (1999).34 mg. bAhijevych et al. all participants smoked regular (nonmenthol) cigarettes the first week and then were randomly assigned to menthol or regular Table 2. The impact of menthol on nicotine metabolism during cigarette smoking in humans was examined by Benowitz.36¡0. Peak times ranged from 30 to 120 minutes after a menthol capsule and 20 to 60 minutes after a lozenge or tea. about one-half of the menthol dose in a lozenge or tea (Gelal et al. Urinary menthol concentrations could potentially be assessed to examine possible relationships between menthol and concentrations of biomarkers of toxic smoke constituents such as tobacco-specific carcinogens. which could slow nicotine and cotinine metabolism in menthol smokers. A preliminary examination (Sellers & Tyndale.1 Menthol source Oral dosea Menthol capsule (100 mg) Lozenge or tea (10 mg) Cigarette smokeb Menthol cigarette rod and filter (unsmoked.68 mg (30 mmol) menthol. Puffing pattern was not controlled. The plasma half-life of menthol glucuronide following cigarette smoking was 11. compared with 56 minutes after a menthol capsule and 43 minute after a mint lozenge or tea (Gelal et al.58¡1. and Jacob (2002) in a cross-over design study with 14 subjects (7 Black and 7 White). 2002.NICOTINE & TOBACCO RESEARCH S23 glucuronide.14 Tmax (minutes) 61¡26 30¡12 7. 1999). 1999. 2000).1 Plasma half-life (minutes) 56¡8 43¡16 11. as menthol exposure resulting from natural smoking was being evaluated. The 24-hour urinary menthol glucuronide/cigarette (uncorrected for creatinine concentration) ranged from 193 ng/ml to 389 ng/ml per cigarette (0. Urinary menthol glucuronide may be a useful marker for assessing menthol exposure in future research. 2002).60¡0. constituents in cigarette smoke can induce or inhibit metabolism. at the midpoint of the first cigarette rod..53 mmol/l after 100 mg menthol capsule and 2. a factor not occurring with oral menthol administration.7¡4. Because no menthol was detected. which could lead to the accumulation of cotinine in menthol cigarette smokers.53 2. . Average peak plasma menthol glucuronide concentration of 0.3¡5.73¡5. 2002). menthol glucuronide was used as an indicator of menthol exposure. Recently.34 mg/cigarette62~4. based on GC-MS analysis. (2002). and 3. upon completion of the first cigarette. Blood samples for menthol and menthol glucuronide assay were drawn 1 minute prior to the participant’s first cigarette. For example. In addition.. and 60 minutes after completion of the second cigarette. 30. These concentrations obtained via cigarette smoke inhalation were lower. two mentholated cigarettes contained approximately 4. and peak time (Tmax) was significantly shorter than those reported in subjects following oral administration of menthol (Gelal et al. upon completion of second cigarette. plasma menthol levels following cigarette smoking were reported in a pilot study (Ahijevych et al. Dhatt. nicotine metabolism was inhibited in the presence of cigarette smoke (Benowitz & Jacob. Menthol and nicotine metabolism Sellers (1998) postulated that menthol and possibly other yet-to-be-identified substances found only in menthol cigarettes may influence nicotine and cotinine metabolism. unpublished data) indicated that menthol can inhibit nicotine metabolism with a moderate affinity (Ki~20–40 uM) but one that is higher than the affinity of nicotine metabolism to cotinine (Km~60 uM) and much higher than the affinity of cotinine to 3-OH cotinine (250 uM) (Ahijevych. 45.74 0. aGelal et al. at the midpoint of the second cigarette.73¡5.

one of the earliest identified polycyclic aromatic hydrocarbons (PAHs). Kwon. Interestingly. & Yokoi. No significant difference was noted in women menthol and nonmenthol smokers.025 pmol/min/mg protein in the presence of 1000 uM (2)-menthol (Ahijevych & Morse.. Instrumentation to measure smoking topography includes a flowmeter cigarette holder through which the individual smokes a cigarette. Ahijevych & Parsley. The surgeon general’s report on tobacco use among minority and ethnic populations stated that mentholated cigarettes may promote lung permeability and diffusibility of smoke constituents (USDHHS. Stimulation of laryngeal cold receptors may reduce airway irritation (Orani et al.7-fold higher level of urinary 1-OH-P compared with male nonmenthol smokers.. With limited in vitro and in vivo studies of the effect of menthol on nicotine and cotinine metabolism.915 pmol/min/mg protein with no menthol present to 1. 2000). Components measured include the volume of each puff (milliliters). On Day 5 of the second and third weeks. An important group of conjugation reactions catalyzed by uridine 5’-diphosphate (UDP)-glucuronosyltranserases (UGTs) may affect detoxification pathways of tobacco carcinogens.S24 MENTHOL PHARMACOLOGY AND ITS IMPACT cigarettes in Week 2. Benzo[a]pyrene. Also of interest are the relationships between cigarette smoke constituent exposure and puffing topography parameters.05) reduced from 1. The UGT isoforms involved in nicotine metabolism have not been identified (Ghosheh & Hawes. Gillespie. However. or that other factors such as lack of air dilution of mainstream smoke in many menthol cigarettes (Kozlowski et al. most male menthol smokers were Black. In addition. 1991). In addition. subjects received an intravenous infusion of deuterium-labeled nicotine and cotinine. menthol may play a role as a competitive inhibitor of enzymes in the detoxification of NNAL. and the length of the unsmoked cigarette butt (National Cancer Institute. interpuff interval (seconds). 1999). synergistic mechanisms of tumor promoters and cocarcinogens are likely to be involved in lung carcinogenesis by tobacco smoke (Rubin. CO and nicotine boost refer to this postcigarette change. breath-hold may be increased in the presence of menthol (Sloan et al. is considered a complete carcinogen in that it is carcinogenic and also a tumor promoter (Harvey. we have found menthol inhibition of 7-hydroxy-benzo[a]pyrene (BP-7) conjugation by human UGT1A9 of 46% by (2)-menthol and 57% by (z)-menthol with a menthol-to-substrate ratio of 100:1 (Ahijevych et al. indicating a potential effect of menthol on glucuronidation. and transbuccal permeation may be enhanced by menthol (Shojaei et al. cotinine clearance was not affected. Short-term exposure variables include pre. 259 ng/g creatinine. respectively). 1998) may affect exposure to tar and other mainstream smoke constituents. Therefore. 1996. 1999. a tobacco carcinogen. the number of puffs per cigarette. Demirci. only six published studies were identified that examined smoking topography and exposure to smoke among smokers of menthol and nonmenthol cigarettes (Ahijevych. with cross-over to the opposite condition in Week 3. 2002). Menthol may affect cigarette smoking topography and ultimately exposure to cigarette smoke constituents via several mechanisms. puff duration (seconds). Information from the differential pressure transducer is integrated by a dedicated software program to generate data on the parameters identified above. puff flow (ml/sec).. & Jagadeesh. Plasma cotinine provides information about exposure over time.. & Lazarus. transbuccal permeation and breath holding are not readily measured with current technology.. Zheng. Menthol is known to be conjugated by UGT2B7 (Bhasker et al. The two major UGT enzymes identified as responsible for conjugation of NNAL. are UGT2B7 and UGT1A9 (Ren. 2003). 2001). 2002. Menthol and carcinogen metabolism The possible role of menthol in tobacco carcinogen conjugation may be an important consideration of potential health risks for mentholated cigarette smokers. the nicotine glucuronide–to–nicotine ratio was lower with menthol smoking. Subsequently. 1993). Formation of BP-7 glucuronide was significantly (pv. 1998). whereas male nonmenthol smokers were White.. However. Significantly higher 1-OH-P concentrations were identified in the urine of smokers of menthol cigarettes than in the urine of nonmenthol smokers (425 ng/g vs.. Caskey . Nakajima. Male menthol smokers experienced a 2.and postcigarette carbon monoxide (CO) levels and plasma nicotine concentration. 1991). Tanaka. Smoking topography and menthol cigarettes Cigarette smoking topography is the unique pattern of smoking behavior for each individual cigarette smoker. (2002) used urinary 1-hydroxyprene (1-OH-P) as a marker of benzo[a]pyrene uptake and metabolic activation of PAHs from mainstream cigarette smoke. Yield of benzo[a]pyrene in mainstream smoke of menthol and nonmentholated brands was similar. 1996). In addition. 2000) and could serve as a competitive inhibitor of UGT2B7. Melikian et al. 2002). a gender difference was reported (Zhang et al. Total clearance of nicotine was significantly slower in the menthol smoking condition compared with regular smoking. This observation suggests that menthol may enhance uptake of PAHs from mainstream smoke and possibly alter metabolism. unpublished data). Murphy. definitive conclusions are yet to be determined.

participants smoked their usually preferred brand ad lib. 1996). 1998). 1994). and 8 p. 1999). For women. And finally. In a repeated-measures design. whereas one study examined responses to two levels of menthol in a test cigarette (4 mg and 8 mg) compared with a 0-mg menthol cigarette. samples had a balanced representation of Black and White participants. and higher cotinine levels (239 ng/ml and 130 ng/ml. McCarthy et al. In addition. therefore. whereas in three studies the sample was drawn from participants of inpatient drug abuse treatment programs. 1995.m. Although these effects are speculative. and lower flow rate occurred with menthol cigarettes among 20 men in a cross-over design (Jarvik et al. In a two-factor study of 37 women. menthol smokers had a significantly shorter time to the first cigarette of the day. four studies had fewer than 30 subjects.NICOTINE & TOBACCO RESEARCH S25 et al. in studies with male participants. was higher in menthol than nonmenthol cigarettes. However. respectively). to 5 p. to 10 p. Smoking parameters controlled in the remaining three studies included rapid smoking (40 ml puff every 15 seconds until aversion). and another found no differences by ethnicity or menthol preference. CO boost increased with increasing levels of menthol per cigarette (0. However. Repeated-measures analysis of average puff volume per cigarette and total puff volume per cigarette revealed no significant within-subject differences or significant differences by time. Miller et al. 1993. In summary. no significant differences in CO boost were reported (Ahijevych & Parsley. CO boost increased with increasing levels of menthol per cigarette.. However. No race-menthol preference interaction effects were found. one study found that CO boost was higher among Blacks and nonmenthol smokers.m. 1995.. Significantly higher CO boost was identified in Blacks compared with Whites. unpublished data). Miller et al. which was measured in all studies. Three studies were cross-over designs in which each participant smoked both a menthol and a nonmentholated cigarette.. Miller et al. 1999). 1994). 1995. additional research is needed to clarify potential effects of menthol on topography. 1996). Similar CO boost occurred despite fewer puffs in the menthol cigarette condition with fixed interpuff interval (McCarthy et al. Smoking topography and exposure measurements were obtained on the first cigarette of the day and on a cigarette in each of the following intervals: 10 a. significantly larger puff volumes were identified in menthol smokers (half of whom were Black) compared with nonmenthol smokers (Ahijevych & Parsley. whereas among women. McCarthy et al. in four studies.. and in nonmenthol vs.to postcigarette. 1994). the ratio of carboxyhemoglobin to cumulative puff volume was higher after subjects smoked a menthol cigarette in a cross-over design (Jarvik et al. In four studies. Sample sizes ranged from 10 to 95. an indicator of nicotine dependence..m. two studies were factorial designs with race and menthol preference as factors.m. 1993. No studies included both men and women. no significant topography differences by race or menthol preference were found (Ahijevych et al. the relationship of topography and menthol cigarettes varied...200 ml. Smoking topography was controlled as part of the design in three studies (Caskey et al. 1995). and 8 mg) despite controlled volume of smoke exposure (Miller et al. Evidence was inconclusive regarding the relationship of menthol cigarettes and CO boost pre. For example. Smaller puff volumes. the surgeon general concluded that mentholated cigarettes were not smoked more intensely than regular cigarettes (USDHHS. 30-second interpuff interval and total volume of 1. In the remaining three studies. much is known about the effects of menthol as a nontobacco additive.. Research was designed with only men (four studies) or women (two studies) participants. In this review. 3 p.. McCarthy et al.. 4. Jarvik et al. we attempted to extrapolate the actions of menthol actions as a nontobacco additive to its potential pharmacological and physiological effects in cigarettes. in a larger two-factor study with 95 women. participants were from the community.. 1993. No topography studies included men and women participants in the same protocol examining menthol effects. to noon. 1994.. data on intrasubject variability was obtained during a 6-day inpatient study (Ahijevych. menthol cigarette preference in a sample of 37 women (Ahijevych et al. and did not change despite fewer puffs at fixed intervals. no difference was noted in one study and larger puff volumes were observed in menthol smokers in another. Puffing topography among men yielded smaller volumes with menthol cigarettes. Generally. Future research As reviewed in the present paper. On Days 1 and 4 of the protocol. fewer puffs. and a 15-second interpuff interval protocol (Caskey et al.m. our understanding of the effects of menthol as a tobacco product additive is limited. 1999).. Although concerns exist about the representativeness of topography measures of only one cigarette per subject per condition. 1994). they can . 1994). Protocols varied considerably. 1994). On the basis of findings of four of these studies. Equivocal findings of the six studies are related to sample size and composition and to varied study designs and smoking topography protocols.... women smokers (N~24) were in an ad lib smoking condition of their usual cigarettes.. Different CO boost findings were identified in 2 two-factor design studies in which one-half of each ethnic group (Black and White) smoked menthol cigarettes (Ahijevych & Parsley. in a larger two-factor study with 95 women.

Effects of cigarette smoking and carbon monoxide on nicotine and cotinine metabolism. (2002. Demirci. J. Ahijevych. & Parsley. Biochemistry. Herrera. Baltimore.. Dhatt. & Browning.. (1999).. T. is menthol reinforcing? Not only is it possible for menthol to enhance the addictive and reinforcing effects of tobacco. R. Best. 653–659. Clinical Pharmacology and Therapeutics. Areas of warranted research are discussed below. A. 1995). Factors influencing cotinine half-life during smoking abstinence in African American and Caucasian women. McKinnon. Addictive Behaviors. and menthol cigarette preference? Gaps identified in the existing literature of smoking topography and menthol cigarettes are studies that include both men and women (Black and White) in the same protocol to provide more comprehensive information on the influences of menthol preference. & Jacob. Nicotine & Tobacco Research. K.. C. (2002). Smoke constituent exposure and stage of change in black and white women cigarette smokers. M.e. February). Effects of some cigarette construction parameters on menthol migration and transfer. A. the more commonly conducted cross-sectional designs. Menthol pharmacokinetics in African American women following menthol cigarette smoking [abstract]. A. Savannah. Ishizaki. Ahijevych. race. and gender as well as interactions among these variables. J.. sex. 1999). 2002). III. K. What is the role of menthol in tobacco addiction and reinforcement? Limited findings suggest an involvement of menthol in tobacco addiction. III. (1996). Menthol cigarette smoking inhibits nicotine metabolism [abstract PO1 37]. improvements in technology to accurately measure breath-hold and mouth-hold behaviors during smoking would assist in assessing factors affecting exposure. Dai. O. H.... Acknowledgments This work was funded in part by National Institute on Drug Abuse grant 10809 (KA) and General Clinical Research Center grant M01 RR00034. F. such research will have important implications in the development of more specific smoking cessation medications for smokers of menthol cigarettes. 19. 2002b).. it has not been determined if menthol produces central nervous system effects via specific binding sites in the central nervous system.. and Behavior. Maryland)... Menthol and nonmenthol cigarettes and smoke exposure in black and white women. A more thorough investigation of the relationship between menthol and tobacco addiction is warranted. Bhasker. In the absence of nicotine. (2002). K. K. These findings provide some support for increased tobacco addiction in mentholated cigarette smokers but are still inconclusive. & Chan. Benowitz. What are the influences of menthol and menthol metabolism on the metabolic activation and detoxification of carcinogens in tobacco smoke? Preliminary reports of menthol competitively inhibiting NNAL detoxification and leading to higher concentrations of a marker of metabolic activation of . L. Stone. & Jagadeesh.. 115–120.. 4. (2000). especially in those areas that mediate tobacco addiction and reinforcement. Tyndale. References Ahijevych. 370. GA. Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: Are the pharmacological and physiological effects of menthol mediated by a menthol-specific receptor or some other central nervous system–mediated action? A menthol receptor site that mediates the sensory effects of menthol was recently identified at the level of the brain stem and spinal cord (McKemy et al. Do differences exist in cigarette smoking topography in relation to the interaction of race.S26 MENTHOL PHARMACOLOGY AND ITS IMPACT serve as a basis for ascertaining future research directions on the effects of menthol as a tobacco additive. K.. and Black smokers who prefer mentholated cigarette brands have lower quit rates than White smokers (CDC. because many menthol cigarettes have 0% air dilution (Kozlowski et al. & Jacob. (1993). Nicotine & Tobacco Research. in the absence of nicotine).. 355–360. N. Weed. A mechanism to simulate typical blocking of ventilation holes during topography measures is particularly important with nonmenthol cigarettes. N. 67. Lo.. L. W. From presentation at Society for Research on Nicotine and Tobacco annual conference. Menthol smokers have been shown to score higher on a measure of nicotine dependence (Ahijevych & Parsley. 24. PAHs from mainstream smoke warrant laboratory and human studies to further explicate potential interactions of menthol and carcinogens. 53. 1995). W. Kubota. (2000).. J. but also it may have the ability to produce these effects on its own (i. K. B. Benowitz. R. L. & Miners. Recent Advances in Tobacco Science. G. C. P. tobacco industry research has shown that menthol increases nicotine impact in smokers. 4. 423–431.. More research is needed to determine if menthol is addictive. T.. In addition. This equipment will improve longitudinal data collection design vs. F. This same study showed that menthol is capable of producing increases in impact when administered alone (Philip Morris. Gillespie. 1998).. R. 155–201. P. Pharmacology. However. As mentioned above. Industry findings also have shown that menthol is capable of increasing nicotine impact in cigarette smokers (Philip Morris. Use of a portable topography device with menthol and nonmenthol smokers would provide data in the home and in social and work environments (Plowshare Technology. G.. Ahijevych.

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