Role of mentholated cigarettes in increased nicotine dependence and greater risk of tobacco-attributable disease

Preventive Medicine 38 (2004) 793 – 798 www.elsevier.com/locate/ypmed

Role of mentholated cigarettes in increased nicotine dependence and $ greater risk of tobacco-attributable disease Samuel Garten, M.S., M.S., Ph.D. * and R. Victor Falkner, M.A., M.S., M.A.L.S. Department of Social and Preventive Medicine, State University of New York, Buffalo, NY, USA Department of Cancer Prevention, Epidemiology and Biostatistics, Roswell Park Cancer Institute, Buffalo, NY, USA Available online 21 March 2004

Abstract Background. Cold air stimulates upper airway cold receptors causing a reflex depressive effect on respiratory activity. Menthol, in low concentrations can also stimulate these same cold receptors causing a depressive effect on respiratory activity. Menthol cigarettes when smoked, deliver enough menthol to stimulate cold receptors resulting in the smoker experiencing a ‘‘cool sensation.’’ The ‘‘cool sensation’’ experienced by the menthol smoker can result in a reflex-depressive effect on respiratory activity. Method. Literature searches were done for the NLM databases (e.g., MEDLINE from 1966, TOXLINE, OLDMEDLINE (1985 – 1965), CANCERLIT, plus tobacco industry documents and hardcopy indices. The evidence was evaluated with application to mentholated cigarette smoking. Results and Discussion. A logical progression is presented that develops the framework to prove that menthol found in mentholated cigarettes may cause respiratory depression resulting in greater exposure to the toxic substances found in tobacco smoke. Conclusion. As a result of breath holding that results from the stimulation of cold receptors there is a greater opportunity for exposure and transfer of the contents of the lungs to the pulmonary circulation. For the menthol smoker this results in a greater exposure to nicotine and the particulate matter (tar) of the smoked cigarette. This exposure can result in increased nicotine dependence and greater chance of tobaccoattributable disease. D 2004 The Institute For Cancer Prevention and Elsevier Inc. All rights reserved. Keywords: Menthol; Lung; Respiratory system; Airway resistance; Thermoreceptors; Neoplasms; Smoking; Tars; Nicotine; Tobacco

Introduction Many investigators have commented that menthol in mentholated cigarettes may enhance the absorption of nicotine without providing a mechanism of action on how this could possibly occur [1– 5]. This paper and its companion paper (PMED2) are the first attempt at developing an understanding of the pharmacological actions of menthol as related to tobacco smoking. Lloyd Spud Hughes of Mingo Junction, Ohio in the 1920s developed, quite by accident, the first menthol cigarettes $

Funding Sources: No funding was applied for or accepted from tobacco control agencies or pro-tobacco groups that could possibly influence the results of this study. * Corresponding author. E-mail address: [email protected] (S. Garten).

called Spud. He had placed the menthol crystals used to treat his cold with his cigarettes in a closed container and the next morning, he had mentholated cigarettes [6]. Menthol has numerous biological actions (Dr. James Duke’s USDA Phytochemical database) and has been used for many years in medication for the temporary relief of coughs and minor throat irritation due to colds or inhaled irritants. A previous companion paper [53] has provided evidence linking the continuous delivery of menthol that results from smoking mentholated cigarettes to the masking of the early warning symptoms of respiratory distress. The upper airway cooling that results from the administration of low dose of menthol [7– 10] like that delivered when smoking mentholated cigarettes may depress respiratory activity. This reduced activity can result in breath holding that results in a greater exposure to nicotine, carbon monoxide and 4000+ other substances delivered in a smok-

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Scheme 1.

ing mentholated cigarette (USDHHS, Smoking Tobacco and Health: A Fact Book, DHHS Publications, (CDC) 87-8377, 1989). The majority of African-American smokers smoke mentholated cigarettes [11]. African-Americans have higher rates of tobacco-attributable illnesses such as cancer, stroke and heart disease compared to whites [11]. Also, AfricanAmericans may have a higher nicotine dependence than whites [2,4,5,12 –15] even though they smoke fewer cigarettes per day [16 –19] and start smoking at an older age ([13,14] MMWR Nov 8, 1991/40(434): 754 –757). This paper based on a thorough review of the available literature develops the theoretical framework to logically prove that menthol found in mentholated cigarettes may cause respiratory depression resulting in greater exposure to the toxic substances found in tobacco smoke.

Methods Based on the thorough literature review, the approach was initially to gather and then piece together all the information on the actions of menthol with emphasis on the pulmonary system. After completing this phase of study, it was determined, based on the literature gathered if these actions would be experienced by the menthol cigarette smoker. The search procedure was applied generally to the National Library of Medicine (NLM) databases (e.g., MEDLINE from 1966, TOXLINE, OLDMEDLINE from 1958– 1965, CANCERLIT), tobacco industry documents and hard copy indices for older journals (Printer’s Ink, Decker Communications Inc, New York, a journal for advertisers, founded in 1888). The various steps carried out in conducting these searches followed the conceptual design shown in Scheme 1. KEYWORDS: all keywords (e.g., menthol, smoke, cold receptors, apnea, nicotine) were used in the NLM and Tobacco Archive databases in structured searches (e.g, NLM MESH searches, Tobacco Archive field searches) and in Boolean searches (e.g., logical full-text searches).

Results and discussion Menthol’s actions—stimulation of cold receptors Some of menthol’s actions on the respiratory tract are the result of stimulation of cold receptors [20]. Menthol at

low concentration induces a cold sensation when applied to skin or mucus membranes with the underlying mechanism being a stimulating action on cold receptors (i.e., sensory nerve endings). The stimulation of cold receptors by menthol was independent of any change in temperature [21]. The selective stimulation of cold receptors by menthol is thought to be a result of the inhibition of calcium movement across nerve ending cell membranes that form the cold receptors [22]. More recent cellular and molecular studies indicate menthol and cold temperature activate a calcium-permeable channel on trigeminal and dorsal root ganglion sensory neurons [23]. At higher concentrations of menthol both an irritant and local anesthetic action can occur [20]. Potter [24] found in using menthol for treating patients with upper airway disease, that the proper percentage of menthol produced a pleasant, cool sensation. It has been demonstrated that stimulation of cold receptors in the upper respiratory tract with inhalation of menthol reduces the respiratory discomfort and increases the sensation of increased airflow. Total nasal resistance to airflow was measured in 31 subjects before and after 5-min exposure to menthol vapors. It was found that menthol inhalation had no consistent effect on nasal resistance but the majority of subjects reported an increased sensation of nasal airflow and a ‘‘cooling sensation’’ from menthol [25,26]. Smoking menthol cigarettes also can produce a ‘‘cool sensation.’’ The American Cancer Society, in its current awareness educational material indicates that there is enough menthol in mentholated cigarettes to induce a ‘‘cool sensation’’(http://www.cancer.org/tobacco/quitting. html). Richard Klugar (in his book, Ashes to Ashes) points out that the coolness property has been exploited by the tobacco industry touting menthol cigarettes as ‘‘refreshing,’’ ‘‘cool’’ and possessing an aura of ‘‘springtime’’ [27]. Rudoff Hopp in his paper in Recent Advances in Tobacco Science [28] points out that menthol provides a ‘‘cool sensation’’ in the lungs when added to cigarettes or inhaled as an aerosol spray and to the gastrointestinal tract when ingested leaders on the biochemistry and physiological effects of menthol in cigarettes have concluded that the cooling effect most commonly associated with menthol in combination with anesthetic and/or respiratory effects may contribute to reduced perception of irritation from cigarette smoke and altered inhalation pattern, influencing overall smoke and smoke/nicotine intake [29].

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Upper airway cooling-depressive effect on respiratory activity Studies in normal volunteers have shown that cold air breathed through the nose inhibits ventilation and is not related to an increase in flow resistance [30,31]. Just like the response to a cold stimulus, inhalation of menthol has been shown to inhibit respiration via upper respiratory airway cold receptors [7 –10]. Sloan et al. [10] provided evidence that stimulation of upper airway cold receptors resulted in increased breath-hold times. Twenty healthy volunteers (age 18 – 39) were asked to hold their breath for as long as possible at total lung capacity. The procedure was repeated three more times, this time sucking a lozenge containing 11 mg of menthol or placebo. It was found that breath-hold time was significantly prolonged after menthol ingestion. Respiratory distress has also been reported in infants and small children when menthol products were used to treat cold symptoms [32 – 36]. Breath holding as a result of depressed respiratory activity Reflex breath holding resulting from stimulation of cold receptors may also occur when smoking mentholated cigarettes. As we have seen above, experiencing the ‘‘cool sensation’’ is one of the primary reasons these smokers smoke mentholated cigarettes. A menthol smoker remarked ‘‘They give a nice cool sensation down your throat and always fulfill your nicotine addiction. It has a nice menthol flavor that doesn’t leave an aftertaste’’ (http://myreviews.ratetail.com). When breath holding occurs, it results in prolonged exposure to the contents of the lungs and also greater transfer of the contents of the lungs into the pulmonary circulation. Breath holding is recommended to increase the effectiveness of asthma inhalers in depositing medicated aerosol droplets within the lungs (Dr. Stephen Newman, personal communication). Marijuana smokers have learned that breath holding hastens the onset of CNS effects of this substance [37]. Also, the decrease in volume of the lungs with breath holding results in greater pressure within the lungs contributing to the increased transfer of inhaled constituents into the blood [38]. The relaxing effect of menthol on the terminal bronchioles smooth muscle [39] may contribute to both the prolonged exposure and greater transfer. If the delivery agent for menthol is the inhaled smoke from a mentholated cigarettes, this will result in greater exposure to the smoke in the respiratory tract and greater transfer of the smoke’s constituents into the pulmonary circulation. As a result, the menthol cigarette smoker may be exposed to higher amounts of nicotine, carbon monoxide and other toxic substances. Jarvik et al. [40] have shown that carbon monoxide levels correlate highly with nicotine blood levels. Investigators have found that menthol smokers experience a greater boost of carbon monoxide levels [1,41]. Fig. 1 summarizes the possible events that occur when menthol is inhaled in general and when the particular

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delivery agent is the smoking mentholated cigarette. In general—as previously stated—inhalation of menthol may increase the exposure and transfer of the contents of the lungs into the pulmonary circulation. Mentholated cigarettes—increased nicotine dependence and greater risk of tobacco-attributable disease Tobacco Documents It is indicated that menthol especially at low concentrations of nicotine can enhance nicotine impact. (Impact is the feeling (drug effect of nicotine) rather than an odor or taste). One study concluded that it may be possible to increase smoke impact in low nicotine delivery menthol cigarettes by utilizing higher menthol delivery levels than usual (Philip Morris document #2062951249_1265, 1975). In another study (Philip Morris document #2031421329_1336, April 15, 1991) results suggested that to increase the nicotine impact of a half-nic menthol (Merit menthol cigarettes compared with a Merit menthols with half the nicotine content), the menthol per puff would need to be increased to about 0.07 (units not provided, most likely milligrams). In a more current study (Philip Morris document #2062951249_1265), it was concluded that menthol has a pronounced effect on nicotine-derived ‘‘impact’’ and should be taken into account when targeting cigarettes for degree of perceived impact. Menthol inhalation with other substances In a 1972 memo, a Philip Morris scientist noted that Kool cigarettes were considered the best after a marijuana ciga-

Fig. 1.

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rette to smoke to maintain the high created by using marijuana (Philip Morris document #1003288772). More current, the increase in African-American teen smoking from 1992 to 1997 may have been related to the finding that smoking mentholated cigarettes enhances the effects of marijuana (Mermelstein, 1999) [42]. Even ecstasy users have discovered that the inhalation of menthol fumes (including the smoking of menthol cigarettes) heightens the drug experience (Drug Enforcement Administration News Release, August 30, 2001). Recently, Raudenbush et al. [43] have found that the administration of peppermint odor (menthol is responsible for peppermint’s odor and taste) can enhance athletic performance, which obviously necessitates an increased oxygen uptake. Mentholated cigarettes and African-Americans The majority of African-American smokers smoke mentholated cigarettes [11]. Approximately three out of four African-American adult smokers used menthols compared with one in four for white smokers. Among black youths that smoke, 9 of 10 choose menthols [11]. Dr. Robin Mermelstein, the principal investigator in an ongoing study (for the federal government) of why teenagers smoke, has stated, ‘‘Cigarettes have a totally different functional value (what smokers get out of smoking—the functional utility, e.g., to deal with boredom, to socialize, to control their weight, etc.) for black and white kids.’’ (The New York Times, April 22, 1998). African-Americans continue to suffer disproportionately from chronic and preventable disease compared with white Americans. Of the three leading causes of death—heart disease, cancer and stroke—smoking and other tobacco uses are major contributors [11]. Some studies have shown that African-Americans are strongly motivated to quit smoking [2,4,5,12 –15] when compared to whites but are less likely than whites to remain abstinent for a year or more, even after adjusting for socioeconomic factors ([11] MMWR 42: 504 – 507, 1993). Investigators using Community Intervention Trial for Smoking Cessation (COMMIT) data found that no consistent associations were observed for menthol use and indicators of dependence in both overall and race specific analyses. It was concluded that future work is needed to clarify the physiological and sociocultural mechanisms involved in mentholated cigarette smoking [44]. At the First Conference on Menthol Cigarettes (March 21 and 22, 2002) Dr. Steve Sidney, a leading researcher on menthol remarked that menthol may make cigarettes more addictive. He continued: anything that would make smoking more addictive would be bad for your health. Another leading investigator (Dr. Karen Ahijevych) indicated that preliminary data showed that menthol increased exposure to carbon monoxide, at least in men and causes higher levels of nicotine in the plasma (The Detroit News, Friday, March 22, 2002). The famous Roper Study on Menthols in 1979 (A Study of Smokers’ Habits and Attitudes with Special Emphasis on Low Tar and Menthol Cigarettes, Philip Morris document 1002476448_6981, March 1979) pointed out that

African-Americans, young people and women, who have in common the fact that they are light smokers and tend to like menthols, reinforces the concept that menthol provides an ‘‘extra something.’’ It was concluded that menthol seems to compensate or make up both for few cigarettes and for light cigarettes. One possible explanation for greater occurrence of chronic disease and the greater difficulty in quitting is because African-American smokers predominantly smoke mentholated cigarettes. Cancer and menthol smokers There are conflicting reports on whether there is an association between smoking mentholated cigarettes and cancer in humans. Kabat and Hebert [45 – 47] were not able to demonstrate an association between the smoking of mentholated cigarettes and the risks of lung, esophageal or oropharyngeal cancers in a series of case-control studies. Those studies were hampered by the inclusion of few blacks and by the subjects’ relatively short-term use of menthol cigarettes [48]. In 1995, Sidney et al. [49] looked at medical records for 5771 men and 3990 women aged 30 –89 who had smoked for at least 20 years. They found that there was an increased risk of lung cancer with increasing duration of mentholated cigarette use for men (RR=1.45) but not in women (RR = 0.75). Carpenter et al. [50] in a case-control study found no significant relationship between menthol cigarettes and lung cancer. A recent American Health Foundation study found that black smokers had higher levels of cancer-causing tobacco byproducts in their blood and urine than a comparable group of white study participants [51].

Conclusion (1) The proper amount of menthol per puff on a cigarette can result in the stimulation of cold receptors resulting in the smoker experiencing a ‘‘cool sensation.’’ (2) This ‘‘cool sensation’’ causes a reflex inhibition of respiration manifested as breath holding. (3) As a result of breath holding, there is a greater opportunity for exposure and the transfer of the contents of the large surface areas of the alveolar area of the lungs to the pulmonary circulation. (4) For the menthol smoker this results in a greater exposure to nicotine and the particulate matter (tar) of a smoked cigarette. This exposure can result in increased nicotine dependence and greater chance of tobacco-attributable disease. According to the evidence of this study, further study will validate the observed increase in level of dependence and increase in tobacco-attributable disease in smokers of mentholated cigarettes. Quantitative studies also should be carried out to determine the extent of prolonged lung exposure

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and increased pulmonary circulation transfer from inhaled mentholated cigarette smoke. Also, as brought out in a study by Muscat et al. [52] studies should be carried out to determine the risk of cardiovascular in those that smoke mentholated cigarettes.

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Acknowledgments We would like to thank Professor Ronald Eccles, Director of the Common Cold Center, Cardiff School of Biosciences for being there for us when an expert opinion was needed. Also, we appreciated the input provided by Dr. Stephen Newman former Principal Physicist in the Department of Thoracic Medicine, Royal Free Hospital and School of Medicine whose considered an authority on inhalation drug therapy. In addition, we would like to thank Dr. Michael Cummings, Dr. Gary Giovino and Dr. Andrew Hyland for introducing us to the world of tobacco control.

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