Cold air stimulates upper airway cold receptors causing a reflex inhibition of respiration. Menthol can also selectively stimulate cold receptors causing a depressive effect on respiratory activity. Mentholated cigarettes do contain enough menthol to stimulate cold receptors to produce a "cool sensation." Unconscious breath holding (apnea) that can result from inhibition of respiration may allow for greater transfer of inhaled tobacco smoking constituents into the pulmonary blood. The greater transfer of nicotine and tar may lead to a greater dependence on nicotine and also a greater risk of tobacco attributable disease. Breath holding has been used to enhance the uptake of various therapeutic substances from the alveoli of the lungs into the blood stream. Marijuana smokers have deliberately held their breath to allow for a more rapid uptake (along with any tar residue) into the circulation and therefore increased onset of the CNS effects of this abused drug. Evidence is presented below to provide support for this possible mechanism of action to help explain the effects of menthol on tobacco smoking.
Upper airway cooling has a 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 resistence (Burgess and Whitelaw, 1988, McBride and Whitelaw, 1981). This stimulation of upper airway cold receptors causing a reflex inhibition of respiration has also been found in animal studies.. Ramos (1960) blew cool air gently out through the nose of a cat and found that breathing was inhibited. A study using guinea pigs showed that warm air had no effect but cold air trials lowered laryngeal but not nasal temperature and resulted in reduced ventilation. Exposure of the nasal cavity to cold air enhanced the ventilatory inhibition (Orani et al., 1991). Another study in cats confirmed that directing cold air through the larynx causes reflex inhibition of ventilatory activity (Ukabam et al., 1992).
Studies in adult male volunteers who breathed either cold air or warm air through the nose by means of a face mask found that the depressant effect of cold air breathing was mediated by skin and mucosal temperature receptors connected to the respiratory centers of the brain rather than a direct cooling of the hypothalamus. (Burgess et al., 1988). Mathew et al. (1990) found in newborn puppies that the depresant effect of cold airflow through the upper airway was entirely due to a decrease in larygeal temperature and was mediated by superior larygeal nerve afferents. Warm airflow induced no significant changes and superior laryngeal nerve section abolished the effects of cooling on breathing pattern. These data provide evidence that cold airflow activates cold receptors (nerve endings) sending an afferent nerve impulse to the brain.
The major effect of menthol when applied to the skin or a mucosal surface is to cause the sensation of coolness or warmth. This cool sensation is apparent when low or threshold concentrations of menthol is present and the feeling of warmth at higher concentrations. Potter (1890) found using menthol for treating patients with upper airway diseases found that in the proper percentage menthol produced a pleasant, cool sensation. When menthol was used in full strength patients experienced a feeling of great heat. Hensel and Zotterman (1951) determined that menthol stimulated cold receptors independent of any change in temperature.
Many of the uses of menthol have exploited the cooling action of menthol. Peppermnt oil composed primarily of menthol which results in the cooling sensation produced when a peppermint is eaten (possibly after dinner) (Hay and Waterman, 1993). Proctor & Gamble (2/12/98) marketed Head & Shoulders Menthol shampoo in India because of the cool tingling a person would experence when using the product in a hot, humid climate - Head & Shoulders is the number one selling shampoo in the world(http://www.pg.com/about/news/indianew.htm#menthol"). - for more information on the Chemistry and Uses of Menthol Menthol - Chemistry and Many Uses...
Most of menthols actions on the respiratory tract are a result of experiencing the "cool sensation". It has been demonstrated that stimulation of cold receptors in the upper respiratory tract with nasal inhalation of menthol reduces the respiratory discomfort associated with loaded breathing (Nishino et al.,1997). Total nasal resistance to airflow was measured in 31 subjects before an after five minute exposure to menthol vapors. Menthol inhalation had no consistent effect on nasal resistance but the majority of subjects reported on increased sensation of nasal airflow and a cooling of menthol. These results suggested that menthol stimulated cold receptors to create an increased sensation of airflow. No evidence was found in support of any nasal decongestant action of menthol (Eccles and Jones, 1983; Eccles, 1990 ).
The selective stimulation of cold receptors by menthol is thought to be a result of the inhibition of calcium movement across the cell membranes of the nerve endings that form the thermoreceptors. (Swadulla et al., 1986) - for more information on Cold Receptors and the Inhibition of Calcium Movement see related module - Calcium - Cold Receptors.
Just like the response to a cold stimulus, inhalation of menthol has been shown to inhibit respiration via upper respiratory airway cold receptors (Eccles et al., 1989, Orani et al., 1991, FB Sant'Ambrogio et al., 1992). Sloan et al. (1993) provided evidence that stimulation of upper airway cold receptors resulted in increased breath-hold times. Twenty healthy volunteers (18-39 years old) were asked to hold their breath for as long as possible at total lung capacity three times at five minute intervals. The procedure was repeated three more times, this time sucking a lozenge containing 11mg of menthol or a placebo five minutes before each breath- holds. It was found that breath-hold time was significantly prolonged after menthol. This was accompanied by a significant increase in the partial pressure of CO2, No significant change in either breath-hold time or partial pressure of CO2 was seen after giving the placebo. A recent review has put forward the hypothesis that menthol, by its effect on sensory cold receptors may influence thirst, the drive to breathe and arousal (Eccles, 2000). --->Coming soon information on the relationship of menthol stimualtion of cold receptors and age<---
Respiratory Distress has been reported in infants exposed to menthol..
Mentholated cigarettes do contain enough menthol for the smoker to experience the "cool sensation" http://www.cancer.org/tobacco/quitting.html. - see related document concerned with How Menthol is Applied to Tobacco and the Amounts of Menthol in Cigarettes and in Smoke - Menthol - Applied to Tobacco, etc..
We have seen that menthol because of its stimulation of cold receptors has been shown consistently to cause an inhibition of breathing. The unconscious breath holding that results may allow for greater transfer of inhaled tobacco smoking constituents into the pulmonary blood. The greater transfer of nicotine and tar leads to a greater dependence on nicotine and also a greater risk of tobacco attributable disease. Also, during breath holding the lungs may decrease in volume so the alveolar pressure would increase forcing more smoking constituents into the blood stream (Stevens, et al, 1946). An African American that smokes menthols may have started smoking at an older age and smoke less cigarettes per day but their enhanced exposure to tar and nicotine quickly catches up to others and may even surpass their exposure.
Breath holding has been used to enhance the uptake of various substances from the alveoli of the lungs into the blood stream. In inhalation therapy a way to enhance the transfer of drug delivery into the pulmonary circulation is to have the patient hold their breath for a short period of time after inhaling (Newman, 1991). Studies by Tashkin and colleagues (Matthias et al., 1997) at UCLA have shown that breath holding by marijuana smokers increases the onset of CNS effects but also led to a greater deposition of tar.
Thus, the cigarette serves as a delivery device for at least two pharmacologic agents: nicotine and menthol.
Burgess KR and WA Whitelaw, Effects of nasal cold receptors on pattern of breathing, J. Appl.
Physiol. 64(1):371-6, 1988.
Burgess KR JA Evans and WA Whitelaw, No evidence for hypothalamic cooling during nasal cold air breathing in man, Clin. Invest. Med. 11(2): 134-8, 1988.
Eccles R and AS Jones, The effect of menthol on nasal resistance to airflow, J. Laryngol. Otol. 97(8): 705-709, 1983.
Eccles R MS Jawad and S Morris, The effects of oral administration of (-)-menthol on nasal resistance to airflow and congtestion assocaited with the common cold, J. Pharm. Pharmacol. 42: 652-654, 1990.
Eccles R, Menthol and Related Cooling Compounds, J. Pharm. Pharmacol. 46: 618-630, 1994.
Eccles R, Role of cold receptors and menthol in thirst, the drive to breathe and arousal, Appetite 34:29-35, 2000.
Hay R and PG Waterman, Volatile Oil Crops: Their Biology, Bichemistry and Production, Longman Scientific and Technical, New York, NY 1993.
Hensel H and Y Zotterman, The effect of menthol on the thermoreceptors, Acta Physiol. Scand. 24: 27-34, 1951.
Mathew OP JW Anderson GP Orani FB Sant'Ambrogio and G Sant'Ambrogio, Cooling mediates the ventilatory depression associated with airflow through the larynx, Respir. Physiol. 82(3): 359-67, 1990.
Matthias P DP Tashkin JA Marques-Magallanes JN Wilkons and MS Simmon, Effect of varying matijuana potency on disposition of tar and delta9-THC in the lung during smoking, Pharmacol. Biochem. Behav. 58(4):1145-50, 1997.
McBride B and WA Whitelaw, A physiological stimulus to upper airway receptors in humans, J. Appl. Physiol. 51: 1189-1197, 1981.
Newman SP, Aerosol Generators and Delivery Systems, Resp. Care 36(9): 939-951, 1991.
Nishino T Y Tagaito and Y Sakurai, Nasal inhalation of l-menthol reduces respiratory discomfort associated with loaded breathing, Am. J. Respir. Crit. Care Med. 156: 309-313, 1997.
Orani GP JW Anderson G Sant'Ambrogio and FB Sant'Ambrogio, Upper airway cooling and l-menthol reduce ventilation in the guinea pig, J. Appl. Physiol. 70(5): 2080-6, 1991.
Potter FH, The use of menthol in disease of the upper air-passages, J. Amer. Med. Assoc. 14:147-149, 1890.
Orani GP JW Anderson G Sant'Ambrogio and FB Sant'Ambrogio, Upper airway cooling and l-menthol reduce ventilation in the guinea pig, J. Appl. Physiol. 70(5): 2080-6, 1991.
Ramos JG, On the integration of respiratory movements. III. The fifth nerve afferents, Acta Physiol. L. Amer. 10: 104-113, 1960.
Sant'Ambrogio FB JW Anderson and G Sant'Ambrogio, Effect of l-menthol on larnygeal receptors, J. Appl. Physiol. 70: 788-793, 1991.
Sloan A SC DeCort and R Eccles, Prolongation of breath-hold time following treatment with an L-menthol lozenge in healthy man, J. Physiol. 473, 53P.
Stevens CD EB Ferris JP Webb GL Engel and M Logan, Voluntary Breathholding. I. Pulmonary gas exchange during breathholding, J. Clin. Invest. 25: 723-728, 1946.
Swandulla D K Schafer and HG Lux, Calcium channel current inactivation is selectively modulated by menthol, Neurosci. Letters 68:23-28, 1986.
Ukabam CU SL Knuth and D Bartlett Jr, Phrenic and hypoglossal neural response to cold airflow in the upper airway, Respir. Physiol. 87(2): 157-64, 1992.