A topographical and physiological exploration of C-tactile afferents and their response to menthol and histamine.

Unmyelinated tactile (C-tactile or CT) afferents are abundant in arm hairy skin and have been suggested to signal features of social affective touch. Here, we recorded from unmyelinated low-threshold mechanosensitive afferents in the peroneal and radial nerves. The most distal receptive fields were located on the proximal phalanx of the third finger for the superficial branch of the radial nerve and near the lateral malleolus for the peroneal nerve. We found that the physiological properties with regard to conduction velocity and mechanical threshold, as well as their tuning to brush velocity, were similar in CT units across the antebrachial (n = 27), radial (n = 8), and peroneal (n = 4) nerves. Moreover, we found that although CT afferents are readily found during microneurography of the arm nerves, they appear to be much more sparse in the lower leg compared with C-nociceptors. We continued to explore CT afferents with regard to their chemical sensitivity and found that they could not be activated by topical application to their receptive field of either the cooling agent menthol or the pruritogen histamine. In light of previous studies showing the combined effects that temperature and mechanical stimuli have on these neurons, these findings add to the growing body of research suggesting that CT afferents constitute a unique class of sensory afferents with highly specialized mechanisms for transducing gentle touch.NEW & NOTEWORHY Unmyelinated tactile (CT) afferents are abundant in arm hairy skin and are thought to signal features of social affective touch. We show that CTs are also present but are relatively sparse in the lower leg compared with C-nociceptors. CTs display similar physiological properties across the arm and leg nerves. Furthermore, CT afferents do not respond to the cooling agent menthol or the pruritogen histamine, and their mechanical response properties are not altered by these chemicals.

Combination of TRP channel dietary agonists induces energy expending and glucose utilizing phenotype in HFD-fed mice.

BACKGROUND: Bioactive dietary constituents activating Transient receptor potential (TRP) channels have emerged as promising candidates for the prevention of metabolic disorders. OBJECTIVE: The present study is an attempt to evaluate anti-obesity potential of a dietary TRP-based tri-agonist, combination of sub-effective doses of capsaicin (TRPV1 agonist), menthol (TRPM8 agonist), and cinnamaldehyde (TRPA1 agonist) in high-fat diet (HFD)-fed mice. DESIGN: Male C57BL/6 J mice divided into three groups (n = 8), were fed on normal pellet diet (NPD), or high-fat diet (HFD) (60% energy by fat) and HFD + CB (combination of capsaicin 0.4 mg/Kg, menthol 20 mg/Kg, and cinnamaldehyde 2 mg/Kg; p.o) for 12 weeks. Effects on HFD-induced weight gain, biochemical, histological and genomic changes in the WAT, BAT, liver and hypothalamus tissues were studied. RESULTS: Administration of tri-agonist prevented HFD-induced increase in weight gain, improved altered morphometric parameters, glucose homeostasis, and adipose tissue hypertrophy. Tri-agonist supplementation was found to induce browning of white adipose tissue and promote brown adipose tissue activation. Enhanced glucose utilization and prevention of lipid accumulation and insulin resistance in the liver was observed in mice supplemented with a tri-agonist. CONCLUSION: The present work provides evidence that the new approach based on combination of sub-effective doses of TRP channel agonists (TRI-AGONIST) can be employed to develop concept-based functional food for therapeutic and preventive strategies against HFD-associated pathological complications.

Menthol-induced activation of TRPM8 receptors increases cutaneous blood flow across the dermatome.

Topical menthol-based analgesics increase skin blood flow (SkBF) through transient receptor potential melastatin 8 (TRPM8) receptor-dependent activation of sensory nerves and endothelium-derived hyperpolarization factors. It is unclear if menthol-induced TRPM8 activation mediates a reflex change in SkBF across the dermatome in an area not directly treated with menthol. The purpose of this study was to determine the effects of localized topical menthol application on SkBF across a common dermatome. We hypothesized that SkBF would be increased with menthol at the site of application and across the dermatome (contralateral limb) through a spinal reflex mechanism. In a double blind, placebo controlled, cross-over design, 15 healthy participants (7 men; age = 22 ± 1 yrs) were treated with direct application (3 ml over 8 × 13 cm) of 5% menthol gel (Biofreeze™) or placebo gel on the L4 dermatome, separated by 48 h. Red blood cell flux was measured using laser Doppler flowmetry over the area of application, on the contralateral leg of the same dermatome, and in a separate dermatome (L5/S1) to serve as control. Cutaneous vascular conductance was calculated for each measurement site (CVC = flux/MAP). At baseline there were no differences in CVC between menthol and placebo gels, or among sites (all p > 0.05). After 30 ± 6 min, CVC increased at the treated site with menthol (0.12 ± 0.02 vs. 1.36 ± 0.19 flux/mm Hg, p < 0.01) but not the placebo (0.10 ± 0.01 vs. 0.18 ± 0.04 flux/mm Hg, p = 0.91). There was a modest increase in CVC at the contralateral L4 dermatome with menthol gel (0.16 ± 0.04 vs. 0.29 ± 0.06 flux/mm Hg, p < 0.01), but not placebo (0.11 ± 0.02 vs. 0.15 ± 0.03 flux/mm Hg, p = 0.41). There was no effect on SkBF from either treatments at the L5/S1 control dermatome (both, p > 0.05), suggesting the lack of a systemic response. In conclusion, menthol containing topical analgesic gels increased SkBF at the treated site, and modestly throughout the dermatome. These data suggest menthol-induced activation of the TRPM8 receptors induces an increase in SkBF across the area of common innervation through a localized spinal reflex mechanism.

Protein profiling in the habenula after chronic (-)-menthol exposure in mice.

The identification of proteins that are altered following nicotine/tobacco exposure can facilitate and positively impact the investigation of related diseases. In this report, we investigated the effects of chronic (-)-menthol exposure in 14 murine brain regions for changes in total ß2 subunit protein levels and changes in epibatidine binding levels using immunoblotting and radioligand binding assays. We identified the habenula as a region of interest due to the region's marked decreases in ß2 subunit and nAChR levels in response to chronic (-)-menthol alone. Thus, we further examined the habenula, a brain region associated with both the reward and withdrawal components of addiction, for additional protein level alterations using mass spectrometry. A total of 552 proteins with altered levels were identified after chronic (-)-menthol exposure. Enriched in the proteins with altered levels after (-)-menthol exposure were proteins associated with signaling, immune systems, RNA regulation, and protein transport. The continuation and expansion of the brain region-specific protein profiling in response to (-)-menthol will provide a better understanding of how this common flavorant in tobacco and e-liquid products may affect addiction and general health.

Impact of elevated core temperature on cognition in hot environments within a military context.

PURPOSE: Cognition can be impaired during exercise in the heat, potentially contributing to military casualties. To our knowledge, the independent role of elevated core temperature during exercise has not been determined. The aim of the current study was to evaluate effects of elevated core temperature on cognition during physically encumbering, heated exercise, and to determine whether the perceptual cooling effects of menthol preserves cognition. METHODS: Eight participants complete three trials in randomised order: one normothermic (CON) and two with elevated (38.5°C) core temperature, induced by prior immersion in neutral versus hot water The CON trial and one hot trial (HOT) used a water mouth-rinse following each cognitive task of the trial, (HOT) while the other used a menthol mouth-rinse (MENT). Participants walked in humid heat (33°C, 75% relative humidity) in military clothing, completing a cognitive battery of reaction time, perceptual processing, working memory, executive function, cognitive flexibility, vigilance, and declarative memory. RESULTS: No differences in cognitive performance were observed between any conditions. Near-infrared spectroscopy showed greater oxygenated haemoglobin tissue content in HOT and MENT compared to CON (ΔO2Hb-deO2Hb: 2.3 ± 4.5 µM, p < .024), and lower deoxygenated haemoglobin in MENT than in CON or HOT (p = .017), suggesting higher brain metabolism during the more stressful conditions. CONCLUSION: Moderately elevated core (38.5°C) and skin temperature does not appear to impair cognitive performance during exercise despite mildly elevated cerebral metabolism. The effects of menthol remain undetermined due to the lack of heat-mediated cognitive impairment.

Development of a "Cooling" Menthol Energy Gel for Endurance Athletes: Effect of Menthol Concentration on Acceptability and Preferences.

Menthol is effective at stimulating thermosensitive neurons that evoke pleasant cooling sensations. Internal application of menthol can be ergogenic for athletes, and hence, addition of menthol to sports nutrition products may be beneficial for athletes. The aim of this study was to develop a menthol energy gel for consumption during exercise and to determine acceptability and preferences for gels with different menthol concentrations. With a randomized, crossover, and double-blind placebo-controlled design, 40 endurance athletes (20 females) ingested an energy gel with a menthol additive at a high (0.5%; HIGH) or low concentration (0.1%; LOW), or a mint-flavored placebo (CON), on separate occasions during outdoor endurance training sessions. The athletes rated the gels for cooling sensation, mint flavor intensity, sweetness, and overall experience and provided feedback. Results are reported as median (interquartile range). Both menthol gels successfully delivered a cooling sensation, with a significantly greater response for HIGH (5.0 [4.0-5.0]) compared with LOW (3.5 [3.0-4.0]; p = .022) and CON (1.0 [1.0-2.0]; p < .0005), and LOW compared with CON (p < .0005). Ratings of mint flavor intensity followed the same trend as cooling sensation, while ratings of overall experience were significantly worse for HIGH (2.0 [1.0-3.0]) compared with LOW (4.0 [2.0-4.0]; p = .001) and CON (4.0 [3.0-4.0]; p < .0005). An energy gel with the addition of menthol at 0.1-0.5% provides a cooling sensation for athletes with a dose-response when ingested during exercise. The 0.1% concentration is recommended to maximize the overall experience of the gel.

The effect of body surface area exposure to menthol on temperature regulation and perception in men.

INTRODUCTION: In warm conditions topical application of menthol increases cool sensations and influences deep body temperature. The purpose of this experiment was to explore whether different body surface areas (BSA) exposed to menthol influence these responses. It was hypothesized that the forcing function exerted by menthol will be proportionally related to BSA. METHOD: Using a within-participant design, 13 participants underwent three BSA exposures (Small [S; finger]; Medium [M; arm]; Large [L; upper/lower body]) to 4.13% menthol, and one Placebo exposure. During each exposure participants rested supine in a tent (30 °C, 50%rh) for 30-min before their intervention and 30-min thereafter. Measures included thermal sensation, thermal comfort, irritation, skin blood flow (finger SkBF; laser Doppler flowmetry), rectal temperature (Tre), and skin temperature (chest, forearm, thigh, calf). The Area Under the Curve from minute 30 to 60 was calculated and analyzed using a one-way ANOVA or Friedman's test with post-hoc testing (0.05 alpha level). RESULTS: There was no significant difference in any measure of thermometry (p > 0.05), while SKBF was significantly lowered in L, M, and S vs. P respectively (p < 0.05). Participants in L felt cooler vs. P and S (p < 0.05). Losses in thermal comfort were noted in L and M vs. P and S (p < 0.05), along with increased irritation in L vs. S (p < 0.05). CONCLUSIONS: Despite similar skin temperatures, larger BSA's exposed to menthol caused cooler sensations, likely due to the activation of a larger pool of menthol-sensitive neurons. This occurred in the absence of thermal discomfort and without perceptions of irritation exceeding 'weak'. Larger BSA's also exhibited greater alterations in Tre, likely driven by a reduction in SkBF, but despite this mean body temperature was regulated suggesting the thermoregulatory system can cope with the range of BSA exposures studied herein.

Energy-Dependent Endocytosis Is Responsible for Skin Penetration of Formulations Based on a Combination of Indomethacin Nanoparticles and l-Menthol in Rat and Göttingen Minipig.

We previously designed a Carbopol gel formulation (N-IND/MEN) based on a combination of indomethacin solid nanoparticles (IND-NPs) and l-menthol, and we reported that the N-IND/MEN showed high transdermal penetration. However, the detailed mechanism for transdermal penetration of IND-NPs was not clearly defined. In this study, we investigated whether endocytosis in the skin tissue of rat and Göttingen minipig is related to the transdermal penetration of IND-NPs using pharmacological inhibitors of endocytosis. The pharmacological inhibitors used in this study are as follows: 54 µM nystatin, a caveolae-mediated endocytosis (CavME) inhibitor; 40 µM dynasore, a clathrin-mediated endocytosis (CME) inhibitor; and 2 µM rottlerin, a micropinocytosis (MP) inhibitor. The N-IND/MEN was prepared by a bead mill method, and the particle size of solid indomethacin was 79-216 nm. In both rat and Göttingen minipig skin, skin penetration of approximately 80% IND-NPs was limited by the stratum corneum (SC), although the penetration of SC was improved by the combination of l-menthol. On the other hand, the treatment of nystatin and dynasore decreased the transdermal penetration of indomethacin in rats and Göttingen minipigs treated with N-IND/MEN. Moreover, in addition to nystatin and dynasore, rottlerin attenuated the transdermal penetration of IND-NPs in the Göttingen minipigs' skin. In conclusion, we found that l-menthol enhanced the SC penetration of IND-NPs. In addition, this study suggests that the SC-passed IND-NPs are absorbed into the skin tissue by energy-dependent endocytosis (CavME, CME, and/or MP pathways) on the epidermis under the SC, resulting in an enhancement in transdermal penetration of IND-NPs. These findings provide significant information for the design of nanomedicines in transdermal formulations.

The impact of menthol essential oil against inflammation, immunosuppression, and histopathological alterations induced by chlorpyrifos in Nile tilapia.

Chlorpyrifos (CPF) is one of the predominant water pollutants associated with inflammation and immunodepression in aquatic animals. In this study, menthol oil (MNT) impacted the immunity, antioxidative, and anti-inflammatory responses against CPF toxicity in Nile tilapia. Fish fed two diets with or without MNT and placed in four groups (control, CPF, MNT, and CPF/MNT). After 30 days, fish fed MNT displayed higher growth performance and lower FCR than CPF-intoxicated fish without feeding MNT (P < 0.05). The survival rate of fish was reduced in the CPF group without MNT feeding (P < 0.05). Blood Hb, PCV, RBCs, and WBCs were decreased in fish by CPF toxicity, while the highest Hb, PCV, RBCs, and WBCs were observed in fish fed MNT followed by those fed the control without CPF toxicity (P < 0.05). Fish fed MNT had the highest total protein, albumin, and globulin, as well as the lowest urea, bilirubin, and creatinine after 15 and 30 days. However, fish under CPF toxicity had the most inferior total protein, albumin, and globulin, as well as the highest urea, bilirubin, and creatinine among the groups (P < 0.05). The enzyme activities of ALP and ALT displayed low levels by MNT with or without CPF exposure than fish fed without MNT with or without CPF exposure after 15 and 30 days (P < 0.05). The lysozyme and phagocytic activities displayed reduced levels by CPF without MNT feeding after 15 and 30 days, while increased activities were noticed by MNT feeding without CPF toxicity followed by fish fed MNT with CPF toxicity (P < 0.05). The transcription of CAT and GPX genes displayed upregulated levels in tilapia fed MNT and exposed to CPF (P < 0.05). Also, CPF toxicity increased the transcription of the IFN-γ gene but decreased the IL-8 and IL-1ß genes. The transcription of HSP70 displayed lower levels (P < 0.05) by CPF without supplementing MNT than fish fed MNT and exposed to CPF. Histopathological analysis revealed that inflammation existed in the liver, gills, and intestine of tilapia due to CPF toxicity while MNT protected tissues from inflammation. To conclude, MNT activated the immunity, antioxidative, and anti-inflammatory responses of Nile tilapia under CPF toxicity.

Use of Mentholated Cigarettes and Likelihood of Smoking Cessation in the United States: A Meta-Analysis.

INTRODUCTION: Previous qualitative reviews have summarized evidence of an association between menthol cigarette use and likelihood of smoking cessation. The objective of this meta-analysis was to provide a quantitative summary of effect sizes, their variability, and factors related to the variability in effect size for the association between menthol use and likelihood of smoking cessation. METHODS: We systematically searched Medline, PsycINFO, and Embase for prospective and cross-sectional studies of the association between menthol use and smoking cessation. We analyzed data with random effects meta-analyses and meta-regression. RESULTS: Our review identified 22 reports from 19 studies of the association between menthol use and cessation. All identified study samples included only US smokers, with one exception that included both Canadian and US smokers. Our overall model did not demonstrate a significant association between menthol use and cessation; however, menthol users were significantly less likely to quit among blacks/African American smokers (odds ratio = 0.88). CONCLUSIONS: Among blacks/African Americans predominantly in the US menthol users have approximately 12% lower odds of smoking cessation compared to non-menthol users. This difference is likely the result of the tobacco industry's ongoing marketing influence on the black/African American Community, suggesting that a menthol ban may have a unique public health benefit for black/African American smokers by encouraging quitting behavior. IMPLICATIONS: This study adds a quantitative summary of the association between menthol cigarette use and smoking cessation in the United States. Findings of an association with lower likelihood of cessation among black/African American smokers, likely resulting from the tobacco industry's marketing influence, support the ban of menthol flavoring as part of a comprehensive tobacco control effort to increase cessation among black/African American smokers.

Menthol Cigarettes, Tobacco Dependence, and Smoking Persistence: The Need to Examine Enhanced Cognitive Functioning as a Neuropsychological Mechanism.

INTRODUCTION: Despite the overall decline in the prevalence of cigarette use in the United States, menthol cigarette use among smokers is rising, and evidence shows that it may lead to more detrimental effects on public health than regular cigarette use. One of the mechanisms by which nicotine sustains tobacco use and dependence is due to its cognitive enhancing properties, and basic science literature suggests that menthol may also enhance nicotine's acute effect on cognition. AIMS AND METHODS: The purpose of this review is to suggest that the cognitive enhancing effects of menthol may be a potentially important neuropsychological mechanism that has yet to be examined. In this narrative review, we provide an overview of basic science studies examining neurobiological and cognitive effects of menthol and menthol cigarette smoking. We also review studies examining menthol essential oils among humans that indicate menthol alone has acute cognitive enhancing properties. Finally, we present factors influencing the rising prevalence of menthol cigarette use among smokers and the importance of this gap in the literature to improve public health and smoking cessation treatment. CONCLUSIONS: Despite the compelling evidence for menthol's acute cognitive enhancing and reinforcing effects, this mechanism for sustaining tobacco dependence and cigarette use has yet to be examined and validated among humans. On the basis of the basic science evidence for menthol's neurobiological effects on nicotinic receptors and neurotransmitters, perhaps clarifying menthol's effect on cognitive performance can help to elucidate the complicated literature examining menthol and tobacco dependence. IMPLICATIONS: Menthol cigarette use has continued to be a topic of debate among researchers and policy makers, because of its implications for understanding menthol's contribution to nicotine dependence and smoking persistence, as well as its continued use as a prevalent flavoring in tobacco and nicotine products in the United States and internationally. As international tobacco regulation policies have begun to target menthol cigarettes, research studies need to examine how flavoring additives, specifically menthol, may acutely influence neurobiological and cognitive functioning as a potential mechanism of sustained smoking behavior to develop more effective treatments.

Reduction in Exposure to Selected Harmful and Potentially Harmful Constituents Approaching Those Observed Upon Smoking Abstinence in Smokers Switching to the Menthol Tobacco Heating System 2.2 for 3 Months (Part 1).

INTRODUCTION: The Tobacco Heating System (THS) is a "heat-not-burn" tobacco product designed to generate significantly lower levels of harmful and potentially harmful constituents (HPHCs) and present lower risk of harm than cigarettes. This study assessed the exposure reduction to selected HPHCs in smokers switching to menthol Tobacco Heating System (mTHS) 2.2 compared with smokers continuing smoking menthol cigarettes (mCCs) and smoking abstinence (SA) for 5 days in a confined setting, followed by an 86-day ambulatory period. METHODS: A total of 160 healthy adult US smokers participated in this randomized, three-arm parallel group, controlled clinical study. Biomarkers of exposure to 16 HPHCs were measured in blood and 24-hour urine. Safety was monitored throughout the study. Information was also gathered on product evaluation, product use, subjective effects, and clinical risk markers (co-publication Part 2). RESULTS: Nicotine uptake was comparable in both exposure groups (mTHS:mCC ratio of 96% on day 90). On day 5, biomarker of exposure levels to other HPHCs were reduced by 51%-96% in the mTHS group compared with the mCC group, and these reductions were sustained for most biomarkers of exposure over ambulatory period. After 90 days of use, the level of satisfaction with mTHS and suppression of urge to smoke were comparable to mCC. CONCLUSION: Switching from mCCs to mTHS significantly reduced the exposure to HPHCs to levels approaching those observed in subjects who abstained from smoking for the duration of the study. IMPLICATIONS: This study compared the impact of switching to mTHS on biomarkers of exposure, relative to continued smoking or SA. TRIAL REGISTRATION: NCT01989156 (ClinicalTrials.gov).

Impact of Menthol on Oral Nicotine Consumption in Female and Male Sprague Dawley Rats.

INTRODUCTION: One of the preferable flavors in oral nicotine delivery systems is menthol which masks the harshness of tobacco. However, possible interactions between oral menthol and nicotine on intake and preference remain unclear. Therefore, we aimed to determine the impact of menthol on oral nicotine consumption. METHODS: Adult Sprague Dawley female and male rats (n = 8 per group) were given a choice of water or drug solution by using two-bottle free choice paradigm for 2 weeks: vehicle (5% ethanol), nicotine (20 mg/L), menthol (1 g/L) and mentholated nicotine groups. At the end of the study, plasma nicotine levels were determined. RESULTS: When rats were given a choice of nicotine or water, nicotine intake was similar between female and male rats. Menthol addition to nicotine solution significantly increased nicotine intake and preference in male but not female rats without a considerable effect on total fluid intake and body weight change in either sex. The average nicotine intake in male rats was 0.5 ± 0.05 and 1.4 ± 0.12 mg/kg/day for nicotine and menthol-nicotine combination (p < .05), respectively. The average nicotine intake in female rats was 0.6 ± 0.05 and 0.6 ± 0.03 mg/kg/day for nicotine and menthol-nicotine combination (p > .05), respectively. Plasma nicotine levels were not significantly different between the groups in either male (nicotine group: 20.8 ± 4.9, mentholated nicotine group: 31.9 ± 3.2 ng/mL) or female (nicotine group: 24.0 ± 3.3, mentholated nicotine group: 17.8 ± 2.9 ng/mL) rats (p > .05). CONCLUSIONS: Menthol increases oral nicotine consumption in male, but not female, rats. IMPLICATIONS: This study may provide data on the co-use of menthol and nicotine in smokeless tobacco, particularly oral dissolvable tobacco products.

Nicotine Self-Administration With Tobacco Flavor Additives in Male Rats.

INTRODUCTION: Nicotine can robustly increase responding for conditioned reinforcers (CRs), stimuli that acquire reinforcing properties based on association with primary reinforcers. Menthol and licorice are tobacco flavoring agents also found in sweet foods (eg, candy and ice cream), making them putative CRs before they are consumed in tobacco. We sought to determine if intravenous self-administration (IVSA) of nicotine was enhanced by the inclusion of oral tobacco flavor CRs. METHODS: Menthol (160 or 320 µM) or licorice root extract (0.1% or 1%) were established as CRs (paired with 20% sucrose) or "neutral" stimuli (paired with water) in separate groups. During subsequent IVSA tests, nicotine was delivered in conjunction with oral presentations of the CR. RESULTS: In experiment 1, a menthol CR significantly shifted the peak nicotine dose from 15 µg/kg/infusion (Neutral group) to 3.25 µg/kg/infusion (CR group). In experiment 2, a menthol CR significantly increased operant licks for nicotine (3 µg/kg/infusion) relative to control groups. In experiment 3, both licorice and menthol CRs significantly increased operant licks for nicotine (7.5 µg/kg/infusion) relative to an "inactive" sipper. The licorice CR increased nicotine IVSA in proportion to the strength of the flavor, but both menthol concentrations increased nicotine IVSA to a similar extent. CONCLUSION: Tobacco flavor additives with conditioned reinforcing properties promote acquisition of nicotine self-administration at low unit doses and may have robust impact on tobacco consumption when nicotine yield is low. IMPLICATIONS: Tobacco flavor additives are found in rewarding foods (eg, ice cream) and gain palatability based on associations with primary rewards (eg, sugar) making them "conditioned reinforcers." Nicotine increases the motivation for flavor conditioned reinforcers and the present studies show that tobacco flavor additives can interact with nicotine to promote more nicotine self-administration. The interaction between flavors additives and nicotine may promote nicotine exposure and subsequently dependence.

Favorable Changes in Biomarkers of Potential Harm to Reduce the Adverse Health Effects of Smoking in Smokers Switching to the Menthol Tobacco Heating System 2.2 for 3 Months (Part 2).

INTRODUCTION: Tobacco Heating System (THS) 2.2, a candidate modified-risk tobacco product, aims at offering an alternative to cigarettes for smokers while substantially reducing the exposure to harmful and potentially harmful constituents found in cigarette smoke. METHODS: One hundred and sixty healthy adult US smokers participated in this randomized, three-arm parallel group, controlled clinical study. Subjects were randomized in a 2:1:1 ratio to menthol Tobacco Heating System 2.2 (mTHS), menthol cigarette, or smoking abstinence for 5 days in confinement and 86 subsequent ambulatory days. Endpoints included biomarkers of exposure to harmful and potentially harmful constituents (reported in our co-publication, Part 1) and biomarkers of potential harm (BOPH). RESULTS: Compliance (protocol and allocated product exposure) was 51% and 18% in the mTHS and smoking abstinence arms, respectively, on day 90. Nonetheless, favorable changes in BOPHs of lipid metabolism (total cholesterol and high- and low-density cholesterol), endothelial dysfunction (soluble intercellular adhesion molecule-1), oxidative stress (8-epi-prostaglandin F2α), and cardiovascular risk factors (eg, high-sensitivity C-reactive protein) were observed in the mTHS group. Favorable effects in other BOPHs, including ones related to platelet activation (11-dehydrothromboxane B2) and metabolic syndrome (glucose), were more pronounced in normal weight subjects. CONCLUSIONS: The results suggest that the reduced exposure demonstrated when switching to mTHS is associated with overall improvements in BOPHs, which are indicative of pathomechanistic pathways underlying the development of smoking-related diseases, with some stronger effects in normal weight subjects. IMPLICATIONS: Switching to mTHS was associated with favorable changes for some BOPHs indicative of biological pathway alterations (eg, oxidative stress and endothelial dysfunction). The results suggest that switching to mTHS has the potential to reduce the adverse health effects of smoking and ultimately the risk of smoking-related diseases. Switching to mTHS for 90 days led to reductions in a number of biomarkers of exposure in smokers, relative to those who continued smoking cigarettes, which were close to those observed when stopping smoking (reported in our co-publication, Part 1). Initial findings suggest reduced levels of 8-epi-prostaglandin F2α and intercellular adhesion molecule 1, when switching to mTHS for 90 days. These changes are comparable to what is observed upon smoking cessation. In normal weight subjects, additional favorable changes were seen in 11-dehydrothromboxane B2, fibrinogen, homocysteine, hs-CRP, percentage of predicted forced expiratory volume in 1 second, systolic blood pressure, diastolic blood pressure, glucose, high-density lipoprotein, apolipoprotein A1, and triglycerides. TRIAL REGISTRATION: NCT01989156.

Effects of L-Menthol and Carbon Dioxide on the Adenoma Detection Rate during Colonoscopy: L-Menthol and Carbon Dioxide on Colonoscopy.

BACKGROUND AND AIMS: We examined the efficacy of the combined use of L-menthol spraying (L-mentholS) as an antispasmodic agent and carbon dioxide insufflation (CO2I) on the adenoma detection rate (ADR) in a prospective, single-center trial with a 2 × 2 factorial design. METHODS: We randomly assigned 611 patients scheduled to undergo colonoscopy to 4 groups: (1) the L-mentholS + CO2I (n = 153), (2) L-mentholS + air insufflation (AI; n = 156), (3) CO2I (n = 153), and (4) AI (n = 149) groups. We used 20 mL of 0.8%-L-menthol solution for the L-mentholS. The primary outcome was the difference in the ADR, and the secondary outcomes were the differences in colonic peristalsis and abdominal pain. -Results: The ADRs were not different among the groups: 1/2/3/4; 39.9%/43.6%/41.2%/51.0%. CO2I was associated with a significant decrease in the ADR (OR 0.57; 95% CI 0.35- 0.93) with a multiple logistic regression. The interaction between L-mentholS and CO2I was associated with a suppression of the decrease in the ADR. Both L-mentholS and CO2I were associated with a significant decrease in abdominal pain, and L-mentholS was associated with a significant improvement of peristalsis. CONCLUSIONS: The fact that CO2I was associated with significant decreases in the ADR was a problem. The combined use of L-mentholS and CO2I could help to suppress the decrease in the ADR.

Skin Application of 4% Menthol Enhances Running Performance in Hot and Humid Climate.

Aerobic performance is negatively impacted by tropical climate due to impairment of thermoregulatory mechanisms. We tested the hypothesis that a torso application of a 4% menthol solution would have the same effect on a best performance 10-km run as an external use of cold water. Thirteen trained male athletes completed four outdoor 10-km runs (T=29.0±1.3°C, relative humidity 59.0±13.6%) wearing a tee-shirt soaked every 2-km either in a cold (~6°C) or warm/ambient (~28°C) solution, consisting in water or in a 4% menthol solution, (CTL, MENT-Amb, CLD and MENT-CLD). Run performances were improved from 4.8 to 6.1% in CLD (51.4±5.5 min), MENT-Amb (52.2±5.9 min) and MENT-CLD (51.4±5.1 min) conditions (vs. CTL, 55.4±8.4 min, P<0.05), without differences between these three conditions, whereas heart rate (177±13bpm), body temperature (38.7±0.6°C) and drink ingestion (356±170 g) were not modified. Thermal sensation after running was lower in MENT-CLD (vs. CTL, P<0.01) and thermal acceptability was higher in CLD and MENT-Amb (vs. CTL, P<0.05), but thermal comfort, feeling scale and rate of perceived exertion remained unchanged. The use of menthol on skin enhances aerobic performance in a tropical climate, and no differences in performance were observed between menthol and traditional percooling strategies. However, combining both menthol and traditional percooling brought no further improvements.

The use of mentholated popsicle to reduce thirst during preoperative fasting: A randomised controlled trial.

AIMS AND OBJECTIVES: To compare mentholated popsicle with usual care (absolute fasting) in the change of thirst intensity and discomfort of patients in the preoperative fasting. BACKGROUND: Thirst is defined as the desire to drink water, and it is considered to be a multifactorial symptom. In the preoperative fasting, the patient may experience intense thirst, often for a long time, that can lead to feelings of suffocation, desperation, fear and anxiety. DESIGN: A randomised controlled trial. METHODS: Forty patients, aged between 18-60 years, were randomised to mentholated popsicle group or absolute fasting group (twenty in each). The primary outcomes were thirst intensity, evaluated by a numeric scale ranging from 0 (no thirst)-10 (the worst possible thirst), and discomfort from thirst (evaluated by the Perioperative Thirst Discomfort Scale), both measured twice (baseline and after 20 min of intervention). The CONSORT checklist was used to report this study. RESULTS: Mean age was similar in both groups (38 years in the mentholated popsicle group and 39 in the absolute fasting group). At baseline, the mentholated popsicle group had higher median for the scales of intensity (6.5) and discomfort (7.5) from thirst than the absolute fasting group (5.0 and 5.0, respectively). At the end of 20 min, the popsicle group had a statistically significant decrease in intensity and discomfort from thirst (median decreases of 5.0 and 7.0 points, respectively) when compared to the absolute fasting group (median increases of 0.5 and 1.0 points, respectively). CONCLUSIONS: The use of mentholated popsicle decreased the intensity and discomfort from thirst, and it is a viable strategy for the management of thirst in the preoperative fasting. RELEVANCE TO CLINICAL PRACTICE: In the preoperative fasting, making mentholated popsicles available to patients is an easy strategy to manage thirst, which might lead to better care.

Influence of Menthol on Recovery From Exercise-Induced Muscle Damage.

Gillis, DJ, Vellante, A, Gallo, JA, and D'Amico, AP. Influence of menthol on recovery from exercise-induced muscle damage. J Strength Cond Res 34(2): 451-462, 2020-This study assessed the influence of menthol, a cold receptor agonist, on recovery from exercise-induced muscle damage (EIMD). Forty-seven healthy males were allocated to a Control (CON, n = 18), Placebo (P, n = 14), or 4.0% Menthol (M, n = 15) condition. Participants were familiarized with a testing battery (TB) including: perception of lower-body muscle soreness, hip flexion/abduction range of motion, vertical jump (VJ), and the agility T-test. Muscle damage was induced on day 1 using 40 × 15-m sprints with a 5-m deceleration zone. The TB immediately followed this and was repeated once-daily for 5 days. Over this time, participants in M and P applied gels to the lower body immediately after sprinting and twice-daily thereafter, whereas CON did nothing. Dependent variables were compared by condition using the Kruskal-Wallis test (α = 0.05), and mean differences with 90% confidence intervals were calculated with small, moderate, and large effects. A significant difference by condition (p < 0.05) in muscle soreness was found, and moderate to large effects were observed in the reduction of muscle soreness with P, compared with M or CON, indicating a placebo effect. A reduction in VJ height across all conditions was observed, with a significant effect (p < 0.05) by condition, and moderate to large effects (1-5 cm) were observed in its preservation with menthol, compared with P or CON. No other differences were observed. These findings raise the possibility that menthol influences recovery of lower-body power after EIMD, and this may have practical implications for menthol's use when recovery of muscle power is important.

Community-Led Action to Reduce Menthol Cigarette Use in the African American Community.

Background. African Americans suffer a disproportionate burden of tobacco harm and researchers have posited that menthol cigarettes are a key contributor to this disparity. In 2015, a county health department and African American community-based organization (CBO) in Minnesota partnered to educate and engage the African American community on menthol and its role in tobacco-related health disparities. The following case study describes successes, challenges, and recommendations from this work. We focus on the role of a public health and community partnership in menthol policy adoption so others can more effectively implement a community-driven approach in their own communities. Methods. Interviews were conducted with local and state public health staff, leadership from the CBO, youth coordinators, and change agents-that is, leaders in the African American community recruited to educate and engage the community on menthol. Interviews were transcribed verbatim and analyzed in Atlas.ti using thematic analysis. Results. Participants identified several successes: (1) assessment data from community members helped inform policy decision making, (2) collaboration between local public health and CBO was powerful and a key to success, and (3) change agents were trusted communicators and effectively engaged and provided education to the community. Participants faced challenges related to stylistic and cultural differences in communication. Participants recommended engaging youth and incorporating cessation into the broader context of issues systemically affecting African American communities (e.g., economic inequity, police violence, incarceration). Implications. Menthol tobacco restrictions have the potential to reduce tobacco-related health inequities for African Americans. Findings highlight the role that public health and community partnerships can play in supporting this critical work to effect policy change.