Nicotine Delivery of a Menthol-Flavored Heat-not-Burn Tobacco Product During Directed Use.

INTRODUCTION: IQOS was authorized by the U.S. Food and Drug Administration (FDA) as a modified-risk tobacco product. We conducted a pharmacokinetic study evaluating the nicotine delivery and subjective effects of IQOS use among current menthol cigarette smokers to better understand if IQOS is an acceptable cigarette alternative in light of the proposed menthol cigarette ban. AIMS AND METHODS: Participants were adult smokers of >4 menthol cigarettes per day. After 14-hour nicotine abstinence, participants were provided an IQOS device and menthol heatstick to puff every 20 seconds for a total of 14 puffs. Blood samples were collected at baseline and during active use to calculate nicotine boost from baseline to peak concentration. Nicotine withdrawal symptoms were collected before and after IQOS use. In addition, a modified Product Evaluation Scale for IQOS was collected after use. RESULTS: Participants (n = 8) were a mean age of 43.9 years, 63% were female, 88% identified as White, and they smoked a mean of 17.1 menthol cigarettes per day. After IQOS use, the mean nicotine boost obtained was 15.96 ng/mL (SD = 6.91) (range 9.31 to 30.55 ng/mL). Most (75%) participants reported enjoying use of the product "a lot" or greater and more than half (62.5%) reported reduced cigarette cravings. Most participants reported no side effects after use; however, two experienced dry mouth, three experienced dizziness, one experienced throat irritation, and one experienced headache. CONCLUSION: We found that directed use (14 puffs) of menthol IQOS delivered a mean nicotine boost of 15.96 ng/mL which reduced craving for a cigarette. The majority of participants enjoyed use of IQOS and reported mild side effects. IMPLICATIONS: Menthol IQOS delivered a sufficient dose of nicotine perceived as satisfying by menthol cigarette smokers and it reduced craving with mild side effects. Menthol IQOS has potential to serve as a less harmful alternative for menthol cigarette smokers. The availability of modified risk products like IQOS should be considered by FDA's Comprehensive Plan for Tobacco and Nicotine Regulation.

Electronic cigarette menthol flavoring is associated with increased inhaled micro and sub-micron particles and worse lung function in combustion cigarette smokers.

Flavored electronic cigarettes (ECs) present a serious health challenge globally. Currently, it is unknown whether the addition of highly popular menthol flavoring to e-liquid is associated with changes in the number of aerosolized particles generated or altered lung function. Here, we first performed preclinical studies using our novel robotic platform Human Vaping Mimetic Real-Time Particle Analyzer (HUMITIPAA). HUMITIPAA generates fresh aerosols for any desired EC in a very controlled and user-definable manner and utilizes an optical sensing system to quantitate and analyze sub-micron and microparticles from every puff over the course of vaping session in real-time while emulating clinically relevant breathing mechanics and vaping topography. We discovered that addition of menthol flavoring to freshly prepared e-liquid base propylene glycol-vegetable glycerin leads to enhanced particle counts in all tested size fractions, similar to the effect of adding vitamin E acetate to e-liquid we previously reported. Similarly, we found that menthol vs. non-menthol (tobacco) flavored pods from commercially available ECs leads to generation of significantly higher quantities of 1-10 µm particles upon inhalation. We then retrospectively analyzed data from the COPDGene study and identified an association between the use of menthol flavored ECs and reduced FEV1% predicted and FEV1/FVC independent of age, gender, race, pack-years of smoking, and use of nicotine or cannabis-containing vaping products. Our results reveal an association between enhanced inhaled particle due to menthol addition to ECs and worse lung function indices. Detailed causal relation remains to be demonstrated in future large-scale prospective clinical studies. Importantly, here we demonstrate utility of the HUMITIPAA as a predictive enabling technology to identify inhalation toxicological potential of emerging ECs as the chemical formulation of e-liquid gets modified.

Do products containing menthol exacerbate allergic rhinitis? A narrative review.

The aim of this paper is to review whether products containing menthol exacerbate allergic rhinitis. A literature survey was performed on PubMed, Google and Google Scholar concerning allergic rhinitis (AR). Allergic rhinitis is an inflammatory condition of the nasal mucosa characterized by wheeze, congestion, nasal pruritus and discharge, or any combination thereof. Menthol is a naturally occurring phytochemical, with the formula C10H20O. The L-isomeric form creates the typical odor of peppermints and causes a sensation of coolness when applied to the skin or mucosae. Inhaling menthol vapor is known to affect the respiratory system in a number of different ways. The cooling agent, menthol, is also recognized as a trigger for asthma, AR and urticaria. The menthol molecule stimulates the TRPM8 receptor and may stimulate histamine release in a dose-dependent manner from RBL-2H3 cell cultures. The addition of menthol to products produces symptomatic relief in some patients by providing an impression of freer nasal air flow. It does this by stimulating cold receptors on branches of the fifth cranial nerve. Menthol is capable of provoking allergic hypersensitivity reactions and disorders, including asthma, AR and urticaria. It may also trigger an anaphylactic response. The use of menthol-containing products is best avoided in cases where an allergic disorder exists.

Efficacy and safety of a food supplement with standardized menthol, limonene, and gingerol content in patients with irritable bowel syndrome: A double-blind, randomized, placebo-controlled trial.

BACKGROUND: Irritable bowel syndrome (IBS) affects 9,2% of the global population and places a considerable burden on healthcare systems. Most medications for treating IBS, including spasmolytics, laxatives, and antidiarrheals, have low efficacy. Effective and safe therapeutic treatments have yet to be developed for IBS. PURPOSE: This study assessed the efficacy and safety of a food supplement containing standardized menthol, limonene, and gingerol in human participants with IBS or IBS/functional dyspepsia (FD). DESIGN: A double-blind, randomized, placebo-controlled trial. METHODS: We randomly assigned 56 patients with IBS or IBS/FD to an intervention group (Group 1) or control group (Group 2) that were given supplement or placebo, respectively, in addition to the standard treatment regimen for 30 d. Three outpatient visits were conducted during the study. Symptom severity was measured at each visit using a 7×7 questionnaire. Qualitative and quantitative composition of the intestinal microbiota were assessed at visits 1 and 3 based on 16S rRNA gene sequencing. RESULTS: At visit 1 (before treatment), the median total 7×7 questionnaire score was in the moderately ill range for both groups, with no difference between the groups (p = 0.1). At visit 2, the total 7×7 score decreased to mildly ill, with no difference between the groups (p = 0.4). At visit 3, the total score for group 1 indicated borderline illness and for group 2 remained indicated mild illness (p = 0.009). Even though we observed some variations in gut microbiota between the groups, we did not find any statistically significant changes. CONCLUSION: The food supplement with standardized menthol, limonene, and gingerol content increased the efficacy of standard therapy in IBS and FD patients. The use of the supplement did not cause any obvious side effects. REGISTRATION: ClinicalTrials.gov Identifier: NCT04484467.

FDA Aims to Ban Menthol in Cigarettes.

The FDA has proposed a ban on menthol flavoring in cigarettes. If enacted, the prohibition would increase smoking cessation rates and decrease first-time tobacco use, in turn drastically reducing smoking-related cancer deaths.

"Because There's Just Something About That Menthol": Exploring African American Smokers' Perspectives on Menthol Smoking and Local Menthol Sales Restrictions.

INTRODUCTION: Local governments are pursuing policies to limit the availability of menthol cigarettes at the point-of-sale. Although African Americans are disproportionately impacted by menthol cigarettes, little is known about African American smokers' perspectives on emerging menthol policy. The purpose of this study was to fill a gap in the literature by exploring African American adult (25+) smoker perspectives on menthol and a local menthol sales restriction. METHODS: In-depth semi-structured interviews were conducted with African American smokers (n = 27) in the Minneapolis-St. Paul area June-September 2017. Interviews explored smoking behaviors, harm perceptions, perspectives of menthol in the community and reactions to local menthol sales restrictions. The framework method guided identification of key themes and synthesis of findings. RESULTS: Almost all (96%) participants smoked Newport cigarettes. The majority of participants indicated that menthol cigarettes were more harmful than non-menthol cigarettes, citing strength and additives and because they were targeted to African Americans. Some participants were receptive to policy change while others viewed the policy as inconvenient and unfair. Overall, there was a lack of understanding of the policy's intended public health impact. Some participants indicated that the policy would have no impact on their purchasing or smoking behaviors while others who were contemplating quitting noted that a menthol restriction was encouragement to prompt a quit attempt. CONCLUSIONS: Sales restrictions can provide a unique opportunity to persuade menthol smokers to quit. Efforts are needed to increase awareness and support of these policies as well as to support African American menthol smokers achieve cessation. IMPLICATIONS: There is growing momentum to restrict local menthol tobacco sales; however, little is known about perceptions among populations most impacted. In Minneapolis-St. Paul, where menthol restrictions were passed in 2017, African American smokers expressed limited awareness and uneven policy support. While some participants were unconvinced the restriction would impact smoking, others indicated it would encourage decreased consumption and prompt quit attempts. There is a need for public education to increase awareness of menthol's harms, to help menthol smokers quit, and to increase support for menthol policies.

L-Menthol for Gastrointestinal Endoscopy: A Systematic Review and Meta-Analysis.

INTRODUCTION: In randomized controlled trials, L-menthol inhibits gastrointestinal peristalsis during endoscopy. Our goal was to quantitatively synthesize the available evidence to evaluate the efficacy and safety of L-menthol for gastrointestinal endoscopy. METHODS: We comprehensively searched for relevant studies published up to January 2020 in PubMed, EMBASE, Web of Science, and Cochrane Library. The main outcomes consisted of the proportion of no peristalsis, proportion of no or mild peristalsis, adenoma detection rate, and adverse events. RESULTS: Eight randomized controlled trials analyzing 1,366 subjects were included. According to the pooled data, L-menthol significantly improved the proportion of no peristalsis (odds ratio [OR] = 6.51, 95% confidence interval [CI] = 4.94-8.57, P < 0.00001), and the proportion of no or mild peristalsis (OR = 7.89, 95% CI = 5.03-12.39, P < 0.00001) compared with the placebo, whereas it was not associated with an improvement in the adenoma detection rate (OR = 1.03, 95% CI = 0.54-1.99, P = 0.92). Adverse events did not differ significantly between the 2 groups (OR = 1.40, 95% CI = 0.75-2.59, P = 0.29). DISCUSSION: The findings of this study support the use of L-menthol to suppress gastrointestinal peristalsis during endoscopic procedure.

Lacrimal gland excision in male and female mice causes ocular pain and anxiety-like behaviors.

Lacrimal gland excision (LGE) induced dry eye produces more severe corneal damage in female mice, yet signs of LGE-induced ocular pain and anxiety in male and female mice have not been characterized. Excision of either the extraorbital gland (single LGE), or both the extraorbital and intraorbital glands (double LGE) was performed in male and female C57BL/6J mice to induce moderate and severe dry eye. Ongoing pain was assessed by quantifying palpebral opening and evoked nociceptive responses after corneal application of capsaicin and menthol. The open-field and plus maze were used to assess anxiety. Single LGE caused a reduction in palpebral opening and an increase in capsaicin and menthol-evoked responses only in female mice. Furthermore, single LGE produced signs of increased anxiety in female but not male mice. Overall, female mice appear more susceptible to signs of ocular pain, irritation, and anxiety in response to aqueous tear deficiency.

Menthol in electronic cigarettes: A contributor to respiratory disease?

Menthol is widely used in tobacco products. This study compared the effects of menthol on human bronchial epithelium using submerged cultures, a VITROCELL® cloud chamber that provides air liquid interface (ALI) exposure without solvents or heating, and a Cultex ALI system that delivers aerosol equivalent to that inhaled during vaping. In submerged culture, menthol significantly increased calcium influx and mitochondrial reactive oxygen species (ROS) via the TRPM8 receptor, responses that were inhibited by a TRPM8 antagonist. VITROCELL® cloud chamber exposure of BEAS-2B monolayers increased mitochondrial protein oxidation, expression of the antioxidant enzyme SOD2, activation of NF-κB, and secretion of inflammatory cytokines (IL-6 and IL-8). Proteomics data collected following ALI exposure of 3D EpiAirway tissue in the Cultex showed upregulation of NRF-2-mediated oxidative stress, oxidative phosphorylation, and IL-8 signaling. Across the three platforms, menthol adversely effected human bronchial epithelium in a manner that could lead to respiratory disease.

Menthol additives to tobacco products. Reasons for withdrawing mentholated cigarettes in European Union on 20th may 2020 according to tobacco products directive (2014/40/EU).

Menthol, which is a natural cyclic monoterpene alcohol with a minty smell, is one of the main constituents of essential oils that naturally occur in some aromatic plants, such as Mentha × piperita L. This natural compound shows many biological properties, such as anesthetic, analgesic, antibacterial and antifungal, immunomodulating, and skin penetration-enhancing. It is added to a variety of goods, such as food, oral-care products, OTC products, cosmetics, and tobacco products. Menthol is not just a simple flavoring agent, especially when it comes to tobacco products. Its ability to 'mask' the negative effects of nicotine and its additional positive sensory effects makes it the most common additive in such products. For the customers, mentholated tobacco products may be mistakenly perceived as less harmful for health, which may increase their consumption. However, as the evidence shows, menthol cigarettes are no safer than conventional cigarettes and may lead to more frequent disease exacerbation during prolonged exposure to smoke from such products. In addition, because of its complex interactions with nicotine, menthol may affect smoking behavior and may increase addiction to nicotine. For those reasons, the European Union banned flavored cigarettes (whose sale size reached more than 3% of the total tobacco product market) by implementing the Tobacco Products Directive (2014/40/EU) on 20th May 2020. While the menthol ban was based on health concerns, the ultimate effect on consumers, regarding potential quitting, is yet to be determined.

Acute Eosinophilic Pneumonia Secondary to Menthol Cigarette Use: A Rare Phenomenon With a Review of Literature.

Idiopathic acute eosinophilic pneumonia (AEP) is a very rare disease with fewer than 200 cases reported. It has been hypothesized to be a hypersensitivity reaction to an unidentified antigen. The clinical presentation typically involves fever, nonproductive cough, shortness of breath, and bibasilar inspiratory crackles within the first week of antigen exposure. Chest imaging usually reveals bilateral reticular and/or ground-glass opacities. Bronchoalveolar lavage demonstrates >25% eosinophils. Corticosteroids are the mainstay of treatment with good results; however, optimum dose and length of treatment are unclear. We present a case of a 31-year-old male who presented with 2 days of shortness of breath, cough, pleuritic chest pain, fevers, chills, nausea, and poor appetite in the setting of initiation of menthol-flavored cigarettes 2 weeks before presentation. He rapidly progressed to respiratory failure requiring intubation despite broad antibiotic coverage. His course was complicated by severe acute respiratory distress syndrome, circulatory shock, and renal failure. He underwent bronchoalveolar lavage testing that revealed 60% eosinophils. He was treated with steroids and was subsequently extubated and discharged. Eosinophilic counts in the blood peaked on the 10th day of admission to 34%. One week later, the patient was completely free of symptoms. The initiation of menthol cigarette use in this patient is the likely reason for ensuing acute eosinophilic pneumonia, hence adding to the sporadic reports on the role of menthol-flavored cigarettes. This case emphasizes a greater reliance on risk factors, as opposed to eosinophilic markers, for the diagnosis and treatment of acute eosinophilic pneumonia to prevent subsequent respiratory failure and intubation in such patients.

Measures of dependence in menthol and nonmenthol smokers - A comprehensive narrative review.

Introduction. More than a decade ago, concerns were raised that menthol in cigarettes might enhance addiction to smoking. This article provides a comprehensive review of published studies examining cigarette dependence among menthol and nonmenthol smokers. The purpose of the review is to evaluate the scientific evidence to determine if menthol increases cigarette dependence. Materials and Methods. The published literature was searched in 2019 for studies that provide evidence on cigarette dependence among menthol compared to nonmenthol smokers. Included in this review are published studies that compare menthol and nonmenthol smokers based on widely accepted and validated measures of dependence, or other established predictors of dependence (age of smoking initiation [first cigarette]/age of progression [regular/daily smoking]) and indicators of dependence (smoking frequency, cigarettes smoked per day, time to first cigarette after waking, night waking to smoke, smoking duration). Results and Conclusion. Based on a review of the available studies, including those with adjusted results and large representative samples, reliable and consistent empirical evidence supports a conclusion that menthol smokers are not more dependent than nonmenthol smokers and thus menthol in cigarettes does not increase dependence.

Menthol Cigarettes and Smoking Cessation among Adult Smokers in the US.

Objectives: In this study, we identified differences in cessation, nicotine dependence, and quit attempts between smokers using non-menthol cigarettes and smokers using menthol cigarettes differing in menthol delivery method (eg, menthol in the tobacco only, crushable capsules only or both). Methods: We analyzed data from the Population Assessment of Tobacco and Health Study, Waves 1 and 2 (W1 and W2), to determine associations of delivery method of menthol with cessation, nicotine dependence, and quit attempts among current adult cigarette smokers. Results: Nearly 40% of US smokers reported using a mentholated cigarette product with most using a product mentholated in the tobacco only. Smokers included in this analysis had a moderate to low heaviness of smoking index score. The lowest average score was among those using products mentholated in a filter capsule only (1.3, SE = .10), and the highest among those using non-mentholated products (2.4, SE = .03). About 12% of smokers quit between W1 and W2. Cessation, nicotine dependence, and quit attempts at W2 were not associated with delivery method of menthol at W1. Conclusions: Method of menthol delivery did not impact cessation, nicotine dependence, and quit attempts.

Evaluating a Real World Ban on Menthol Cigarettes: An Interrupted Time-Series Analysis of Sales.

BACKGROUND: Menthol in cigarettes has been shown to increase regular cigarette smoking and nicotine dependence, and decrease success in smoking cessation. Owing to these reasons, in May 2015, the province of Ontario introduced a menthol ban on tobacco products that came into effect in January 2017 prior to a Federal Canadian Ban in October 2017. The objective of this article was to assess the effect of a provincial menthol ban on cigarette wholesale sales in Ontario. METHODS: Wholesale data submitted by tobacco manufacturers to Health Canada pursuant to the federal Tobacco Reporting Regulations from October 2012 to September 2017 were analyzed using interrupted time-series analysis. Changes in sales of cigarettes with and without menthol were estimated, using the province of British Columbia as a comparison. Analyses were seasonally adjusted. RESULTS: Sales of menthol and nonmenthol cigarettes increased from 2013 until the implementation of the 2017 provincial ban. Subsequently, a sharp decline of 55 million menthol cigarettes and 128 million total cigarettes was observed in Ontario. As a comparison, no significant changes were observed in British Columbia. CONCLUSION: This study supports the conclusion that implementation of a menthol ban in Ontario was associated with significant reduction of menthol cigarette sales and total cigarettes sales, compared to British Columbia where there was no provincial menthol ban. This suggests that menthol regulations in jurisdictions with a larger percentage of menthol smokers are likely to be highly effective. IMPLICATIONS: The 2017 menthol ban was associated with significant reduction of menthol cigarette sales and total cigarette sales suggesting that menthol regulations will have important effects on cigarette consumption.

The Biological Impact of Menthol on Tobacco Dependence.

In the 1920s, tobacco companies created a marketing campaign for what would one day be their most profitable series of products: mentholated tobacco cigarettes. Menthol provides the smoker with a pleasant mint flavor in addition to a cooling sensation of the mouth, throat, and lungs, giving relief from the painful irritation caused by tobacco smoke. Promising a healthier cigarette using pictures of doctors in white coats and even cartoon penguins, tobacco companies promoted these cigarettes to young, beginner smokers and those with respiratory health concerns. Today, smoking tobacco cigarettes causes one in five US Americans to die prematurely, crowning it as the leading cause of preventable death. In contrast to the dubious health claims by tobacco companies, mentholated cigarettes are in fact more addictive. Smokers of mentholated cigarettes have lower successful quit rates and in some cases are resistant to both behavioral and pharmacological treatment strategies. There is now considerable evidence, especially in the last 5 years, that suggest menthol might influence the addictive potential of nicotine-containing tobacco products via biological mechanisms. First, menthol alters the expression, stoichiometry, and function of nicotinic receptors. Second, menthol's chemosensory properties operate to mask aversive properties of using tobacco products. Third, menthol's chemosensory properties aid in serving as a conditioned cue that can both enhance nicotine intake and drive relapse. Fourth, menthol alters nicotine metabolism, increasing its bioavailability. This review discusses emerging evidence for these mechanisms, with an emphasis on preclinical findings that may shed light on why menthol smokers exhibit greater dependence. IMPLICATIONS: Mentholated cigarettes have been shown to have greater addictive potential than their nonmentholated counterparts. Evidence is pointing toward multiple mechanisms of action by which menthol may alter tobacco dependence. Understanding menthol's biological functions as it pertains to nicotine dependence will be helpful in crafting novel pharmacotherapies that might better serve menthol smokers. In addition, a better understanding of menthol's pharmacology as it relates to tobacco dependence will be valuable for informing policy decisions on the regulation of mentholated cigarettes.

Adults' favorability toward prohibiting flavors in all tobacco products in the United States.

In November 2018, US Food and Drug Administration announced its intent to prohibit menthol in combustible tobacco products, prohibit flavored cigars, and prohibit flavored e-cigarettes unless they are sold in age-restricted, in-person locations. This study assessed adult attitudes toward prohibiting flavors in all tobacco products, including e-cigarettes. Data were from the 2016 Summer Styles survey of 4203 US adults aged ≥18 years. Respondents were asked whether they favored or opposed prohibiting flavors (e.g., menthol, spicy, sweet, or fruity flavor) in all tobacco products. Prevalence and correlates of favorability were assessed using weighted percentages and adjusted prevalence ratios (aPR) respectively. Assessed correlates were: sex, age, race/ethnicity, income, US Census region, marital status, children <18 years living in the home, perceptions toward e-cigarette advertising, and current (past 30-day) tobacco product use. Overall, 47.3% of adults reported favorable attitudes toward prohibiting flavors in all tobacco products. By tobacco product use status, prevalence was 52.0%, 48.4%, and 34.8% among never, former, and current users, respectively (p < .05). Among current tobacco product users, favorability was more likely among adults who believed e-cigarette ads exposure makes youth think about smoking (aPR = 1.82; 95% CI = 1.20-2.78) and those with any children aged <18 years in their household (aPR = 1.38; 95% CI = 1.05-1.82). To conclude, nearly half of adults favored prohibiting flavors in all tobacco products, including e-cigarettes. Prohibiting flavors in tobacco products could benefit public health by reducing both individual-level and population-level harms, including tobacco use initiation especially among youth.

An in silico investigation of menthol metabolism.

Prevalence of mentholated products for consumption has brought great importance to studies on menthol's metabolic pathways to ensure safety, design more potent derivatives, and identify therapeutic benefits. Proposed pathways of (-)-menthol metabolism based on metabolites found experimentally in previous works by Yamaguchi, Caldwell & Farmer, Madyastha & Srivatsan and Hiki et al. were not in agreement. This in silico approach is based on the three in vivo studies and aims to resolve the discrepancies. Reactions in the pathways are conjugation with glucuronic acid/sulfate, oxidation to alcohol, aldehyde & carboxylic acid, and formation of a four-membered/five-membered ring. Gas-phase structures, standard Gibbs energies and SMD solvation energies at B3LYP/6-311++G(d,p) level were obtained for 102 compounds in the pathways. This study provides a more complete picture of menthol metabolism by combining information from three experimental studies and filling missing links in previously published pathways.