Catalytic asymmetric synthesis of cannabinoids and menthol from neral.

The selective conversion of natural or synthetic neral to (1R,6S)-trans-isopiperitenol would enable and expedite sustainable routes to menthol1,2 and cannabinoids3-5. However, this reaction has been considered impossible because its product is more reactive to the required acid catalysts than its starting material, resulting in several side products6-9. We now show that an unsymmetric, strong and confined chiral acid, a highly fluorinated imino-imidodiphosphate, catalyses this process with excellent efficiency and selectivity. Expanding the method to other α,ß-unsaturated aldehydes could enable access to new cannabinoids and menthol derivatives not readily accessible previously. Mechanistic studies suggest that the confined catalyst accomplishes this reaction by binding the product in an unreactive conformation, thereby preventing its decomposition. We also show how (1R,6S)-trans-isopiperitenol can be readily converted to pharmaceutically useful cannabinoids and menthol, each in the shortest and most atom-economic routes so far.

KCNQ1 is an essential mediator of the sex-dependent perception of moderate cold temperatures.

Low temperatures and cooling agents like menthol induce cold sensation by activating the peripheral cold receptors TRPM8 and TRPA1, cation channels belonging to the TRP channel family, while the reduction of potassium currents provides an additional and/or synergistic mechanism of cold sensation. Despite extensive studies over the past decades to identify the molecular receptors that mediate thermosensation, cold sensation is still not fully understood and many cold-sensitive peripheral neurons do not express the well-established cold sensor TRPM8. We found that the voltage-gated potassium channel KCNQ1 (Kv7.1), which is defective in cardiac LQT1 syndrome, is, in addition to its known function in the heart, a highly relevant and sex-specific sensor of moderately cold temperatures. We found that KCNQ1 is expressed in skin and dorsal root ganglion neurons, is sensitive to menthol and cooling agents, and is highly sensitive to moderately cold temperatures, in a temperature range at which TRPM8 is not thermosensitive. C-fiber recordings from KCNQ1-/- mice displayed altered action potential firing properties. Strikingly, only male KCNQ1-/- mice showed substantial deficits in cold avoidance at moderately cold temperatures, with a strength of the phenotype similar to that observed in TRPM8-/- animals. While sex-dependent differences in thermal sensitivity have been well documented in humans and mice, KCNQ1 is the first gene reported to play a role in sex-specific temperature sensation. Moreover, we propose that KCNQ1, together with TRPM8, is a key instrumentalist that orchestrates the range and intensity of cold sensation.

Roles of Intramolecular Interactions in the Regulation of TRP Channels.

The transient receptor potential (TRP) channels, classified into six (-A, -V, -P, -C, -M, -ML, -N and -Y) subfamilies, are important membrane sensors and mediators of diverse stimuli including pH, light, mechano-force, temperature, pain, taste, and smell. The mammalian TRP superfamily of 28 members share similar membrane topology with six membrane-spanning helices (S1-S6) and cytosolic N-/C-terminus. Abnormal function or expression of TRP channels is associated with cancer, skeletal dysplasia, immunodeficiency, and cardiac, renal, and neuronal diseases. The majority of TRP members share common functional regulators such as phospholipid PIP2, 2-aminoethoxydiphenyl borate (2-APB), and cannabinoid, while other ligands are more specific, such as allyl isothiocyanate (TRPA1), vanilloids (TRPV1), menthol (TRPM8), ADP-ribose (TRPM2), and ML-SA1 (TRPML1). The mechanisms underlying the gating and regulation of TRP channels remain largely unclear. Recent advances in cryogenic electron microscopy provided structural insights into 19 different TRP channels which all revealed close proximity of the C-terminus with the N-terminus and intracellular S4-S5 linker. Further studies found that some highly conserved residues in these regions of TRPV, -P, -C and -M members mediate functionally critical intramolecular interactions (i.e., within one subunit) between these regions. This review provides an overview on (1) intramolecular interactions in TRP channels and their effect on channel function; (2) functional roles of interplays between PIP2 (and other ligands) and TRP intramolecular interactions; and (3) relevance of the ligand-induced modulation of intramolecular interaction to diseases.

Current View of Ligand and Lipid Recognition by the Menthol Receptor TRPM8.

Transient receptor potential (TRP) melastatin member 8 (TRPM8), which is a calcium-permeable ion channel, functions as the primary molecular sensor of cold and menthol in humans. Recent cryoelectron microscopy (cryo-EM) studies of TRPM8 have shown distinct structural features in its architecture and domain assembly compared with the capsaicin receptor TRP vanilloid member 1 (TRPV1). Moreover, ligand-bound TRPM8 structures have uncovered unforeseen binding sites for both cooling agonists and membrane lipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. These complex structures unveil the molecular basis of cooling agonist sensing by TRPM8 and the allosteric role of PI(4,5)P2 in agonist binding for TRPM8 activation. Here, we review the recent advances in TRPM8 structural biology and investigate the molecular principles governing the distinguishing role of TRPM8 as the evolutionarily conserved menthol receptor.

The powerful potential of amino acid menthyl esters for anti-inflammatory and anti-obesity therapies.

Our newly developed menthyl esters of valine and isoleucine exhibit anti-inflammatory properties beyond those of the well-known menthol in macrophages stimulated by lipopolysaccharide (LPS) and in a mouse model of colitis induced by sodium dextran sulfate. Unlike menthol, which acts primarily through the cold-sensitive TRPM8 channel, these menthyl esters displayed unique mechanisms that operate independently of this receptor. They readily penetrated target cells and efficiently suppressed LPS-stimulated tumour necrosis factor-alpha (Tnf) expression mediated by liver X receptor (LXR), a key nuclear receptor that regulates intracellular cholesterol and lipid balance. The menthyl esters showed affinity for LXR and enhanced the transcriptional activity through their non-competitive and potentially synergistic agonistic effect. This effect can be attributed to the crucial involvement of SCD1, an enzyme regulated by LXR, which is central to lipid metabolism and plays a key role in the anti-inflammatory response. In addition, we discovered that the menthyl esters showed remarkable efficacy in suppressing adipogenesis in 3T3-L1 adipocytes at the mitotic clonal expansion stage in an LXR-independent manner as well as in mice subjected to diet-induced obesity. These multiple capabilities of our compounds establish them as formidable allies in the fight against inflammation and obesity, paving the way for a range of potential therapeutic applications.

The role of strigolactone in alleviating salinity stress in chili pepper.

Salinity stress can significantly delay plant growth. It can disrupt water and nutrient uptake, reducing crop yields and poor plant health. The use of strigolactone can be an effective technique to overcome this issue. Strigolactone enhances plant growth by promoting root development and improvement in physiological attributes. The current pot study used strigolactone to amend chili under no salinity and salinity stress environments. There were four treatments, i.e., 0, 10µM strigolactone, 20µM strigolactone and 30µM strigolactone. All treatments were applied in four replications following a completely randomized design (CRD). Results showed that 20µM strigolactone caused a significant increase in chili plant height (21.07%), dry weight (33.60%), fruit length (19.24%), fruit girth (35.37%), and fruit yield (60.74%) compared to control under salinity stress. Significant enhancement in chili chlorophyll a (18.65%), chlorophyll b (43.52%), and total chlorophyll (25.09%) under salinity stress validated the effectiveness of 20µM strigolactone application as treatment over control. Furthermore, improvement in nitrogen, phosphorus, and potassium concentration in leaves confirmed the efficient functioning of 20µM strigolactone compared to other concentrations under salinity stress. The study concluded that 20µM strigolactone is recommended for mitigating salinity stress in chili plants. Growers are advised to apply 20µM strigolactone to enhance their chili production under salinity stress.

Studying the impact of titanium dioxide nanoparticles on the expression of pivotal genes related to menthol biosynthesis and certain biochemical parameters in peppermint plants (Mentha Piperita L.).

BACKGROUND: This study examines the impact of titanium dioxide nanoparticles (TiO2NPs) on gene expression associated with menthol biosynthesis and selected biochemical parameters in peppermint plants (Mentha piperita L.). Menthol, the active ingredient in peppermint, is synthesized through various pathways involving key genes like geranyl diphosphate synthase, menthone reductase, and menthofuran synthase. Seedlings were treated with different concentrations of TiO2NPs (50, 100, 200, and 300 ppm) via foliar spray. After three weeks of treatment, leaf samples were gathered and kept at -70 °C for analysis. RESULTS: According to our findings, there was a significant elevation (P ≤ 0.05) in proline content at concentrations of 200 and 300 ppm in comparison with the control. Specifically, the highest proline level was registered at 200 ppm, reaching 259.64 ± 33.33 µg/g FW. Additionally, hydrogen peroxide and malondialdehyde content exhibited a decreasing trend following nanoparticle treatments. Catalase activity was notably affected by varying TiO2NP concentrations, with a significant decrease observed at 200 and 300 ppm compared to the control (P ≤ 0.05). Conversely, at 100 ppm, catalase activity significantly increased (11.035 ± 1.12 units/mg of protein/min). Guaiacol peroxidase activity decreased across all nanoparticle concentrations. Furthermore, RT-qPCR analysis indicated increased expression of the studied genes at 300 ppm concentration. CONCLUSIONS: Hence, it can be inferred that at the transcript level, this nanoparticle exhibited efficacy in influencing the biosynthetic pathway of menthol.

Effects of MhMYB1 and MhMYB2 transcription factors on the monoterpenoid biosynthesis pathway in l-menthol chemotype of Mentha haplocalyx Briq.

MAIN CONCLUSION: Transcription factors MhMYB1 and MhMYB2 correlate with monoterpenoid biosynthesis pathway in l-menthol chemotype of Mentha haplocalyx Briq, which could affect the contents of ( -)-menthol and ( -)-menthone. Mentha haplocalyx Briq., a plant with traditional medicinal and edible uses, is renowned for its rich essential oil content. The distinct functional activities and aromatic flavors of mint essential oils arise from various chemotypes. While the biosynthetic pathways of the main monoterpenes in mint are well understood, the regulatory mechanisms governing different chemotypes remain inadequately explored. In this investigation, we identified and cloned two transcription factor genes from the M. haplocalyx MYB family, namely MhMYB1 (PP236792) and MhMYB2 (PP236793), previously identified by our research group. Bioinformatics analysis revealed that MhMYB1 possesses two conserved MYB domains, while MhMYB2 contains a conserved SANT domain. Yeast one-hybrid (Y1H) analysis results demonstrated that both MhMYB1 and MhMYB2 interacted with the promoter regions of MhMD and MhPR, critical enzymes in the monoterpenoid biosynthesis pathway of M. haplocalyx. Subsequent virus-induced gene silencing (VIGS) of MhMYB1 and MhMYB2 led to a significant reduction (P < 0.01) in the relative expression levels of MhMD and MhPR genes in the VIGS groups of M. haplocalyx. In addition, there was a noteworthy decrease (P < 0.05) in the contents of ( -)-menthol and ( -)-menthone in the essential oil of M. haplocalyx. These findings suggest that MhMYB1 and MhMYB2 transcription factors play a positive regulatory role in ( -)-menthol biosynthesis, consequently influencing the essential oil composition in the l-menthol chemotype of M. haplocalyx. This study serves as a pivotal foundation for unraveling the regulatory mechanisms governing monoterpenoid biosynthesis in different chemotypes of M. haplocalyx.

Tobacco and menthol flavored nicotine-free electronic cigarettes induced inflammation and dysregulated repair in lung fibroblast and epithelium.

BACKGROUND: Electronic cigarette (e-cig) vaping has increased in the past decade in the US, and e-cig use is misleadingly marketed as a safe cessation for quitting smoking. The main constituents in e-liquid are humectants, such as propylene glycol (PG) and vegetable glycerine (VG), but different flavoring chemicals are also used. However, the toxicology profile of flavored e-cigs in the pulmonary tract is lacking. We hypothesized that menthol and tobacco-flavored e-cig (nicotine-free) exposure results in inflammatory responses and dysregulated repair in lung fibroblast and epithelium. METHOD: We exposed lung fibroblast (HFL-1) and epithelium (BEAS-2B) to Air, PG/VG, menthol flavored, or tobacco-flavored e-cig, and determined the cytotoxicity, inflammation, and wound healing ability in 2D cells and 3D microtissue chip models. RESULTS: After exposure, HFL-1 showed decreased cell number with increased IL-8 levels in the tobacco flavor group compared to air. BEAS-2B also showed increased IL-8 secretion after PG/VG and tobacco flavor exposure, while menthol flavor exposure showed no change. Both menthol and tobacco-flavored e-cig exposure showed decreased protein abundance of type 1 collagen α 1 (COL1A1), α-smooth-muscle actin (αSMA), and fibronectin as well as decreased gene expression level of αSMA (Acta2) in HFL-1. After tobacco flavor e-cig exposure, HFL-1 mediated wound healing and tissue contractility were inhibited. Furthermore, BEAS-2B exposed to menthol flavor showed significantly decreased tight junction gene expressions, such as CDH1, OCLN, and TJP1. CONCLUSION: Overall, tobacco-flavored e-cig exposure induces inflammation in both epithelium and fibroblasts, and tobacco-flavored e-cig inhibits wound healing ability in fibroblasts.

Multifunctional Deep Eutectic Solvent-Based Microemulsion for Transdermal Delivery of Artemisinin.

As a serious public health issue, malaria threatens the health of millions of people. Artemisinin, a gift from traditional Chinese medicine, has been used in the treatment of malaria and has shown good therapeutic efficiency. However, due to its low solubility, poor bioavailability, and short half-life time, some smart delivery strategies are still required. Herein, a multifunctional DES prepared from ibuprofen and menthol was prepared. This DES was shown to efficiently promote the solubility of artemisinin up to 400-fold. Then, it was further applied as the oil phase to construct an O/W microemulsion with the help of Tween-80 + Span-20 mixed surfactants. The prepared microemulsion displayed high efficiency in improving the permeability of artemisinin, which can be ascribed to the presence of the permeation enhancer menthol in DES and the microstructure of the O/W microemulsion. Moreover, the simultaneous permeation of artemisinin and ibuprofen further indicated the potential benefits of the presented formulation in the treatment of malaria. To sum up, the microemulsion based on multifunctional DES presented herein provided an effective method for transdermal delivery of artemisinin.

Use patterns of flavored non-cigarette tobacco products among US adults, 2010-2019.

OBJECTIVE: Flavored non-cigarette tobacco product (NCTP) use is common among US adult tobacco users. To update the estimates of use patterns of flavored NCTPs, this study assessed current NCTP use among adults by flavor use and flavor categories from 2010 to 2019. METHODS: We analyzed data from the 2010-2019 Tobacco Use Supplement to the Current Population Survey to estimate the weighted proportion of adult NCTP users by flavor use across survey waves. Flavor use was defined as past 30-day use of any menthol/mint or fruit/other flavors. We used the 2018-2019 data to examine the differences in demographic characteristics and tobacco use patterns among users of menthol/mint or fruit/other flavors compared to exclusive users of tobacco flavor, by product type. RESULTS: Compared to 2014-2015, electronic nicotine delivery system (ENDS) users were more likely (79.0% vs. 66.6%, p < 0.001) to report flavor use in 2018-2019, whereas cigar (26.9% vs. 31.2%, p = 0.030) and pipe (56.3% vs. 65.5%, p = 0.015) smokers were less likely to report flavor use in 2018-2019. In 2018-2019, the most prevalent flavor categories were exclusive use of tobacco flavor among cigar (73.1%) and smokeless tobacco (48.3%) users, and use of fruit/other flavors among ENDS (64.9%) and pipe (48.4%) users. Flavored users were more likely to be young adults aged 18-24 years (cigars, ENDS, smokeless tobacco) and Non-Hispanic Black or Hispanic persons (cigars, ENDS, pipes) compared to tobacco-flavored users. CONCLUSIONS: Flavored product use increased among adult ENDS users but decreased among cigar and pipe smokers. These findings could inform tobacco regulatory efforts concerning flavored NCTPs.

Would banning menthol cigarettes, flavored cigars, and flavored e-cigarettes prompt users to seek illicit channels for obtaining them in the United States?

BACKGROUND: Banning flavors in tobacco and nicotine products may reduce youth initiation and prompt quit attempts but such bans may lead to illicit markets. We examined how likely current users would be to seek flavored products from illicit channels under various ban scenarios. METHODS: Cross-sectional surveys of 2552 current users of menthol cigarettes or flavored cigars and 2347 users of flavored e-cigarettes were conducted between 2021 and 2022 in the United States. For each ban scenario, respondents reported if they would have intentions to seek the banned flavored products from any illicit channels and identified the specific illicit channel they would consider. Logistic regressions were used to estimate how the likelihood of having intentions to seek illicit channels was associated with demographics, ban scenarios, and status of tobacco use. RESULTS: Under various ban scenarios, 24-30% of people who smoked said they would seek illicit channels to obtain the banned products compared with 21-41% of dual users and 35-39% of users of flavored e-cigarettes. Online retailers were favored by people who smoked while users of flavored e-cigarettes favored local retailers. Heavy users were more likely to say they would try illicit channels. Under bans restricting more types of flavored tobacco products, users would be less likely to try illegal channels. CONCLUSIONS: A significant proportion of users of flavored tobacco and nicotine products would not reject using illicit banned products. Tailored programs are needed to apply to the groups with a higher risk of seeking illicit channels for banned products.

Prevalence of menthol cigarette use among adults who smoke from the United States by census division and demographic subgroup, 2002-2020: findings from the International Tobacco Control (ITC) project.

BACKGROUND: Targeted marketing of menthol cigarettes in the US influences disparities in the prevalence of menthol smoking. There has been no analysis of sub-national data documenting differences in use across demographic subgroups. This study estimated trends in the prevalence of menthol use among adults who smoke in the nine US census divisions by sex, age, and race/ethnicity from 2002 to 2020. METHODS: Data from 12 waves of the US ITC Survey were used to estimate the prevalence of menthol cigarette use across census divisions and demographic subgroups using multilevel regression and post-stratification (n = 12,020). Multilevel logistic regression was used to predict the prevalence of menthol cigarette use in 72 cross-classified groups of adults who smoke defined by sex, age, race/ethnicity, and socioeconomic status; division-level effects were fit with a random intercept. Predicted prevalence was weighted by the total number of adults who smoke in each cross-classified group and aggregated to divisions within demographic subgroup. Estimates were validated against the Tobacco Use Supplement to the Current Population Survey (TUS-CPS). RESULTS: Overall modeled prevalence of menthol cigarette use was similar to TUS-CPS estimates. Prevalence among adults who smoke increased in each division from 2002 to 2020. By 2020, prevalence was highest in the Middle (46.3%) and South Atlantic (42.7%) and lowest in the Pacific (25.9%) and Mountain (24.2%) divisions. Prevalence was higher among adults aged 18-29 (vs. 50+) and females (vs. males). Prevalence among non-Hispanic Black people exceeded 80% in the Middle Atlantic, East North Central, West North Central, and South Atlantic in all years and varied most among Hispanic people in 2020 (Pacific: 26.5%, New England: 55.1%). CONCLUSIONS: Significant geographic variation in the prevalence of menthol cigarette use among adults who smoke suggests the proposed US Food and Drug Administration (FDA) menthol cigarette ban will exert differential public health benefits and challenges across geographic and demographic subgroups.

Changes in Sales of Vaping Products and Cigarettes Associated With the New York State Flavored Vaping Product Sales Restriction.

INTRODUCTION: New York (NY) implemented a statewide restriction on the retail sale of flavored vaping products to reduce availability of vaping products having youth-appealing flavors in 2020. We assessed the intended effects of the NY law on sales of flavored vaping products and explored whether policy implementation had unintended effects on consumer behavior by evaluating policy-associated changes in sales of combusted cigarettes, which could serve as more harmful substitute products for NY consumers of flavored vaping products. AIMS AND METHODS: We analyzed custom product-level weekly retail tobacco sales scanner data for NY and a comparison state (California [CA]) for convenience stores and other outlets from June 2018 through June 2021. We categorized flavor descriptors for vaping products as flavored or as tobacco or unflavored and categorized cigarettes as menthol or non-menthol. We used a difference-in-difference model to assess the effect of the sales restriction on unit sales of flavored and unflavored vaping products and menthol and non-menthol cigarettes in NY compared with CA. RESULTS: Following NY policy implementation, flavored and total vaping product sales decreased in NY relative to CA. Unflavored vaping product sales increased in NY, while menthol cigarette sales did not change significantly relative to CA sales. CONCLUSIONS: The NY flavored vaping product policy was associated with fewer sales of flavored and total vaping products. The increase in sales of unflavored vaping products did not suggest complete substitution, and sales data suggest that consumers did not turn to cigarettes after flavored vaping products became unavailable. IMPLICATIONS: This study provides evidence that NY's flavored vaping product policy is associated with reduced flavored vaping product access and sales. Our analyses of potential unintended consequences indicate that some consumers switched from flavored to unflavored vaping products, but that cigarette sales did not change concurrent with the policy which means that decreased availability of flavored vaping products did not result in vapers switching to cigarettes. NY's policy had its intended effect with limited unintended consequences.

The Impact of High or Low Doses of Nicotine in a Mouse Model of Vapor Self-Administration.

INTRODUCTION: A wide variety of nicotine concentrations and formulations are available to users of electronic nicotine delivery systems (ENDS). This is increasingly true when considering the many flavors available with ENDS products. To date, there have been few preclinical investigations into the impact of nicotine doses, with and without flavors, on vaping-related behaviors. This present study evaluated how nicotine concentrations relevant to tank-based and pod-based ENDS, with and without flavors, impact reinforcement-related behavior in a mouse model. AIMS AND METHODS: Adult male and female C57/BL6J mice were used in vapor-inhalation self-administration assays. Mice were assigned e-liquids containing 6 mg/mL or 60 mg/mL nicotine. Additional mice were assigned these nicotine doses with green apple or menthol flavorants. Mice were trained on fixed-ratio 1 for 10, 2-hour sessions, then five sessions at FR3, three progressive ratio sessions, and two FR3 sessions. RESULTS: We observed male mice exhibited higher reinforcement-related behavior to menthol-flavored 6 mg/mL nicotine when compared to female mice. Males were only observed to have a menthol-induced enhancement of self-administration at 6 mg/mL nicotine and not 60 mg/mL nicotine. However, female mice exhibited significant menthol-induced increases in reinforcement-related behaviors with 60 mg/mL nicotine. CONCLUSIONS: These data provide evidence that males and females exhibit different dose sensitivities to nicotine. These sex-dependent differences in nicotine sensitivity also indicate that flavor-induced enhancement in nicotine intake is dependent on the different doses for each sex. IMPLICATIONS: There has been much discussion recently regarding the impact of flavors on vaping-related behavior. Our current study may support prior investigations that suggest flavors enhance the palatability of nicotine-containing products. However, this current study provides evidence that males and females exhibit different sensitivities to nicotine.

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.

Improving Prediction of Tobacco Use Over Time: Findings from Waves 1-4 of the Population Assessment of Tobacco and Health Study.

INTRODUCTION: First-order Markov models assume future tobacco use behavior is dependent on current tobacco use and are often used to characterize patterns of tobacco use over time. Higher-order Markov models that assume future behavior is dependent on current and prior tobacco use may better estimate patterns of tobacco use. AIMS AND METHODS: This study compared Markov models of different orders to examine whether incorporating information about tobacco use history improves model estimation of tobacco use and estimated tobacco use transition probabilities. We used data from four waves of the Population Assessment of Tobacco and Health Study. In each Wave, a participant was categorized into one of the following tobacco use states: never smoker, former smoker, menthol cigarette smoker, non-menthol cigarette smoker, or e-cigarette/dual user. We compared first-, second-, and third-order Markov models using multinomial logistic regression and estimated transition probabilities between tobacco use states. `RESULTS: The third-order model was the best fit for the data. The percentage of former smokers, menthol cigarette smokers, non-menthol cigarette smokers, and e-cigarette/dual users in Wave 3 that remained in the same tobacco use state in Wave 4 ranged from 63.4% to 97.2%, 29.2% to 89.8%, 34.8% to 89.7%, and 20.5% to 80.0%, respectively, dependent on tobacco use history. Individuals who were current tobacco users, but former smokers in the prior two years, were most likely to quit. CONCLUSIONS: Transition probabilities between tobacco use states varied widely depending on tobacco use history. Higher-order Markov models improve estimation of tobacco use over time and can inform understanding of trajectories of tobacco use behavior. IMPLICATIONS: Findings from this study suggest that transition probabilities between tobacco use states vary widely depending on tobacco use history. Tobacco product users (cigarette or e-cigarette/dual users) who were in the same tobacco use state in the prior two years were least likely to quit. Individuals who were current tobacco users, but former smokers in the prior two years, were most likely to quit. Quitting smoking for at least two years is an important milestone in the process of cessation.

Menthol and Other Flavor Chemicals in Cigarettes from Vietnam and the Philippines.

INTRODUCTION: Tobacco product flavors can increase product appeal, adolescent initiation and experimentation, and difficulty quitting. Flavored tobacco products are not restricted in Vietnam or the Philippines despite the high smoking prevalence among those 15 years of age and older (24% and 23%, respectively). There are no published reports to our knowledge on the levels of flavor chemicals in the cigarettes sold in these two countries. METHODS: Cigarettes were purchased in Vietnam (32 brand variants) and the Philippines (19 brand variants) during 2020. Chemical analyses gave the mg/filter, mg/rod, and mg/stick (= mg/(filter + rod)) values for 180 individual flavor chemicals. Values were calculated for menthol, clove-related compounds, and "other flavor chemicals" (OFCs). RESULTS: Five flavor groupings were found among the brand variants purchased in Vietnam: menthol + OFCs (n = 15), OFCs only (n = 8), nonflavored (n = 7), menthol + OFCs with a clove flavorant (n = 1) and menthol only (n = 1). Three flavor groupings were found among the brand variants purchased in the Philippines: menthol + OFCs (n = 10), nonflavored (n = 5), and menthol only (n = 4). CONCLUSIONS: A range of flavored cigarette products are being offered by tobacco companies in Vietnam and the Philippines, presumably to maximize cigarette sales. Regulation of flavor chemicals should be considered in these two countries. IMPLICATIONS: Article 9 of the WHO Framework Convention on Tobacco Control (FCTC), ratified by both Vietnam and the Philippines, states that "there is no justification for permitting the use of ingredients, such as flavoring agents, which help make tobacco products attractive." Flavors increase product appeal, adolescent initiation and experimentation, and difficulty quitting. These analyses found that cigarettes purchased in Vietnam and the Philippines contained menthol and other flavor chemicals. Tobacco companies are offering multiple flavor chemical profiles and nominally nonflavored versions in these countries; regulation of flavor chemicals should be considered in these two countries.

Exploring #MentholBan on TikTok: A Thematic and Semantic Network Analysis.

INTRODUCTION: In April 2021, the U.S. Food and Drug Administration (FDA) announced its intention to ban the sale of menthol cigarettes and cigars. Decades of research support the premise that a menthol ban will reduce initiation and disparities in tobacco-related disease among menthol smokers. The tobacco industry opposed such a policy and worked for decades to shape public opposition. Social media discourse can inform our understanding of public opinion about the proposed ban and guide communication strategies and policy implementation. AIMS AND METHODS: This research employed a mixed-methods design to explore TikTok posts discussing the announced menthol ban. Using a TikTok web scraper to extract all content in the #mentholban hashtag (n = 171), we coded for 11 themes, characterized content with descriptive statistics, and created a semantic network of co-occurring hashtags. RESULTS: We found primarily negative attitudes towards the U.S. ban announcement and a large volume of menthol "hacks" to circumvent the bans. Our semantic network analysis revealed strong co-occurrences between #mentholban and popularity-seeking hashtags. The metadata associated with each TikTok demonstrated that most posters in #mentholban are not "influencers" in the sense of having many followers, aside from a few niche organizations with multiple posts. We found that perceived political and racial motivations shaped posters' assessments of the menthol ban. Furthermore, we uncovered how individuals and organizational actors shaped menthol ban content on TikTok. CONCLUSIONS: Our study indicates targeted marketing from alternative menthol product companies and advocacy organizations. The latter of these organizations is more likely to saturate the TikTok landscape with multiple posts and strategic hashtags. IMPLICATIONS: This study pursued an exploration of tobacco policy discussion on TikTok, specifically related to the FDA-proposed menthol ban. TikTok is a newer platform and our study provides early evidence of policy discussion emerging there, including the types of accounts creating the content and their valence toward the policy.

Impact of Smoking Cessation Motivations and Barriers on Quit Intentions Following a Hypothetical Flavor Ban Among African American/Black Individuals Who Use Menthol Cigarettes: A Mixed-Methods Study.

INTRODUCTION: The Food and Drug Administration (FDA) has proposed banning cigarettes and cigars with characterizing flavors-products used disproportionately by African American/black (AA/B) individuals. Little is known about how AA/B individuals who smoke menthol cigarettes will respond to flavor bans or how to amplify the intended benefits. This study explored predictors of quit intentions following a hypothetical flavor ban and further probed anticipated ban-related responses. AIMS AND METHODS: We recruited 213 AA/B individuals who use menthol cigarettes from Richmond, VA (September 2021-August 2022) for a mixed-methods study. Participants rated seven motivations for quitting and six barriers to quitting (Not a motivation or challenge[1]-Major motivation or challenge[4]), then reported how likely they were to quit smoking if characterizing flavors were banned in cigarettes and cigars. A subsample of 31 participants completed semi-structured interviews to further explore reactions to flavor restriction policies. RESULTS: Multivariable linear regressions suggested that participants who were more motivated to quit smoking because of "information about health hazards" and the "cost of cigarettes" reported higher quit intentions following a hypothetical menthol ban (p < .05). Additionally, those with cessation-related weight concerns reported lower post-ban quit intentions (p < .05). Interview themes highlighted smoking for stress reduction, harm/addiction perceptions of flavored tobacco products, trusted sources of tobacco-related information (including testimonials from people who formerly smoked), potential ban responses, and varying experiences with cessation strategies. CONCLUSIONS: Culturally specific cessation strategies that emphasize the health-related benefits of quitting, particularly those featuring the experiences of people who formerly smoked, may help AA/B individuals who smoke menthol cigarettes quit following a menthol ban. IMPLICATIONS: For the FDA's proposed bans on characterizing flavors in cigarettes and cigars to advance racial health equity, they must maximize cessation among African American/black (AA/B) individuals who use menthol cigarettes. This work suggests information on the health hazards and costs of smoking, as well as concerns over gaining weight, were predictors of quit intentions in a hypothetical flavor ban. Qualitative data suggest messaging highlighting the experiences of individuals who successfully quit may constitute an effective communication strategy. These insights can be used in the development of culturally specific cessation strategies for AA/B individuals who smoke menthol cigarettes.