Effect of Menthol on ENDS Users' Addiction and Exposure

The use of electronic nicotine delivery systems (ENDS; e-cigarettes) has reached epidemic levels among young people in the US. While estimates vary, ENDS have become the leading tobacco product used by young people in this country. ENDS heat and vaporize a nicotine-containing liquid to produce an inhalable aerosol mist. While generally considered less harmful than combustible cigarettes, ENDS use exposes users to dependence-producing nicotine and other respiratory and cardiovascular toxicants such as aldehydes.

ENDS appealing design, flavors, and marketing on social media have gained them increased popularity among young people in the US. Flavor, especially, is a major driver of ENDS use among young people, thus limiting flavors for prefilled cartridge ENDS "pod mods" to menthol and tobacco was the first major action taken by the FDA to reduce the spread of ENDS. More recently, the FDA announced its commitment to banning mentholated cigarettes and cigars. Menthol ENDS, however, continue to pose a potential risk due to their increasing popularity among young people, and menthol's known initiation- and dependence-enhancing properties. Specifically, menthol can potentiate 1) inhalation by reducing irritation and allowing deeper puffs and aerosol deposition, and 2) the effect of nicotine by altering nicotinic acetylcholine receptors and increasing nicotine's bioavailability. Mentholated tobacco products, moreover, tend to affect minorities, youth, and women disproportionately. Yet, the extent of menthol's ability to alter ENDS use experience and puffing patterns, and how these affect dependence, clinical, and toxicant emissions outcomes in different users continue to be understudied.

Our team of experts in tobacco regulatory science will conduct a 2×2 (pre-post × menthol vs. tobacco flavor) crossover clinical lab study. The investigators will recruit current (past month) closed system ENDS users (n=250, 21-35 yrs, use pod-mods, or disposable ENDS), who will come to the lab for two use sessions once with menthol, and once with tobacco flavored ENDS. While the investigators apply standard lab models suitable for regulatory science, the investigators supplement them with cutting-edge puffing robot technology to explore ENDS-associated toxicant emissions (e.g., aldehydes) in the two flavor conditions. The proposed studies will answer two key regulatory-driven hypotheses consistent with this RFA's focus on the role of flavor in tobacco products' addiction and toxicity: 1) compared to tobacco flavor, does menthol carry additional risk by enhancing puffing, abuse liability, and toxicant exposure in ENDS users, and; 2) is this effect more pronounced among high dependence compared to other users. Other outcomes such as harm perception, satisfaction, respiratory symptoms and function, intention to quit or use in the future, and group comparisons according to race, and sex will provide FDA with a comprehensive assessment of the pros and cons of regulating mentholated ENDS for different users. the investigators will test these hypotheses by assessing compared to tobacco-flavored ENDS:

Aim 1. The effects of menthol flavor on subjective, puffing, and respiratory outcomes.

Aim 2. The effects of menthol flavor on ENDS toxicant emissions.

• Minnesota Nicotine Withdrawal Scale [Time frame: During participants' 2 study visits. Questionnaire will be administered 2 times in each e-cigarette use session: before and after an approximately 60 minutes ad lib use period]
• Tiffany-Drobes Questionnaire of Smoking Urges [Time frame: During participants' 2 study visits. Questionnaire will be administered 2 times in each e-cigarette use session: before and after an approximately 60 minutes ad lib use period]
• Carbon monoxide levels [Time frame: During participants' 2 study visits. Carbon monoxide levels will be measured 2 times in each e-cigarette use session: before and after an approximately 60 minutes ad lib use period]
• Harm perception [Time frame: During participants' 2 study visits. Questionnaire will be administered after each of the 2 e-cigarette use sessions. Each session is approximately 60 minutes ad lib use period]
• Duke Sensory Questionnaire [Time frame: During participants' 2 study visits. Questionnaire will be administered after each of the 2 e-cigarette use sessions. Each session is approximately 60 minutes ad lib use period]
• The Cigarette/ENDS Evaluation Scale (WES) [Time frame: During participants' 2 study visits. Questionnaire will be administered after each of the 2 e-cigarette use sessions. Each session is approximately 60 minutes ad lib use period]
• Forced expiratory volume (FEV1) [Time frame: During participants' 2 study visits. FEV tests will be measured 2 times in each e-cigarette use session: before and after an approximately 60 minutes ad lib use period]
• Forced vital capacity (FVC) [Time frame: During participants' 2 study visits. FVC tests will be measured 2 times in each e-cigarette use session: before and after an approximately 60 minutes ad lib use period]
• Peak expiratory flow (PEF) [Time frame: During participants' 2 study visits. PEF tests will be measured 2 times in each e-cigarette use session: before and after an approximately 60 minutes ad lib use period]
• Forced expiratory flow [Time frame: During participants' 2 study visits. Forced expiratory flow tests will be measured 2 times in each e-cigarette use session: before and after an approximately 60 minutes ad lib use period]
• Puff number using eTOP topography machine [Time frame: During participants' 2 study visits. Puff number is continuously measured during each e-cigarette use session (an approximately 60 minutes ad lib use period)]
• Puff duration (seconds) using eTOP topography machine [Time frame: During participants' 2 study visits. Puff duration is continuously measured during each e-cigarette use session (an approximately 60 minutes ad lib use period)]