The use of electronic nicotine delivery systems (ENDS; e-cigarettes) has reached epidemic levels among young people in the United States (US). 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 respiratory and cardiovascular toxicants such as aldehydes. Flavor is a major factor in getting young people to use ENDS, thus limiting flavors to menthol and tobacco for prefilled cartridge ENDS "pod mods" was the first major action taken by the FDA to reduce the spread of ENDS among young people. Menthol flavor, however, can present a potential risk given its increasing popularity among young people in the US, and its puffing and nicotine-enhancing properties. Yet, the extent of menthol's ability to affect users' experience and puffing patterns, and how these affect dependence, exposure to toxicants, and clinical outcomes continue to be understudied. Such evidence will be critical to the FDA's ability to set further regulatory standards to reduce ENDS potential harm. The investigators will conduct a 2x2 (pre-post x menthol vs. tobacco flavor) crossover clinical lab study. The investigator will recruit current/past month ENDS users (n=250, 21-35 yrs), who will attend two sessions and use their ENDS once with menthol and once with tobacco flavors. The proposed studies will answer two key regulatory questions consistent with FDA'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, clinical responses, intention to use or quit, and group comparisons such as according to race, and sex will allow the FDA a comprehensive assessment of the pros and cons of regulating mentholated ENDS for different segments of the society. Such evidence will help advance FDA regulatory policies with the potential to reduce ENDS harm.

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.

Inclusion Criteria:

• Generally healthy individuals (determined by physical examination).
• Age of 21-35 years.
• Is willing to provide informed consent.
• Is willing to attend the lab as required by the study protocol.
• E-cigarette users (defined as using e-cigarette either daily or occasionally in the past 30 days)
• Have abstained from e-cigarette use for 12 hours prior to each session

Exclusion Criteria:

• Report smoking cigarettes regularly (> 5 cigarettes/month in the past year).
• Report regular use of any other tobacco/nicotine product (e.g., e-cig, pipes, cigars) in the past year.
• Women who are breast-feeding or test positive for pregnancy (by urinalysis at screening).
• Individuals with self-reported history of chronic disease or psychiatric conditions.
• Individuals with history of or active cardiovascular disease, low or high blood pressure, seizures, and regular use of prescription medications (other than vitamins or birth control).
• Individuals that report current THC (marijuana) smoking/vaping.
• Individuals that report current EVALI or COVID-19 related symptoms (i.e., cough, shortness of breath, chest pain, nausea, vomiting, abdominal pain, diarrhea, fever, chills, or weight loss)
• Individuals that have or have been exposed to COVID-19 in the last 14 days.

Participant will be blinded to study condition