Abuse Liability and Appeal of Oral Nicotine Products

E-cigarettes (ECs) have been the predominant flavored non-combustible tobacco product used by young adults since 2014, and are disproportionately used by sexual/gender minorities (SGM). However, patterns are likely to change due to: 1) increasing regulatory restrictions on non-tobacco flavored ECs, and 2) the emergence new nonmedicinal oral nicotine products (ONPs; e.g., pouches and gums) with enhanced palatability (e.g., improved flavoring). Preliminary data shows that many young adult e-cigarette users with no intention to quit vaping perceive ONPs as secondary means of nicotine consumption when vaping is prohibited.

Because EC+ONP dual use could exacerbate nicotine dependence by increasing daily nicotine intake, it is important to identify drivers of ONP appeal and abuse liability in young adult EC users to inform regulations that prevent adverse dual use in young people. Nicotine concentration and flavors are two putative drivers of ONP appeal and abuse liability, given that ONPs deliver substantial buccal nicotine absorption and, like ECs, their flavors elicit pleasant sensory effects. Certain ONP flavors may offset nicotine's oral irritating effects via anesthetizing cooling effects (mint flavored ONPs with menthol), allowing tolerability of higher doses of nicotine.

ONP type may also be important to ONP appeal. Initial evidence (primarily product interest survey data) suggests young adult EC users and adolescents may have higher affinity for nicotine gum than pouches, and interest in using ONPs was greater within certain vulnerable populations, especially SGMs. The investigators will determine the appeal and abuse (including dual use) liability of gum and pouch ONPs as a function of flavor (mint vs fruit) and nicotine concentration (gum 2mg vs. 6mg; pouch 2mg vs. 6mg) among young adult exclusive EC users (N = 320; ages 21 - 25). Data will be collected via virtual study sessions in which participants residences become 'remote laboratories' (allowing nationwide quota sampling). Following an orientation, participants will be randomized to one of two ONP types (gum or pouch) and nicotine concentrations (low vs. high), resulting in four study groups. The randomized nicotine-ONP combination will then be tested in: (i) a single-visit appeal/sensory attribute testing involving controlled self-administration of mint and fruit flavored ONPs; and (ii) two abuse liability evaluations (one for fruit one for mint) each involving a single-visit controlled ONP self-administration session and 1-week post-visit naturalistic use of the respective ONP.

Overview of Project The investigators will utilize an experimental design to determine the acute appeal and abuse liability of gum and pouch ONPs among young adult current EC users. Data will be collected via three online sessions with participants from across the US in which their own residences become a 'remote lab.' Following an orientation session, participants will be randomized to one of four groups varied by product type (a gum or pouch) and nicotine concentration (low \[2mg\] or high \[6mg\]) and receive that type and nicotine level throughout the entire protocol.

* Experimental Session 1 (Sensory Appeal session): Collect ratings appeal and sensory attributes directly after self-administering 2 fruit (e.g., citrus, pomegranate) and 2 mint (e.g., spearmint, wintergreen) flavored variants of their ONP type/nicotine condition in a single visit. Order of the 4 flavors will be in one of 24 possible sequences randomly assigned for each participant. The highest rated fruit variant and highest rated mint variant will be selected for the subsequent two sessions. * Experimental Sessions 2 \& 3 (Abuse Liability sessions): Involve 30-min self-administration of one ONP (fruit ONP in one session, mint ONP in another session; order counterbalanced) in separate sessions after 18-hours of abstinence. Dependent variables will include withdrawal/urge suppression, subjective effects, and behavioral economic indicators of reward value. In addition, for the 7 days after each abuse liability session visit participants will report on naturalistic use of the same product (a free provision of 30 pieces of each product that was administered in the previous Abuse Liability session will be provided to participants to use ad lib).

Rationale for Methods

* Overall design rationale for the two-part appeal + abuse liability protocol: Based on the integration of paradigms that the investigators developed to assess abuse liability and appeal of ECs, a two-part protocol will be used. The first experimental session (Sensory Appeal session) in the proposed design provides information about the sensory attributes of the user experience that drives appeal of different flavors. Given that multiple products (four) are tested within a single visit, and appeal ratings are collected immediately during use, differences across flavors are driven by sensory experience and cannot be attributed to differences driven by the neuropharmacological effects of nicotine. By contrast, the Abuse Liability experimental sessions (Sessions 2 - 3) test a single flavored product within a session, which will provide a richer source of information about the use and valuation of ONPs due to the combination of the sensory and neuropharmacological effects. * Justification of mixed factorial design: While a fully within-participant design would provide the greatest power to detect divergence between product conditions, an 8 multi-hour abuse liability study sessions would be too burdensome and monotonous to maintain consistent participant engagement. A mixed-factorial design allows sufficient statistical power to estimate the impact of study variables without overburdening participants. * Justification of 7-day monitoring period: Given the limited surveillance (i.e., only nicotine pouches assessed in NYTS, no measures of new ONPs in PATH or NSDUH) of these new nonmedicinal ONPs, and to better understand how young adults may use these products in conjunction with their EC, the investigators include brief (approximately 2 minutes) daily surveys assessing ONP use and use in situations when vaping is constrained. This will provide much needed data on the dual use liability of ONPs and ECs in the natural ecology, and allow assessment of whether use varies by ONP type, flavor, and nicotine strength.

The investigators are well versed in utilizing remote monitoring periods to examine naturalistic use patterns of EC and polytobacco product use behaviors among young adults.

Rationale for Product Type and Characteristics

* Justification of flavors: The investigators could have focused on a particular flavoring constituent (e.g., menthol, vanillin) and designed a study around manipulating the presence or concentration of that constituent to isolate their effect. However, more than 120 different flavoring constituents have been identified in ONPs, including up to 25 flavoring constituents within a single characterizing flavor (e.g., berry) that combine to create the sensory profile. Hence, disaggregating particular constituents would not be representative of the ONP characterizing flavors sold on the market, and FDA has historically regulated according to the characterizing flavor rather than particular constituents. The TCORS methods core will do a flavoring constituent analysis which will provide contextual data on this issue. Among the characterizing flavors, the investigators focus on fruit and mint because they are the preferred EC flavor categories among AYAs and tobacco naïve individuals, and survey data suggesting interest in ONPs of these flavors is high (see above). * Justification of nicotine concentrations: The investigators include 2mg vs. 6mg nicotine because of the prominence of these concentrations on the ONP market. However, there are ONPs currently available with substantially higher nicotine concentration (\>20mg). While many ONP users report titrating up their ONP dose after they become accustomed to the sensations of ONP use, most find nicotine's irritating oral effects as uncomfortable at first. Because study participants are ONP-naïve starting with these two doses (which are low and moderate range) is indicated. The investigators also considered the inclusion of matched products without nicotine. However, the absence of any such marketed products would require imperfectly matched alternatives (e.g., confectionery gums) and would not usefully advance the primary aim of providing information directly relevant to FDA decision-making because FDA-CTP does not regulate such products. * Justification of ONP types: The investigators selected nicotine gum and pouch because extensive industry marketing is currently being directed at both products. The Center includes monitoring of additional nicotine products (including lozenges) and if they emerge as highly popular, the investigators will add lab assessments through the Center's CEC/RRP mechanism.

Eligibility, Procedures \& Screening

* Initial screening: Advertisements will have phone numbers for Research Assistants (RAs), a QR code, and a direct link to an online study screener. Potentially eligible participants are contacted by RAs to conduct a detailed phone screen to confirm all self-report eligibility criteria. Eligible participants will be scheduled orientation session to be conducted over Zoom to provide informed consent. * Orientation (Consent) Session: Before the orientation, participants will be mailed supplies, including for collecting a baseline urine test of recent nicotine use involving a test strips that provide semi-quantitative total nicotine equivalents (TNEs) estimates of nicotine and nicotine metabolites (0-14 levels; \>1 required for eligibility). At the outset of the orientation, presence of a computer, laptop, tablet, or similar device with working camera, microphone, and audio and Internet to complete REDCap surveys will be confirmed. After confirming age and obtaining digital informed consent, the urine nicotine test will be collected and (if positive), participants will be asked to assure that the study products shipped to participants will be kept in a safe place away from children, animals, and minors and used only for the research study. Next, self-report measures of demographics and tobacco product use history will be completed. Finally, participants will be scheduled for their next experimental visits and reminded that 18-hour nicotine abstinence is required and will be confirmed by urine for each visit. To provide some control over daily fluctuations in nicotine craving and withdrawal and to facilitate adherence to the abstinence requirement, efforts will be made to complete those study visits for which abstinence is required in the morning hours (∼8:00-11:00 AM), near waking time. * Randomization to ONP type and nicotine: Participants will be randomized into one product condition (gum or pouch) and one nicotine level (high or low) stratified by region (South, West, Midwest, Northeast) and SGM status, which will determine the products used for the next 3 visits. * Provision of Appeal Session Study Materials: The investigators will mail participants a package that will include ONP products "blinded" (i.e., randomized products will be placed in labeled baggies with numbers indicating each product), remote exhaled carbon monoxide (eCO; Covita) device for biochemical verification of no combustible tobacco use, urine nicotine sample and test strip, and pregnancy test (as appropriate), product disposal bag with tamper seal tape, cleaning supplies, and materials for returning salivary samples. The eCo device is a remote device that connects to the participants cell phone device (both android and iOS) and allows for remote bioverification of smoking status (see D.5.e for cut off eCO values). The investigators will follow all safety hazard protections for product transport guidelines by shipping and courier agenc

• Behavioral economic measures related to abuse liability [Time frame: immediately after the intervention]
• ad lib use at home [Time frame: 7 days after each abuse liability session]