Investigating the Impact of Non-tobacco Nicotine Enantiomeric Ratio on ENDS Abuse Liability

The primary aims of this contract are to determine whether abuse liability, as measured by nicotine exposure, subjective measures, and product use behavior, differs between e-liquids formulated with TDN and NTN, and to determine whether the enantiomeric ratio of S-: R-nicotine (e.g., >99:<1, 75:25, 50:50) impacts abuse liability of e-liquids formulated with NTN.

The Contractor will identify an electronic nicotine delivery system (ENDS) device and manufacture or otherwise obtain four investigational tobacco product (ITP) e-liquids for use in the study. The four ITP e-liquids will have identical total nicotine concentration, nicotine formulation (i.e., freebase, salt), pH, and PG:VG ratio, but will differ by nicotine source (i.e., TDN, NTN) and ratio of S- to R-nicotine. One ITP e-liquid will contain TDN (i.e., >99% S-nicotine), and three e-liquids will contain varying enantiomeric ratios of NTN (e.g., S-: R-nicotine 99:1, 75:25, 50:50). The Contractor shall perform chemical characterization of the ITP e-liquids (including S- and R-nicotine, PG:VG ratio, pH). The Contractor shall conduct a randomized, double-blinded, within-subjects, crossover clinical laboratory study in which adult current users of ENDS (exclusive or dual users of ENDS and combusted cigarettes) will be recruited to complete five laboratory visits where they will use their own brand e-liquid, e-liquid containing TDN, and three e-liquids with NTN varying by enantiomeric ratio. At each laboratory visit, participants will use the assigned product under prescribed use conditions (e.g., 5 minutes with directed puff duration and frequency), then, following an abstinence period (e.g., 120 minutes), participants will use the assigned product under ad libitum conditions (e.g., 180 minutes). During ad libitum use, participants will be allowed to use the products as they please to assess their naturalistic use behavior and corresponding nicotine exposure. Serial blood samples will be collected during both prescribed and ad libitum use conditions to assess S- and R-nicotine pharmacokinetic parameters (AUC, Cmax, Tmax, nicotine boost). Pharmacodynamics (e.g., blood pressure, heart rate) and subjective effects (e.g., liking, withdrawal, sensory effects) will be assessed at designated times throughout each session. Use topography measures (e.g., time to first use, puff count, puff duration) will be determined during the ad libitum phase. Additional abuse liability outcomes, such as hypothetical purchasing tasks, will be collected at the end of each session.

The Contractor shall perform all data analyses, provide FDA all raw data, and write study reports. All results and source documents shall be submitted to the Contracting Officer’s Representative (COR) and Study Project Lead(s).