An interventional study of Nicotine vaping visit 1 (free-base nicotine) and Nicotine vaping visit 1 (protonated nicotine) in Nicotine Vaping, sponsored by Yale University. Completed at 1 site in United States. Open to participants aged 21 Years and older, including healthy volunteers. Per ClinicalTrials.gov, last updated 2025-11-18.
Sponsored by Yale University · Not applicable, Interventional, and Other
The investigators will examine the relationship between nicotine flux, nicotine form, and the rate and dose of nicotine delivery. Participants will puff on electronic nicotine delivery system (ENDS) devices under conditions that differ by flux and form, while arterial blood is sampled in high time resolution. The outcome will indicate the degree to which nicotine flux and form determine the speed and dose of ENDS nicotine delivery, and thus, abuse liability.
The purpose of this study is to examine the influence of nicotine flux, and nicotine form, on the rate and dose of nicotine delivery obtained from arterial blood measurements. This study involves a 4 x 2 crossover experimental design of four nicotine fluxes: 9, 18, 27, 35 μg/sec, and two nicotine forms (i.e., free-base and protonated). These nicotine fluxes are within the range reported for ENDS (3.1-111µg/sec). The investigators will isolate the effect of form on the pharmacokinetics of nicotine delivery by controlling for puffing behavior. The investigators will hold puff topography constant by controlling puff duration, inter-puff interval, and number of puffs using the LabVape PTL and confirm the data using eTop.
The flux/form conditions will be tested by participants in two lab visits separated by three weeks to minimize carryover effects. All sessions will be double-blinded. In the first visit, participants will use the ENDS device with one nicotine form and four fluxes in random order. Participants will be instructed to attend the lab for a second visit, to test the four fluxes but with the other nicotine form. The second visit will allow us to isolate the effect of nicotine form on nicotine delivery. The order of nicotine form in the two visits will be counter-balanced across participants. Outcome measures include arterial blood nicotine delivery, and puff topography.
Participants will be instructed to use the Subox mini C ENDS device connected to the LabVape PTL (which limits puff duration to 3 seconds) in four bouts separated by a 60min resting period. The e-liquids vaped are as follows: Propylene glycol(PG)/Glycerol (VG), 30/70 ratio by volume. Nicotine at different concentrations: (2, 4, 7 and 10mg/mL) Benzoic acid: approximately 1:1 molar ratio with nicotine. All these ingredients will be used to prepare the needed e-liquids to conduct the study.
All bouts will be directed; each bout will consist of 3 puffs in which puff duration is fixed to 3sec, as in 50, and inter-puff interval fixed to 30sec (CORESTA recommended method Nº 81).123 The puff duration and inter-puff interval will be fixed using the LabVape PTL. A puff topography device (eTop) will record the puffing topography to identify any deviation between directed and actual puffs drawn and to measure the puffing flow rate. Participants will be trained to follow the puffing cues prior to sampling using an unpowered ENDS device. For arterial blood sampling, a radial arterial line will be placed on the non-dominant side to provide access to blood samples during vaping sessions. Each blood sample (0.5cc) will be drawn manually by a trained nurse at every time point and stored in the freezer at -25°C. Blood nicotine samples will be assayed using LCMS/ MS with deuterated internal standards, as in 114. Blood will be sampled 30sec prior to the initial puff, 5, 15, and 25sec after each puff, and 60sec after the last puff of a bout. The obtained data will be used to calculate pharmacokinetic parameters of nicotine delivery under each condition (Cmax, Tmax, dCi/dt, and AUC). AUC from 0 to 160min for the four 3-puff directed bouts will be estimated using a non-compartmental model and trapezoidal rule. All measures will be corrected for baseline values by subtracting the blood nicotine concentrations by the initial value (at the start of each bout).
160 studies on the registry are indexed under Vaping; 72 are open to participants now.
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Exclusion Criteria:
Additional Screening Procedures: Significant changes and/or abnormalities in these assessments during the study period may warrant exclusion at the discretion of the PI.
Subjects will receive the either free-base or protonated form of four nicotine fluxes: 9, 18, 27, 35 μg/sec at their first of two visits. In the first visit, participants will use the ENDS device with one nicotine form and four fluxes in random order. Participants will be instructed to attend the lab for a second visit, to test the four fluxes but with the other nicotine form.
Other: Nicotine vaping visit 1 (free-base nicotine) · Other: Nicotine vaping visit 2 (protonated nicotine)
The same subjects from visit 1 will receive the either free-base or protonated form of four nicotine fluxes: 9, 18, 27, 35 μg/sec at their second study visit, using the opposite nicotine form that was used during the first visit.
Other: Nicotine vaping visit 1 (protonated nicotine) · Other: Nicotine vaping visit 2 (free-base nicotine)
Participants will receive the free-base form of four nicotine fluxes: 9, 18, 27, 35 μg/sec at one of their two visits. Participants will use the ENDS device with free-base nicotine and four fluxes in random order.
Participants will receive the protonated form of four nicotine fluxes: 9, 18, 27, 35 μg/sec at the other study visit. Participants will use the ENDS device with protonated nicotine and four fluxes in random order.
Participants who received protonated nicotine during visit 1 will now receive free-base nicotine fluxes for visit 2: 9, 18, 27, 35 μg/sec.
Participants who received free-base nicotine during visit 1 will now receive protonated nicotine fluxes for visit 2: 9, 18, 27, 35 μg/sec.
Change in Maximum Arterial Blood Nicotine Delivery (Cmax)
For arterial blood sampling, a radial arterial line will be placed on the non-dominant side to provide access to blood samples during vaping sessions. Blood will be sampled 30sec prior to the initial puff, 5, 15, and 25sec after each puff, and 60sec after the last puff of a bout (3 puffs per bout; 4 bouts per visit day; two visit days, separated by three weeks). The obtained data will be used to calculate pharmacokinetic parameters of nicotine delivery under each condition.
Time frame: Day 1 and Week 3
Change in Area Under the Curve for Nicotine (AUC)
AUC from 0 to 160min for the four 3-puff directed bouts will be estimated using a non-compartmental model and trapezoidal rule. The four 3-puff directed bouts occur on both visit day 1 and 2, separated by 3 weeks. All measures will be corrected for baseline values by subtracting the blood nicotine concentrations by the initial value (at the start of each bout).
Time frame: Day 1 and Week 3
Change in Liquid Consumed
Determined by ENDS gravimetric weight change. Pre- and Post- vaping on both visit day 1 and 2, separated by 3 weeks.
Time frame: Day 1 and Week 3
Mean Change in Puff Topography
Average puff duration in seconds for 3 puffs on both visit day 1 and 2, separated by 3 weeks. Data presented here is the average duration per condition.
Time frame: Day 1 and Week 3
Change in Rate of Nicotine Rise After the Initial Puff (dCi/dt)
Blood will be sampled 30sec prior to the initial puff, 5, 15, and 25sec after each puff, and 60sec after the last puff of a bout. Measurements occur 4 times per visit day, on both visit day 1 and 2, separated by 3 weeks). The obtained data will be used to calculate pharmacokinetic parameters of nicotine delivery under each condition (dCi/dt).
Time frame: Day 1 and Week 3
Change in Time to Maximum Arterial Blood Level Nicotine Concentration (Tmax)
Blood will be sampled 30sec prior to the initial puff, 5, 15, and 25sec after each puff, and 60sec after the last puff of a bout. Measurements occur 4 times per visit day, on both visit day 1 and 2, separated by 3 weeks). The obtained data will be used to calculate pharmacokinetic parameters of nicotine delivery under each condition (Tmax).
Time frame: Day 1 and Week 3
| Milestone | Free-base nicotine first, then protonated nicotine | Protonated nicotine first, then free-base nicotine |
|---|---|---|
| Started | 11 | 15 |
| 9 μg/s | 11 | 15 |
| 18 μg/s | 11 | 15 |
| 27 μg/s | 11 | 15 |
| 35 μg/s | 11 | 15 |
| Completed | 11 | 15 |
| Not completed | 0 | 0 |
| Milestone | Free-base nicotine first, then protonated nicotine | Protonated nicotine first, then free-base nicotine |
|---|---|---|
| Started | 11 | 15 |
| Completed | 6 | 12 |
| Not completed | 5 | 3 |
| Milestone | Free-base nicotine first, then protonated nicotine | Protonated nicotine first, then free-base nicotine |
|---|---|---|
| Started | 6 | 12 |
| 9 μg/s | 6 | 12 |
| 18 μg/s | 6 | 12 |
| 27 μg/s | 6 | 12 |
| 35 μg/s | 6 | 12 |
| Completed | 6 | 10 |
| Not completed | 0 | 2 |
For arterial blood sampling, a radial arterial line will be placed on the non-dominant side to provide access to blood samples during vaping sessions. Blood will be sampled 30sec prior to the initial puff, 5, 15, and 25sec after each puff, and 60sec after the last puff of a bout (3 puffs per bout; 4 bouts per visit day; two visit days, separated by three weeks). The obtained data will be used to calculate pharmacokinetic parameters of nicotine delivery under each condition.
| ng/ml | Nicotine vaping- protonated | Nicotine vaping- freebase |
|---|---|---|
| 9 μg/s | 3.75 ± 1.96 | 2.48 ± 1.11 |
| 18 μg/s | 8.12 ± 4.81 | 2.96 ± 1.76 |
| 27 μg/s | 13.23 ± 7.7 | 5.13 ± 3.16 |
| 35 μg/s | 18.57 ± 12.19 | 6.11 ± 3.55 |
AUC from 0 to 160min for the four 3-puff directed bouts will be estimated using a non-compartmental model and trapezoidal rule. The four 3-puff directed bouts occur on both visit day 1 and 2, separated by 3 weeks. All measures will be corrected for baseline values by subtracting the blood nicotine concentrations by the initial value (at the start of each bout).
| (ng/ml)*s | Nicotine vaping- protonated | Nicotine vaping- freebase |
|---|---|---|
| 9 μg/s | 316.06 ± 196.91 | 225.68 ± 133.22 |
| 18 μg/s | 643.48 ± 431.98 | 255.38 ± 164.15 |
| 27 μg/s | 1022.42 ± 573.32 | 443.79 ± 231.72 |
| 35 μg/s | 1499.38 ± 1017.08 | 571.53 ± 317.55 |
Determined by ENDS gravimetric weight change. Pre- and Post- vaping on both visit day 1 and 2, separated by 3 weeks.
| grams | Nicotine vaping- protonated | Nicotine vaping- freebase |
|---|---|---|
| 9 μg/s | 0.08 ± 0.06 | 0.08 ± 0.13 |
| 18 μg/s | 0.02 ± 0.01 | 0.09 ± 0.07 |
| 27 μg/s | 0.03 ± 0.01 | 0.09 ± 0.12 |
| 35 μg/s | 0.05 ± 0.03 | 0.08 ± 0.10 |
Average puff duration in seconds for 3 puffs on both visit day 1 and 2, separated by 3 weeks. Data presented here is the average duration per condition.
| seconds | Nicotine vaping- protonated | Nicotine vaping- freebase |
|---|---|---|
| 9 μg/s | 2.81 ± 1.18 | 2.78 ± 1.10 |
| 18 μg/s | 2.81 ± 1.22 | 2.66 ± 1.16 |
| 27 μg/s | 2.83 ± 1.25 | 2.3 ± 1.24 |
| 35 μg/s | 2.8 ± 1.23 | 2.2 ± 1.22 |
Blood will be sampled 30sec prior to the initial puff, 5, 15, and 25sec after each puff, and 60sec after the last puff of a bout. Measurements occur 4 times per visit day, on both visit day 1 and 2, separated by 3 weeks). The obtained data will be used to calculate pharmacokinetic parameters of nicotine delivery under each condition (dCi/dt).
| ng/(ml*s) | Nicotine vaping- protonated | Nicotine vaping- freebase |
|---|---|---|
| 9 μg/s | 0.12 ± 0.11 | 0.09 ± 0.07 |
| 18 μg/s | 0.28 ± 0.22 | 0.08 ± 0.06 |
| 27 μg/s | 0.44 ± 0.34 | 0.13 ± 0.09 |
| 35 μg/s | 0.57 ± 0.42 | 0.18 ± 0.13 |
Blood will be sampled 30sec prior to the initial puff, 5, 15, and 25sec after each puff, and 60sec after the last puff of a bout. Measurements occur 4 times per visit day, on both visit day 1 and 2, separated by 3 weeks). The obtained data will be used to calculate pharmacokinetic parameters of nicotine delivery under each condition (Tmax).
| seconds | Nicotine vaping- protonated | Nicotine vaping- freebase |
|---|---|---|
| 9 μg/s | 93.83 ± 45.33 | 102.88 ± 42.4 |
| 18 μg/s | 100.32 ± 27.85 | 99.81 ± 32.44 |
| 27 μg/s | 99 ± 34.56 | 106.31 ± 23.24 |
| 35 μg/s | 100 ± 28.69 | 109.44 ± 24.10 |
Collected over 3 weeks. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Free-base nicotine | 0/26 (0%) | 0/26 (0%) | 0/26 (0%) |
| Protonated nicotine | 0/26 (0%) | 0/26 (0%) | 0/26 (0%) |
| Arterial-line related | 0/26 (0%) | 0/26 (0%) | 8/26 (30.8%) |
| Between visits | 0/26 (0%) | 1/26 (3.8%) | 0/26 (0%) |
| Event | Free-base nicotine | Protonated nicotine | Arterial-line related | Between visits |
|---|---|---|---|---|
| Self harm episodeInjury, poisoning and procedural complications | 0/26 | 0/26 | 0/26 | 1/26 |
| Event | Free-base nicotine | Protonated nicotine | Arterial-line related | Between visits |
|---|---|---|---|---|
| Wrist discomfortMusculoskeletal and connective tissue disorders | 0/26 | 0/26 | 5/26 | 0/26 |
| VomitingGastrointestinal disorders | 0/26 | 0/26 | 1/26 | 0/26 |
| Pre-syncopeCardiac disorders | 0/26 | 0/26 | 1/26 | 0/26 |
| Arterial vasospasmCardiac disorders | 0/26 | 0/26 | 1/26 | 0/26 |
| Age, Continuous(years) | Nicotine Vaping Group |
|---|---|
| Mean | 34.69 ± 12.77 |
| Sex: Female, Male(Participants) | Nicotine Vaping Group |
|---|---|
| Female | 14 |
| Male | 12 |
| Ethnicity (NIH/OMB)(Participants) | Nicotine Vaping Group |
|---|---|
| Hispanic or Latino | 4 |
| Not Hispanic or Latino | 22 |
| Unknown or Not Reported | 0 |
| Race (NIH/OMB)(Participants) | Nicotine Vaping Group |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 4 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 5 |
| White | 16 |
| More than one race | 1 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(participants) | Nicotine Vaping Group |
|---|---|
| United States | 26 |
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Yale University