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. Author manuscript; available in PMC: 2026 Jan 1.
Published in final edited form as: Drug Alcohol Depend. 2024 Nov 28;266:112508. doi: 10.1016/j.drugalcdep.2024.112508

Dose by design: How limits on nicotine flux and puff duration affect the abuse liability of electronic nicotine delivery systems

Rose S Bono 1,2,*, Augustus M White 1,2,*, Rabia Imran 1,3, Gabrielle T Maldonado 1,3, Thokozeni Lipato 4, Andrew J Barnes 1,2, Caroline O Cobb 1,3
PMCID: PMC11736901  NIHMSID: NIHMS2041798  PMID: 39657440

Abstract

Introduction:

Electronic nicotine delivery system (ENDS) product standards for nicotine flux (nicotine emitted/second), combined with limiting puff duration, could control nicotine dose and support ENDS regulations. We assessed behavioral and subjective abuse liability indices for ENDS varying in nicotine flux with fixed puff duration among people who smoke.

Methods:

This within-subjects study included 32 adults who smoked cigarettes. Own-brand cigarettes (OB) and four unflavored ENDS were evaluated: no-flux (0 μg/s), low-flux (36.01 μg/s), cigarette-like-flux (90.03 μg/s), and high-flux (180.06 μg/s), with ENDS puff duration limited to 2 seconds. Outcomes from behavioral economic choice tasks included demand intensity (drug purchase task [DPT]), cross-price elasticity (cross-product DPT), puffs earned (progressive ratio task [PRT]), and breakpoint (cross-product PRT). Subjective effects were nicotine abstinence symptoms (NAS), aversive effects, product liking, and sensation. Condition differences were analyzed using linear mixed models.

Results:

All ENDS were associated with significantly lower demand intensity, puffs earned, NAS suppression, and liking compared to OB, yet would serve as OB substitutes. Low-flux ENDS were a significantly stronger OB substitute than cigarette-like-flux ENDS, and were associated with more puffs earned than no and high-flux ENDS. Compared with other ENDS, high-flux ENDS generally reduced NAS more, were less pleasant, tasted worse and produced more intense flavor sensation and throat hit.

Conclusions:

ENDS abuse liability and substitution potential varies by nicotine dose, which could be controlled via product standards integrating nicotine flux and puff duration. ENDS that exceed a cigarette nicotine dose may not be necessary to encourage transition from cigarettes to ENDS.

Keywords: Electronic nicotine delivery systems, nicotine flux, clinical laboratory, abuse liability, subjective effects

1. Introduction

When paired with thoughtfully crafted tobacco policy, electronic nicotine delivery systems (ENDS) may represent a lower-harm option for people who use combustible tobacco. At present, ENDS are a heterogenous product class with variable toxicant emissions and efficacy in nicotine delivery [1]. To balance the potential public health benefits and costs associated with ENDS, the United States Food and Drug Administration has signaled that future product standards may address nicotine levels in ENDS liquids.

Several countries as well as the European Union have capped liquid nicotine concentration at 20 mg/mL, though higher and lower limits exist elsewhere [2]. Evidence on the effects of these policies is limited but suggests industry compliance [3,4] and a decline in lifetime ENDS use among youth contemporaneous with the European Union directive [5]. However, ENDS liquids that allow customizable nicotine concentration [6] and the ability to alter ENDS device characteristics (e.g., wattage, coil resistance) to increase aerosol production and nicotine hit [7] threaten the effectiveness of this regulatory strategy.

One ENDS performance characteristic not yet subject to regulation is nicotine flux, the amount of nicotine emitted per second (μg/s). Nicotine delivery from ENDS is determined by several factors including nicotine concentration, propylene glycol (PG)/vegetable glycerin (VG) liquid ratio, device wattage, and use behavior [8,9]. In “open-system” ENDS, limits on ENDS liquid nicotine concentration alone may not effectively control nicotine delivery if device characteristics can be manipulated to increase nicotine flux and/or dose (i.e., nicotine μg/s × puff duration [10,11]) and toxicant exposure [12]. To avoid unintended consequences from regulating liquid nicotine concentration or device wattage in isolation, product standards could target nicotine flux, which can be estimated for any ENDS if device power and liquid composition are known [13].

Crafting effective tobacco product regulations requires understanding a product’s abuse liability, or the likelihood that the product will promote dependence [14]. Abuse liability is assessed using physiological, subjective, and behavioral measures that describe individual experience, nicotine delivery, demand, and substitution potential [14–17] and can predict real-world behavior [18]. Device power and liquid nicotine concentration can affect the nicotine available in ENDS aerosols [19] which may in turn influence ENDS’ abuse liability profile [20–22]. However, clinical laboratory research on the interaction of these characteristics is limited. One study varying ENDS nicotine concentration and device power found that participants worked harder for ENDS with lower nicotine concentration (10 mg/mL) and higher wattage (30W) relative to ENDS with higher nicotine (30 mg/mL) and the same or lower wattage (15W) [23]. However, because the duration of sample puffs was not constrained, nicotine dose may have varied across participants and conditions. A similar study involved ad lib use of ENDS varying in both nicotine concentration (10, 15, 30 mg/mL) and wattage (15, 30W) [24]. Here, higher wattage and nicotine concentrations resulted in the highest plasma nicotine concentrations following a 10-puff bout, but during the subsequent ad lib use period, these differences between ENDS conditions dissipated, potentially because participants altered their puff topography to achieve a desired nicotine dose [24]. These studies suggest that nicotine flux can alter abuse liability but also that manipulating nicotine flux alone allows for flexibility in puffing behavior and, therefore, variable nicotine dose [9]. Given that people who smoke alter their puffing behaviors to achieve desired pharmacologic effects from nicotine [25], nicotine dose emerges as a compelling ENDS regulatory target to optimize substitution from combustibles.

Standardizing nicotine flux and puffing behavior simultaneously would allow more precise control over nicotine dose. Research examining ENDS nicotine dose under controlled settings often does so by varying nicotine concentration, and because these studies also standardize device type and settings (e.g., power) to isolate the effects of nicotine [26–29], flux can be calculated. Still, puff volume and duration can vary [28,29]. Compensatory puffing has been documented in naturalistic settings when ENDS nicotine dose is limited [30,31] and these larger or longer puffs can increase exposure to various toxicants [32]. Product standards that address nicotine flux without limiting puff behavior may thus have unintended consequences for public health. Importantly, existing products demonstrate that limiting puff duration is technologically feasible; for example, Juul ENDS automatically stop emitting aerosol at 5.9 seconds and Vuse ENDS at 3.7–4.9 seconds [33,34].

To inform ENDS product standards, this clinical laboratory study assessed ENDS abuse liability as a function of nicotine dose among people who smoke cigarettes by manipulating nicotine flux and fixing puff duration. We hypothesize that ENDS delivering higher nicotine doses will be associated with greater behavioral economic indices of abuse liability. Secondary analyses examine the effects of ENDS nicotine dose on subjective indices of abuse liability.

2. Material and Methods

2.1. Sample

Participants were recruited using flyers, social media, classified advertisement websites, university listservs, and an internal study registry of previous participants. After completing a phone or online survey to assess initial eligibility, potential participants attended an in-person screening to confirm eligibility, provide informed consent, and complete baseline measures. Of 72 participants who consented to the study, 44 were eligible, and 32 completed the study.

Inclusion was limited to those ages 18–55 who reported daily use of inhaled tobacco products and regular use of cigarettes. Our sample included participants who used cigarettes daily, with ≥5 cigarettes per day; other patterns of tobacco use were allowable but not observed. Use was verified using a semi-quantitative cotinine test (NicAlert, Jant Pharmacal Corporation, Encino, CA). Use of other tobacco products was not exclusionary. Full inclusion and exclusion criteria are available in Appendix A.

Participants who completed the study were compensated up to $565. This study was reviewed and approved by the Virginia Commonwealth University (VCU) Institutional Review Board (HM20018290) and registered on clinicaltrials.gov (NCT04332926).

2.2. Study design and materials

In this within-persons clinical laboratory study, participants evaluated four experimental ENDS devices and own-brand cigarettes (OB). All ENDS used unflavored, unsweetened, protonated nicotine liquid (30% PG:70% VG; >99% nicotine in protonated form; AVAIL Vapor, Richmond, VA) and each liquid’s nicotine concentration was verified by VCU’s Bioanalytical Analysis Core Laboratory to be ±2 mg/mL of the labeled content. ENDS varied in nicotine flux, which was manipulated by keeping wattage (30W) constant while varying nicotine concentration (Appendix B). ENDS conditions were no-flux (0 μg/s), low-flux (36.01 μg/s), cigarette-like-flux (90.03 μg/s), and high-flux (180.06 μg/s), with flux calculated using a validated mathematical model [13]. The cigarette-like-flux condition was similar to the average nicotine flux calculated across 27 cigarette brands (mean 79 [standard deviation [SD] 32] μg/s [35]) and was chosen based on preliminary work showing that an ENDS flux of 75–85 μg/s could yield a blood nicotine concentration equivalent to that of a cigarette after 10 puffs [36].

Puff duration was capped at 2 seconds in all ENDS conditions using customized hardware and software (American University of Beirut; Beirut, Lebanon) which consisted of a visual display of the timer plus directed puffing. The external puff limiter device was attached via a cable to the ENDS, a SUBOX Mini-C with SUBTANK Mini-C (KangerTech, Shenzhen, China). The 2-second duration was based on previous work indicating that those who smoked cigarettes take cigarette puffs for approximately 1.7–2.1 seconds [37] and take puffs of 1.5–2.6 seconds when using the same device and wattage as in this study [24]. Puff duration was not controlled for OB (positive control condition) to avoid underestimating OB abuse liability.

Each product was tested in a separate clinical lab session, separated by ≥48 hours. ENDS conditions were Latin-square ordered to help control for order effects and administered single-blind to reduce participant expectancies. All participants completed the OB condition last (unblinded).

2.3. Procedures

At the in-person screening, study staff confirmed eligibility, obtained written informed consent, familiarized participants with study procedures, and collected baseline data (e.g., demographics, tobacco use history, heart rate, blood pressure, and exhaled carbon monoxide [BreathCO monitor; Vitalograph, Lenexa, KS]). Enrolled participants attended five laboratory sessions, with ≥12 hours nicotine abstinence (verified by exhaled carbon monoxide concentration ≤ half the value observed at screening, or ≤5 ppm if ≤10 ppm at screening) and ≥1-hour caffeine abstinence prior. Sessions lasted ≈220 minutes and began with baseline physiological measures (heart rate, blood pressure, carbon monoxide), administration of four session product sample puffs, and a 60-minute rest period (Figure 1). Subjective and behavioral measures of abuse liability were administered next. In ENDS conditions, participants completed subjective effects measures at four time points as well as a cross-product purchase task and a cross-product progressive ratio task; the OB condition ended after the third set of subjective effects measures were completed.

Figure 1.

Figure 1.

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Session timeline Abbreviations. eCO: exhaled carbon monoxide. ENDS: electronic nicotine delivery system. Min: minutes. OB: own-brand cigarette. Physio: Physiological.

Asterisks (*) represent approximate times of product administration.

2.4. Measures

2.4.1. Baseline measures

At baseline, we assessed participant demographics and tobacco use history, including the Fagerström Test for Nicotine Dependence [38].

2.4.2. Primary outcomes: Behavioral indices of abuse liability

2.4.2.1. Purchase tasks.

The drug purchase task (DPT) is a behavioral economic choice task that asks participants to report how much of a product they would consume at various unit prices [17,39]. Participants assume that all purchases must be consumed in one day, they have no access to any other nicotine/tobacco products, and they have the same income and savings as they normally do. This prompt was repeated across a series of 24 prices per puff of OB or session-specific ENDS. The outcome of interest was demand intensity, or the number of puffs purchased when the product was hypothetically free. We focused on demand intensity as it is the most sensitive index of abuse liability provided by the DPT [40] and is correlated with real consumption when cigarettes are provided free [41].

The cross-product drug purchase task (CP-DPT) is an extension of the DPT in which participants make purchasing decisions for two products available simultaneously [17]. In these tasks (assessed only in ENDS conditions), OB were available at a series of 24 increasing prices per puff, while the session-specific ENDS was available at a fixed price of $0.10/puff. At each price point, participants could choose to purchase puffs of either, both, or neither product. The outcome of interest, cross-price elasticity, indexes how changes in price of OB influence demand for session-specific ENDS.

DPT and CP-DPT responses were not reinforced. Both tasks used the same series of 24 prices: $0 (free), $0.01, $0.02, $0.04, $0.08, $0.16, $0.32, $0.64, $1.28, $2.56, $3.84, $5.12, $6.40, $7.68, $8.96, $10.24, $11.52, $12.80, $14.08, $15.36, $16.64, $17.92, $19.20, and $20.48.

2.4.2.2. Progressive ratio tasks.

Progressive ratio tasks (PRT) use a self-administration paradigm to measure willingness to work for a reinforcer [42,43]. In these computerized tasks, participants press the space bar a specific number of times to earn one puff of the session product (OB or session-specific ENDS). Participants receive the puff immediately, but the work requirement (number of key presses) to earn the next puff increases. The first puff required 10 key presses and the work requirement increased by 30% each subsequent trial (i.e., 10, 13, 17, 22…). The task ended after 15 trials or after five minutes of no participant input. The outcome of interest was the total number of puffs earned.

Participants completed a cross-product progressive ratio task (CP-PRT) in the ENDS conditions [16,44]. The CP-PRT asks participants to work to earn puffs from two products with different work requirements available simultaneously. The work requirement for an ENDS puff is a fixed ratio of 25 ‘A’ key presses in each trial (FR-25), while the work requirement for an OB puff is set using a progressive ratio (PR-25) wherein the first OB puff requires 25 ‘L’ key presses, the second requires 50, and so on until the tenth and final trial (250 ‘L’ key presses). Participants completed all ten trials and then received earned ENDS and/or OB puffs. Delaying reinforcement until the task ends mitigates the potential effects of product satiation, which could occur if responses were immediately reinforced as participants might respond to the lower-effort option simply to complete the task more quickly rather than because they preferred the session-specific ENDS [44]. The CP-PRT produces a breakpoint defined by the highest work requirement participants completed to earn an OB puff (range: 0–250 ‘L’ key presses). In sensitivity analysis, we considered an alternative definition of breakpoint using the highest trial number at which an OB puff was earned (range: trial 1–10). Greater work (e.g., more key presses) for OB puffs was conceptualized to represent lower abuse liability for the potential ENDS substitute in question.

2.4.3. Secondary outcomes: Subjective effects

Thirty-one subjective effects items were completed on a computerized visual analog scale anchored at 0 (“Not at all”) and 100 (“Extremely”). Eleven items assessed nicotine abstinence symptoms: urges to smoke a cigarette, irritability/frustration/anger, anxious, difficulty concentrating, restlessness, hunger, impatient, craving a cigarette, drowsiness, depression/feeling blue, and desire for sweets [45]. Aversive feelings related to nicotine exposure assessed were: nauseous, dizzy, lightheaded, nervous, sweaty, headache, excessive salivation, heart pounding, confused, and weak [46] and whether the product made them feel dizzy [47] or sick [48]. Eight items assessed dimensions of product liking and reinforcing properties, including whether the product was satisfying, pleasant, tasted good, calmed them down, helped them concentrate, made them feel more awake, reduced hunger for food, and whether they would like to use another session product right now [47,48].

Seven items assessed sensations. Participants used a labeled magnitude scale [49] to describe the intensity of the overall flavor sensation, harshness/irritancy, and throat hit of the session product. Text anchors ranged from “No sensation” (corresponding to a score of 0) to “Strongest imaginable sensation of any kind” (100). Participants used a labeled hedonic scale [50] to describe how much they liked the flavor sensation, harshness/irritancy, throat hit, and warmth of the smoke/vapor. The labeled hedonic scale used text anchors ranging from “Most disliked sensation imaginable” (0) to “Neutral” (50) to “Most liked sensation imaginable” (100). Both rating systems are based on non-linear psychophysical scaling [49,50].

While subjective effects items were fielded at multiple points over each session, we limit analyses to time point 1, which occurred an hour after all participants consumed four sample puffs of the session product. Time points 2–4 occurred after participants received puffs earned in the PRT and cross-product PRT, and thus the subjective effects measures do not reflect equivalent exposures to the study product across participants and conditions.

At the end of each ENDS condition, participants were asked whether they thought the ENDS contained nicotine (yes, no, or unsure).

2.5. Analysis

We summarized participant characteristics using frequencies and percentages or means and SDs. A chi-squared test determined differences by condition in participants’ perceptions of whether the session ENDS contained nicotine.

Linear mixed models analyzed differences in behavioral and subjective indices of abuse liability by condition. Because of the within-subjects study design, models contained participant-specific random effects and used robust standard errors. For intensity (DPT), puffs earned (PRT), and subjective effects outcomes, the OB condition served as the reference group, and post-estimation Wald tests assessed pairwise differences between ENDS conditions. For the CP-PRT, similar models tested differences in breakpoint between ENDS conditions but used high-flux ENDS as the reference group.

Cross-price elasticity from the CP-DPT was estimated using linear mixed models with participant-specific random effects and robust standard errors. Here, the predictor was log-OB price and the outcome was the log-number of ENDS puffs purchased at that price. The resulting regression coefficients described the rate and direction of change in consumption for that ENDS as a function of change in price of OB [51]. Pairwise Wald tests compared the cross-price elasticities between ENDS conditions.

We assessed the relationships among the primary behavioral outcomes (intensity, puffs earned, and cross-price elasticity) and select subjective effects items using Pearson correlations (see Appendix F for more detail).

Analyses were conducted using Stata version 15.1 (Statacorp, College Station, TX). Alpha was set to 0.05. The sample size needed (n=32) to test study hypotheses was determined a priori using power analysis (G*Power [52]).

3. Results

3.1. Participant characteristics

Participants (n=32) were on average 38.3 years old (SD 9.0) and were mostly male (66%), non-Hispanic Black (44%) or non-Hispanic White (38%), and used menthol cigarettes (69%; Appendix A). All participants smoked cigarettes daily, using an average of 15.2 (SD 6.4) cigarettes/day. The average nicotine dependence score was 4.4 (SD 2.1), corresponding to low-moderate dependence. Nearly all participants (94%) had tried ENDS at baseline; of these, fewer than half (40%) used them in the past month.

3.2. Behavioral indices of abuse liability

In the DPT, all ENDS conditions were associated with lower demand intensity than OB (ps<0.001; Table 1). On average, participants would consume 154.63 (robust standard error 16.59) puffs of OB in a day if they were free, while predicted means for ENDS conditions ranged from 65.41 (14.33) puffs of a high-flux ENDS to 92.72 (16.71) puffs of a no-flux ENDS. No significant differences in demand intensity emerged between ENDS conditions.

Table 1.

Differences in behavioral measures of abuse liability for own-brand cigarettes and ENDS varying in nicotine flux (N=32)

Task, outcome, and condition Predicted mean (robust SE) Coefficient (robust SE) p 95% confidence interval ENDS comparisons
Drug purchase task: Intensity (number of puffs demanded if each puff cost $0.00)
Own-brand 154.63
cigarettes (16.59) ref
High-flux ENDS 65.41 (14.33) −89.22 (18.77) <0.001 (−126.02, −52.42)
Cigarette-like-flux ENDS 78.56 (14.69) −76.06 (19.16) <0.001 (−113.61, −38.51)
Low-flux ENDS 87.47 (14.73) −67.16 (14.85) <0.001 (−96.26, −38.05)
No-flux ENDS 92.72 (16.71) −61.91 (15.05) <0.001 (−91.40, −32.41)
Progressive ratio task: Reinforcers earned (total number of puffs earned across work requirements)
Own-brand
cigarettes 9.06 (0.48) ref
High-flux ENDS 6.34 (0.77) −2.72 (0.69) <0.001 (−4.08, −1.36) *&
Cigarette-like-flux ENDS 7.31 (0.69) −1.75 (0.68) 0.010 (−3.08, −0.42)
Low-flux ENDS 7.88 (0.61) −1.19 (0.56) 0.034 (−2.29, −0.09) *
No-flux ENDS 7.69 (0.62) −1.38 (0.59) 0.019 (−2.53, −0.22) &
Cross-product purchase task: Cross-price elasticity (rate of change in demand for each ENDS as price of own-brand cigarettes increases)
High-flux ENDS -- 0.30 (0.11) 0.006 (0.09, 0.52)
Cigarette-like-flux ENDS -- 0.28 (0.13) 0.028 (0.03, 0.54) #
Low-flux ENDS -- 0.55 (0.14) <0.001 (0.27, 0.83) #
No-flux ENDS -- 0.49 (0.16) 0.002 (0.18, 0.80)
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Abbreviations. ENDS: electronic nicotine delivery system. Ref: reference group. SE: standard error.

Linear mixed models with participant-specific random effects and robust standard errors were used to assess differences between conditions and generate cross-price elasticity estimates. When two conditions have the same symbol (* or & or #), this indicates that those conditions are significantly different from each other as assessed with Wald tests following the mixed models (p<0.05).

Results from the CP-DPT indicated that each ENDS would serve as a substitute for OB (Table 1; Appendix C). The coefficient for low-flux ENDS was almost double the magnitude of the coefficient for cigarette-like-flux ENDS (p=0.016), suggesting that low-flux ENDS are much stronger substitutes for OB than cigarette-like-flux ENDS.

In the PRT, participants earned significantly more puffs of OB (9.06 [0.48]) compared to all ENDS conditions (ps<0.05, Table 1), indicating higher willingness to work for OB than ENDS of any flux level. Additionally, participants earned more puffs of the low-flux ENDS (7.88 [0.61], p=0.008) and of the no-flux ENDS (7.69 [0.62], p=0.040) compared to the high-flux ENDS (6.34 [0.77]). No differences in cross-PRT breakpoint were found between conditions (Appendix D).

3.3. Subjective effects

In general, ENDS were associated with more intense nicotine abstinence symptoms at 1 hour after use than OB (Appendix E). Among ENDS conditions (Figure 2), the high-flux ENDS improved certain nicotine abstinence symptoms (anxious, craving a cigarette, hunger) more than ENDS with lower flux.

Figure 2.

Figure 2.

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Overview of significant differences in subjective effects across ENDS conditions (N=32) Abbreviations. No: no-flux ENDS. Low: low-flux ENDS. Cig-like: Cigarette-like-flux ENDS. High: high-flux ENDS.

This figure provides a summary of the significance and direction of pairwise differences (assessed using Wald tests following linear mixed effects regression) in subjective effects between ENDS flux conditions (p<0.05). Upward arrows (↑) in dark gray-shaded cells indicate that scores for the ENDS flux condition in the first row is significantly higher on a given item than the ENDS flux condition listed in the second row; for example, the no-flux ENDS was associated with significantly greater ratings of “Anxious” than the high-flux ENDS. Down arrows (↓) in light gray-shaded cells indicate that scores for the ENDS flux condition in the first row are significantly lower on a given item than the ENDS flux condition listed in the second row. Blank cells indicate no significant difference between the two conditions.

Compared to OB, cigarette-like-flux ENDS were associated with higher ratings of light-headedness, headache, and feeling sick, low-flux ENDS were associated with lower dizziness, and no-flux ENDS were associated with lower ratings of ‘nervous’ and ‘dizzy’ (ps<0.05). The no-flux ENDS, which did not deliver nicotine, were associated with more aversive feelings than other ENDS, including greater nervousness versus cigarette-like-flux ENDS (p=0.047), greater confusion versus high-flux ENDS (p=0.046), and less dizziness versus all other ENDS (ps<0.01).

Participants rated OB higher than most ENDS on measures of satisfaction, pleasantness, good taste, calming them down, wanting to use another right now, helping them concentrate, and feeling awake (ps<0.05). High-flux ENDS were less pleasant than low-flux (p=0.011) or no-flux ENDS (p<0.001) and tasted worse than all other ENDS (ps<0.001). Participants wanted to “use another [high-flux ENDS] right now” less than another no-flux ENDS (p=0.012).

OB had a stronger flavor intensity and harshness/irritancy than most ENDS, and participants liked the flavor, harshness/irritancy, and warmth of OB more than ENDS (ps<0.05). OB had less intense and more likable throat hit than high-flux or cigarette-like-flux ENDS and more intense throat hit than no-flux ENDS (ps<0.05). In general, ENDS with higher flux produced more intense sensations, which participants did not like (Figure 3). High-flux ENDS were rated higher on harshness/irritancy and throat hit intensity than any other ENDS, and low-flux ENDS were rated lower on these items than any other ENDS.

Figure 3.

Figure 3.

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Sensation intensity and sensation liking for own-brand cigarettes and ENDS varying in nicotine flux (N=32)

As nicotine flux increased across conditions, the percentage of participants who thought the product did not contain nicotine or were unsure decreased and the percentage of participants who thought the product did contain nicotine increased (X2=15.0, p=0.020; Appendix E).

3.4. Correlations among behavioral and subjective outcomes

Intensity and puffs earned were each weakly-to-moderately correlated with ratings of satisfaction, pleasantness, good taste, how much participants wanted to use another right now, and liking of flavor, harshness, throat hit and warmth sensations (ρ range 0.17–0.53, ps<0.05; Appendix F). Cross-price elasticity was positively but weakly correlated with pleasantness (ρ=0.19, p<0.05) and liking the warmth of the vapor/smoke (ρ=0.20, p<0.05), and moderately correlated with wanting to use another right now (ρ=0.31, p<0.01). Number of PRT puffs earned was weakly correlated with craving a cigarette (ρ=0.16, p<0.05). The intensity of harshness and throat hit sensations exhibited a weak-to-moderate negative correlation with both demand intensity (ps<0.001) and cross-price elasticity (ps<0.05).

4. Discussion

We examined how controlling nicotine dose via nicotine flux and puff duration impacted ENDS abuse liability among people who use cigarettes. Consistent with previous literature [23,53,54], participants preferred their OB cigarettes to any experimental ENDS, yet all ENDS functioned as economic substitutes for OB cigarettes. Additionally, when puff duration was fixed at 2 seconds, low-flux ENDS appeared to be a superior substitute for OB cigarettes than cigarette-like-flux ENDS. Behavioral and subjective measures indicated that when puff duration was fixed, participants preferred no-flux and low-flux ENDS over high-flux ENDS, with the latter associated with lower willingness to work, intensity of demand, and subjective liking as well as greater harshness. Together, these findings suggest that nicotine dose impacts abuse liability in a non-linear fashion. That is, while some level of nicotine delivery is likely necessary for nicotine-dependent individuals to switch from cigarettes to ENDS [55,56], higher dose devices may not be required, or even helpful, for ENDS to substitute for cigarettes. Higher-flux ENDS were comparatively unpleasant, tasted worse, and produced more intense harshness/irritancy and throat hit. These aversive affects may detract from the substitution potential of higher-flux ENDS—indeed, greater harshness and more intense throat hit were correlated with lower demand intensity and substitution potential—leaving the nicotine-delivering and comparatively more enjoyable low-flux ENDS as the preferred choice among the ENDS tested.

Results complement previous work which found participants were willing to work hardest for an ENDS with nicotine flux of ≈60.6 μg/s [23,57] a value which lies between the low-flux (36.03 μg/s) and cigarette-like-flux (90.01 μg/s) ENDS tested here. Moreover, the fewer PRT puffs earned of the high-flux ENDS (180 μg/s) here aligns with the fewer PRT puffs earned of the high nicotine, high wattage (estimated flux 181.2 μg/s) ENDS in previous work [23] and evidence that very high nicotine doses can be aversive [20]. A related study using our same conditions found that high-flux and cigarette-like-flux ENDS resulted in higher plasma nicotine concentrations and greater decreases in cravings for and urges to use cigarettes/ENDS after ad lib use [58]. However, participants also titrated the dose of nicotine by taking shorter and smaller puffs in directed bouts, and fewer puffs with longer inter-puff intervals in ad lib puffing bouts [58]. Because ENDS with higher than cigarette-like flux may have lower abuse potential, nicotine flux levels comparable to combustible tobacco cigarettes (51.4–90.0 μg/s [57]) could serve as an acceptable upper bound for well-regulated ENDS devices.

These findings have important regulatory implications. We demonstrate how nicotine dose can integrate ENDS wattage, liquid nicotine concentration, and puff duration into a single regulatory target which predicts abuse liability. Product standards addressing both flux and puffing duration are needed if the goal is to better control the nicotine dose delivered. Further, the abuse liability of ENDS with nicotine fluxes above that of a cigarette may be limited by their poor palatability, at least when paired with unflavored/unsweetened liquids, suggesting there may be little public health benefit to having such products available on the market.

4.1. Limitations

First, nicotine flux concerns nicotine emitted, not necessarily nicotine delivered to the bloodstream, which may vary with individual differences in anatomy, physiology, or inhalation techniques. Second, because we did not require participants to puff for the full two seconds, there could be differences in nicotine dose that did not correspond to the predicted dose in each condition. However, we expect these differences are minimal because in ad lib sessions using the same devices, observed puff durations were no longer than 2.3 seconds on average [58]. Third, the particular flux levels tested here represent a subset of those available in many markets, and we encourage further testing of nicotine flux levels, particularly at ranges lower than our cigarette-like-flux condition. Fourth, subjective effects were measured 1 hour after participants took 4 sample puffs; the brief sampling period and long rest period may have been insufficient for participants to form stable preferences. Fifth, the unflavored/unsweetened liquid could have reduced the appeal of the experimental ENDS relative to OB, but could also have interacted with the nicotine flux conditions to impact the palatability of the higher nicotine flux ENDS more strongly. Sixth, to what extent greater responding on the PRT represents a greater willingness to work for product access (i.e., higher abuse potential) or lower scores reflect satiety is difficult to disentangle. However, we note that in our data, more puffs earned in the PRT was correlated with higher subjective satisfaction, pleasantness, better taste, sensation liking and desire to ‘use another [session product] right now,’ and was generally not correlated with nicotine abstinence symptoms. Seventh, though we recruited a heterogenous population of people who smoke cigarettes daily, our results may not generalize to people who use other tobacco products or at different frequencies.

5. Conclusion

Nicotine dose may be a compelling regulatory target for ENDS. Under laboratory conditions, nicotine dose can be controlled and alters ENDS abuse liability, and thus the likelihood that people who smoke would substitute ENDS for cigarettes. Further, high nicotine doses may not be necessary to encourage substitution. More evidence is needed to understand how nicotine flux and puff duration interact with other ENDS product characteristics (e.g., flavor, PG/VG ratio) and use behaviors (e.g., breath-holding, puff frequency) to impact abuse liability.

Supplementary Material

1

Highlights.

  • ENDS are a wide product class with variable toxicant emissions, nicotine delivery

  • Nicotine flux (nicotine emitted/s) and puff duration may control ENDS nicotine dose

  • ENDS with nicotine doses exceeding those of cigarettes were harsh and unpleasant

  • Among ENDS, nicotine doses greater than zero but less than a cigarette were more reinforcing than larger doses

  • Product standards for nicotine flux and puff duration could regulate nicotine dose

Acknowledgements

We thank our participants and research staff, without whom this work would not be possible, and our colleagues at the American University of Beirut, who designed and provided the puff limiter device used in this study.

Funding

This research was supported by the National Institute on Drug Abuse of the National Institutes of Health and the Center for Tobacco Products of the U.S. Food and Drug Administration under Award Number U54DA036105 (all authors). The content is solely the responsibility of the authors and does not necessarily represent the views of the NIH or the FDA. Additional support was provided by awards number UL1TR002649 and UM1TR004360 from the National Center for Research Resources and award number F30DA057047 (AMW) from the National Institute on Drug Abuse. The funding source had no other role than financial support.

Abbreviations:

ENDS

electronic nicotine delivery systems

FDA

United States Food and Drug Administration

PG

propylene glycol

VG

vegetable glycerin

OB

own-brand cigarettes

DPT

drug purchase task

CP-DPT

cross-product drug purchase task

PRT

progressive ratio task

CP-PRT

cross-product progressive ratio task

Footnotes

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Conflicts of Interest

The authors report no conflicts of interest.

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Preliminary results were presented at the Society for Research on Nicotine and Tobacco Annual Meetings (San Antonio TX, USA, March 1–4, 2023; Edinburgh, Scotland, March 20–23, 2024).

Data Availability

Data available on request and in Appendices.

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Supplementary Materials

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NIHMS2041798-supplement-1.docx (791.1KB, docx)

Data Availability Statement

Data available on request and in Appendices.

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