Randomized controlled trials using electronic nicotine delivery systems as smoking cessation aids require an accurate, empirically-based understanding of the nicotine delivery profile of the products under study
Editorial Commentary

Randomized controlled trials using electronic nicotine delivery systems as smoking cessation aids require an accurate, empirically-based understanding of the nicotine delivery profile of the products under study

Sarah F. Maloney1,2, Cosima Hoetger1,3, Alyssa K. Rudy1,2, Alisha Eversole1,2, Ashlee N. Sawyer1,2, Caroline O. Cobb1,2, Andrew J. Barnes2,3, Alison Breland1,2, Thomas Eissenberg1,2

1Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA; 2Center for the Study of Tobacco Products, Virginia Commonwealth University, Richmond, VA, USA; 3Department of Health Behavior and Policy, Virginia Commonwealth University, Richmond, VA, USA

Correspondence to: Thomas Eissenberg, PhD. 100 W. Franklin St., Suite 200, Richmond, VA 23220, USA. Email: teissenb@vcu.edu.

Received: 14 November 2020; Accepted: 19 March 2021; Published: 25 June 2021.

doi: 10.21037/jphe-20-124


Randomized controlled trials (RCTs) are a mainstay for determining intervention efficacy and safety and have been used for decades to investigate the role of nicotine replacement in smoking cessation (1). Notably, cessation outcomes generally improve in a nicotine dose-related manner (2), highlighting the importance of drug delivery in intervention efficacy. Since 2013, a variety of reports describe RCTs that explore the efficacy and safety of electronic nicotine delivery systems (ENDS) for smoking cessation or reduction (3-11). One serious limitation shared by all of these RCTs is that the nicotine delivery profile of the ENDS product used was either uncertain (3,5-8,10,11) or minimal (4,9). Perhaps not surprisingly, then, cessation outcomes in many of these ENDS RCTs were modest (4-10). Results from rigorous laboratory research make clear that ENDS are a heterogeneous product class (12,13), and that ENDS nicotine emissions (i.e., yield) and user plasma nicotine concentration (i.e., delivery of nicotine to blood) are influenced by the interaction of device, liquid, and user behavior (14-19). To increase the likelihood of larger effect sizes, investigators planning ENDS RCTs likely would benefit from considering these factors.

ENDS device, liquid, and user behavior are critical for understanding ends nicotine yield and delivery

ENDS nicotine yield and delivery are a function of device power (14,15,17,18,20-22) and device construction (23,24) as well as liquid nicotine concentration (14-16,25,26) and propylene glycol/vegetable glycerin ratio (14,20,26-28). Moreover, because of differences in device characteristics, visual appearance (e.g., “tank” or “mod”) or device “type” (e.g., 1st, 2nd, or 3rd generation) is not necessarily predictive of nicotine delivery (29,30). Therefore, choosing a device for an RCT based on its appearance or type is an unreliable method of assuring that nicotine will be delivered. Notably, several ENDS RCTs provide little information regarding the decision process used for selecting the ENDS products examined, apart from the appearance and/or popularity of the device. Also, user behavior, particularly puff duration, influences nicotine yield and delivery, with longer puffs leading to greater yield/delivery (14-16,31). Thus, even a device/liquid combination that appears to emit/deliver nicotine in controlled settings may fail to do so in an RCT if participants are not instructed regarding how to use it for maximum effectiveness.

One tool that is available to researchers planning an ENDS RCT is a mathematical model that predicts the nicotine emissions of any ENDS device/liquid combination based upon several factors including puff duration, liquid nicotine concentration and device power (15). This mathematical model explains 72% of the variability in ENDS’ rate of nicotine emissions (15) and so may be particularly useful in helping investigators select candidate ENDS devices and liquids for their RCT. For example, if investigators are interested in testing ENDSs that mimic the delivery profile of a combustible cigarette, the mathematical model will reveal which device/liquid combinations achieve cigarette-like nicotine yield in a given number of puffs of various puff durations (16). The nicotine delivery profile of those candidate products can then be determined using clinical laboratory methods.

There is a long tradition of using clinical laboratory methods to explore the nicotine delivery profile and other effects of tobacco products under controlled conditions (32-39). With some adaptation, these methods have revealed the considerable heterogeneity in ENDS nicotine delivery, with some products delivering little to no nicotine (40,41), others delivering some nicotine but dramatically underperforming a tobacco cigarette (31,42-47) and others meeting or exceeding the nicotine delivery of a tobacco cigarette after 10 puffs (18,29). Advantages of clinical laboratory methods are that they allow investigators to learn, in a single study, about how effectively various ENDS device/liquid combinations deliver nicotine to users’ blood under controlled and ad libitum puffing conditions; about how user behavior (i.e., puff duration) with those ENDS device/liquid combinations influences nicotine delivery; and about the acceptability of those ENDS device/liquid combinations as well as their ability to suppress tobacco/abstinence effects in smokers (17,48). Perhaps most important, relative to RCTs that often last multiple years and use between-group designs that often involve large samples [e.g., >500 people (7,10,11)] clinical laboratory studies can be rapid (i.e., 4–6 months) and use sensitive within-group designs involving 10–30 participants (16,17,42,45,48,49). Therefore, clinical laboratory studies can be a critical precursor for ensuring that an ENDS RCT involves products with known nicotine delivery profile(s) and can also help to inform RCT participants how their behavior will influence that profile (e.g., longer puffs increase nicotine delivery).

Ethical cessation-focused ENDS RCTs require knowing nicotine delivery profile

Many investigators likely would agree that an RCT involving a novel method of delivering a proven, systemically-active, life-saving medication should not go forward if the bioavailability of the drug administered via the new method is uncertain. In such a case, where participants have a life-threatening illness, where there is a proven treatment that requires delivery of the drug to the blood, and where the novel delivery system may not deliver the drug effectively, an RCT may risk the health of participants and also expend scarce resources unnecessarily. Determining the bioavailability of the drug using the new delivery method outside of an RCT might be a better first step. Cigarette smoking is lethal and investigators conducting RCTs testing cessation interventions must be mindful of participant health and resource conservation. Proven smoking cessation medications are available, including the drug nicotine that can be delivered efficaciously via several routes of administration. Why, then, would an investigator suggest and an ethics panel (e.g., investigational review board, or IRB) approve an RCT that involves nicotine-dependent, cigarette-smoking, treatment-seeking participants who are offered a proven medication (nicotine) using a method (ENDS) that may deliver no or very little of the drug?

A more rigorous approach would be for RCT investigators to make use of existing tools and empirically-validated, clinical laboratory methods that can be used to demonstrate ENDS nicotine delivery and also provide information regarding how participant behavior can influence nicotine delivery. IRBs can then be assured, as they should be, that the ENDS that will be used in the RCT is capable of delivering nicotine to RCT participants and that the ENDS nicotine delivery profile is at least similar to that of a nicotine replacement medication that has proven efficacy and safety.


ENDS have been called a “disruptive technology” (50) that some advocates believe “have the potential to end cigarette use” (51). This potential is more likely to be realized when policymakers, clinicians, and combustible cigarette smokers are guided by RCTs that investigate ENDSs that have been demonstrated to deliver nicotine effectively. If the nicotine delivery profile of ENDS products is uncertain, those products should not be included in an RCT that involves treatment-seeking cigarette smokers.


Funding: This work is supported by grant number F31DA047018 and U54DA036105 from 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. The content is solely the responsibility of the authors and does not necessarily represent the views of the NIH or the FDA.


Provenance and Peer Review: This article was commissioned by the Guest Editor (Michael Chaiton) for the series “Tobacco and Addiction” published in Journal of Public Health and Emergency. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jphe-20-124). The series “Tobacco and Addiction” was commissioned by the editorial office without any funding or sponsorship. This research is supported by grant number U54DA036105 from 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. The content is solely the responsibility of the authors and does not necessarily represent the views of the NIH or the FDA. Not related to the current work, Dr. COC has received funding from Virginia Foundation for Healthy Youth and Virginia Commonwealth University Massey Cancer Center. The author has also received funds from University of Arkansas for Medical Sciences and Virginia Foundation for Healthy Youth for guest speaking and from NIH-Center for Scientific Review and California Tobacco-Related Disease Research Program for grant review. Dr. AJB has received funding for unrelated work from other state and federal agencies and foundations in the last 36 months. Additionally, Dr. AJB has received royalties for textbooks and consulting fees from the NIH and WHO, none of these are related to the funded project or research experiences this manuscript was based upon. Dr. AB has received funding for unrelated work from other state and federal agencies and foundations in the last 36 months. Additionally, Dr. AB has received payment from the NIH Center for Scientific Review; none of these are related to the funded project. Dr. TE is a paid consultant in litigation against the tobacco industry and also the electronic cigarette industry and is named on one patent for a device that measures the puffing behavior of electronic cigarette users and on another patent for a smartphone app that determines electronic cigarette device and liquid characteristics. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.


  1. Stead LF, Perera R, Bullen C, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 2012;11:CD000146 [PubMed]
  2. Lindson N, Chepkin SC, Ye W, et al. Different doses, durations and modes of delivery of nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 2019;4:CD013308 [Crossref] [PubMed]
  3. Adriaens K, Van Gucht D, Declerck P, et al. Effectiveness of the electronic cigarette: an eight-week Flemish study with six-month follow-up on smoking reduction, craving and experienced benefits and complaints. Int J Environ Res Public Health 2014;11:11220-48. [Crossref] [PubMed]
  4. Bullen C, Howe C, Laugesen M, et al. Electronic cigarettes for smoking cessation: a randomised controlled trial. Lancet 2013;382:1629-37. [Crossref] [PubMed]
  5. Caponnetto P, Campagna D, Cibella F, et al. EffiCiency and Safety of an eLectronic cigAreTte (ECLAT) as tobacco cigarettes substitute: a prospective 12-month randomized control design study. PLoS One 2013;8:e66317 [Crossref] [PubMed]
  6. Carpenter MJ, Heckman BW, Wahlquist AE, et al. A naturalistic, randomized pilot trial of e-cigarettes: uptake, exposure, and behavioral effects. Cancer Epidemiol Biomarkers Prev 2017;26:1795-803. [Crossref] [PubMed]
  7. Halpern SD, Harhay MO, Saulsgiver K, et al. A pragmatic trial of e-cigarettes, incentives, and drugs for smoking cessation. N Engl J Med 2018;378:2302-10. [Crossref] [PubMed]
  8. Masiero M, Lucchiari C, Mazzocco K, et al. E-cigarettes may support smokers with high smoking-related risk awareness to stop smoking in the short run: preliminary results by randomized controlled trial. Nicotine Tob Res 2019;21:119-26. [Crossref] [PubMed]
  9. Tseng TY, Ostroff JS, Campo A, et al. A randomized trial comparing the effect of nicotine versus placebo electronic cigarettes on smoking reduction among young adult smokers. Nicotine Tob Res 2016;18:1937-43. [Crossref] [PubMed]
  10. Walker N, Parag V, Verbiest M, et al. Nicotine patches used in combination with e-cigarettes (with and without nicotine) for smoking cessation: a pragmatic, randomised trial. Lancet Respir Med 2020;8:54-64. [Crossref] [PubMed]
  11. Hajek P, Phillips-Waller A, Przulj D, et al. A randomized trial of e-cigarettes versus nicotine-replacement therapy. N Engl J Med 2019;380:629-37. [Crossref] [PubMed]
  12. Breland A, Soule E, Lopez A, et al. Electronic cigarettes: what are they and what do they do? Ann NY Acad Sci 2017;1394:5. [Crossref] [PubMed]
  13. Zhu SH, Sun JY, Bonnevie E, et al. Four hundred and sixty brands of e-cigarettes and counting: implications for product regulation. Tob Control 2014;23:iii3-9. [Crossref] [PubMed]
  14. Talih S, Balhas Z, Eissenberg T, et al. Effects of user puff topography, device voltage, and liquid nicotine concentration on electronic cigarette nicotine yield: measurements and model predictions. Nicotine Tob Res 2015;17:150-7. [Crossref] [PubMed]
  15. Talih S, Balhas Z, Salman R, et al. Transport phenomena governing nicotine emissions from electronic cigarettes: Model formulation and experimental investigation. Aerosol Sci Technol 2017;51:1. [Crossref] [PubMed]
  16. Hiler M, Breland A, Spindle T, et al. Electronic cigarette user plasma nicotine concentration, puff topography, heart rate, and subjective effects: influence of liquid nicotine concentration and user experience. Exp Clin Psychopharmacol 2017;25:380. [Crossref] [PubMed]
  17. Hiler M, Karaoghlanian N, Talih S, et al. Effects of electronic cigarette heating coil resistance and liquid nicotine concentration on user nicotine delivery, heart rate, subjective effects, puff topography, and liquid consumption. Exp Clin Psychopharmacol 2020;28:527. [Crossref] [PubMed]
  18. Wagener TL, Floyd EL, Stepanov I, et al. Have combustible cigarettes met their match? The nicotine delivery profiles and harmful constituent exposures of second-generation and third-generation electronic cigarette users. Tob Control 2017;26:e23-8. [Crossref] [PubMed]
  19. Fearon IM, Eldridge AC, Gale N, et al. Nicotine pharmacokinetics of electronic cigarettes: a review of the literature. Regul Toxicol Pharmacol 2018;100:25-34. [Crossref] [PubMed]
  20. Kosmider L, Spindle TR, Gawron M, et al. Nicotine emissions from electronic cigarettes: Individual and interactive effects of propylene glycol to vegetable glycerin composition and device power output. Food Chem Toxicol 2018;115:302-5. [Crossref] [PubMed]
  21. Farsalinos KE, Spyrou A, Tsimopoulou K, et al. Nicotine absorption from electronic cigarette use: comparison between first and new-generation devices. Sci Rep 2014;4:4133. [Crossref] [PubMed]
  22. Peace MR, Mulder HA, Baird TR, et al. Evaluation of nicotine and the components of e-liquids generated from e-cigarette aerosols. J Anal Toxicol 2018;42:537-43. [Crossref] [PubMed]
  23. Talih S, Salman R, Karaoghlanian N, et al. “Juice Monsters”: Sub-ohm vaping and toxic volatile aldehyde emissions. Chem Res Toxicol 2017;30:1791-3. [Crossref] [PubMed]
  24. Brown CJ, Cheng JM. Electronic cigarettes: product characterisation and design considerations. Tob Control 2014;23:ii4-10. [Crossref] [PubMed]
  25. Cox S, Kośmider L, McRobbie H, et al. E-cigarette puffing patterns associated with high and low nicotine e-liquid strength: effects on toxicant and carcinogen exposure. BMC Public Health 2016;16:999. [Crossref] [PubMed]
  26. El-Hellani A, Salman R, El-Hage R, et al. Nicotine and carbonyl emissions from popular electronic cigarette products: correlation to liquid composition and design characteristics. Nicotine Tob Res 2018;20:215-23. [PubMed]
  27. Baassiri M, Talih S, Salman R, et al. Clouds and “throat hit”: Effects of liquid composition on nicotine emissions and physical characteristics of electronic cigarette aerosols. Aerosol Sci Technol 2017;51:1231-9. [Crossref] [PubMed]
  28. Spindle TR, Hiler MM, Breland AB, et al. The influence of a mouthpiece-based topography measurement device on electronic cigarette user’s plasma nicotine concentration, heart rate, and subjective effects under directed and ad libitum use conditions. Nicotine Tob Res 2017;19:469-76. [PubMed]
  29. Yingst JM, Foulds J, Veldheer S, et al. Nicotine absorption during electronic cigarette use among regular users. PLoS One 2019;14:e0220300 [Crossref] [PubMed]
  30. O’Connell G, Pritchard JD, Prue C, et al. A randomised, open-label, cross-over clinical study to evaluate the pharmacokinetic profiles of cigarettes and e-cigarettes with nicotine salt formulations in US adult smokers. Intern Emerg Med 2019;14:853-61. [Crossref] [PubMed]
  31. Farsalinos KE, Spyrou A, Stefopoulos C, et al. Nicotine absorption from electronic cigarette use: comparison between experienced consumers (vapers) and naïve users (smokers). Sci Rep 2015;5:11269. [Crossref] [PubMed]
  32. Henningfield JE, Keenan RM. Nicotine delivery kinetics and abuse liability. J Consult Clin Psychol 1993;61:743-50. [Crossref] [PubMed]
  33. Henningfield JE. Nicotine medications for smoking cessation. N Engl J Med 1995;333:1196-203. [Crossref] [PubMed]
  34. Gorsline J, Gupta SK, Dye D, et al. Steady‐state pharmacokinetics and dose relationship of nicotine delivered from Nicoderm®(nicotine transdermal system). J Clin Pharmacol 1993;33:161-8. [Crossref] [PubMed]
  35. Nemeth-Coslett R, Henningfield JE, O'Keeffe MK, et al. Nicotine gum: dose-related effects on cigarette smoking and subjective ratings. Psychopharmacology 1987;92:424-30. [Crossref] [PubMed]
  36. Fant RV, Owen LL, Henningfield JE. Nicotine replacement therapy. Prim Care 1999;26:633-52. [Crossref] [PubMed]
  37. Buchhalter AR, Schrinel L, Eissenberg T. Withdrawal-suppressing effects of a novel smoking system: comparison with own brand, not own brand, and de-nicotinized cigarettes. Nicotine Tob Res 2001;3:111-8. [Crossref] [PubMed]
  38. Breland AB, Buchhalter AR, Evans SE, et al. Evaluating acute effects of potential reduced-exposure products for smokers: clinical laboratory methodology. Nicotine Tob Res 2002;4:S131-40. [Crossref] [PubMed]
  39. Cobb CO, Weaver MF, Eissenberg T. Evaluating the acute effects of oral, non-combustible potential reduced exposure products marketed to smokers. Tob Control 2010;19:367-73. [Crossref] [PubMed]
  40. Vansickel AR, Cobb CO, Weaver MF, et al. A clinical laboratory model for evaluating the acute effects of electronic “cigarettes”: nicotine delivery profile and cardiovascular and subjective effects. Cancer Epidemiol Biomarkers Prev 2010;19:1945-53. [Crossref] [PubMed]
  41. Bullen C, McRobbie H, Thornley S, et al. Effect of an electronic nicotine delivery device (e cigarette) on desire to smoke and withdrawal, user preferences and nicotine delivery: randomised cross-over trial. Tob Control 2010;19:98-103. [Crossref] [PubMed]
  42. Hajek P, Przulj D, Phillips A, et al. Nicotine delivery to users from cigarettes and from different types of e-cigarettes. Psychopharmacology 2017;234:773-9. [Crossref] [PubMed]
  43. Stiles MF, Campbell LR, Graff DW, et al. Pharmacodynamic and pharmacokinetic assessment of electronic cigarettes, combustible cigarettes, and nicotine gum: implications for abuse liability. Psychopharmacology 2017;234:2643-55. [Crossref] [PubMed]
  44. Nides MA, Leischow SJ, Bhatter M, et al. Nicotine blood levels and short-term smoking reduction with an electronic nicotine delivery system. Am J Health Behav 2014;38:265-74. [Crossref] [PubMed]
  45. Dawkins L, Corcoran O. Acute electronic cigarette use: nicotine delivery and subjective effects in regular users. Psychopharmacology 2014;231:401-7. [Crossref] [PubMed]
  46. St Helen G, Havel C, Dempsey DA, et al. Nicotine delivery, retention and pharmacokinetics from various electronic cigarettes. Addiction 2016;111:535-44. [Crossref] [PubMed]
  47. Yan XS, D’Ruiz C. Effects of using electronic cigarettes on nicotine delivery and cardiovascular function in comparison with regular cigarettes. Regul Toxicol Pharmacol 2015;71:24-34. [Crossref] [PubMed]
  48. Spindle TR, Talih S, Hiler MM, et al. Effects of electronic cigarette liquid solvents propylene glycol and vegetable glycerin on user nicotine delivery, heart rate, subjective effects, and puff topography. Drug Alcohol Depend 2018;188:193-9. [Crossref] [PubMed]
  49. D’Ruiz CD, Graff DW, Yan XS. Nicotine delivery, tolerability and reduction of smoking urge in smokers following short-term use of one brand of electronic cigarettes. BMC Public Health 2015;15:991. [Crossref] [PubMed]
  50. Abrams DB. Promise and peril of e-cigarettes: can disruptive technology make cigarettes obsolete? JAMA 2014;311:135-6. [Crossref] [PubMed]
  51. Hajek P, Etter JF, Benowitz N, et al. Electronic cigarettes: review of use, content, safety, effects on smokers and potential for harm and benefit. Addiction 2014;109:1801-10. [Crossref] [PubMed]
doi: 10.21037/jphe-20-124
Cite this article as: Maloney SF, Hoetger C, Rudy AK, Eversole A, Sawyer AN, Cobb CO, Barnes AJ, Breland A, Eissenberg T. Randomized controlled trials using electronic nicotine delivery systems as smoking cessation aids require an accurate, empirically-based understanding of the nicotine delivery profile of the products under study. J Public Health Emerg 2021;5:20.