Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Comparison of brain nicotine uptake from electronic cigarettes and combustible cigarettes


Brain accumulation rate and magnitude are critical for the acute reinforcing effects of nicotine. Despite electronic cigarettes’ (E-cigs) appeal as substitutes for traditional combustible cigarettes (C-cigs), brain nicotine accumulation (BNA) from E-cigs has not been compared with that from C-cigs using a within-subjects design. BNA was directly assessed with 16 adult dual users (10 females) of E-cigs (e-liquid pH 9.4) and C-cigs, using 11C-nicotine and positron emission tomography (PET). Participants went through two 15-min head scanning sessions during which they inhaled a single puff of E-cig vapor or C-cig smoke containing 11C-nicotine in a randomized order. A full-body scan was also conducted at each session to measure total absorbed dose of 11C-nicotine. Mean maximum concentration (Cmax) and area under curve of BNA were 22.1% and 22.7% lower, respectively, following E-cig compared with C-cig inhalation. Meanwhile, T1/2 was 2.7 times longer following inhalation of E-cig vapor relative to C-cig smoke (all ps < 0.005). Whole-body imaging indicated greater nicotine retention in the respiratory tract from vapor versus smoke inhalation (p < 0.0001). Following vapor inhalation, nicotine retention in the respiratory tract was correlated with Cmax values of BNA (rs = −0.59, p < 0.02). Our results confirm that E-cigs with alkaline pH e-liquid can deliver nicotine rapidly to the brain, albeit less efficiently than C-cigs partly due to greater airway retention of nicotine. Since brain nicotine uptake mediates reinforcement, these results help elucidate actions of E-cigs in terms of abuse liability and effectiveness in substituting for combustible cigarettes.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Average brain nicotine accumulation curves (±SE) after inhalation of a single puff of vapor from an E-cig and single puff of smoke from a C-cig (n = 16).
Fig. 2: Kinetic parameters (mean + SEM) of brain nicotine accumulation after inhalation of a single puff of E-cig vapor and C-cig smoke in dual users (n = 16).
Fig. 3: Oropharyngeal and tracheobronchial deposition of nicotine after use of C-cig and E-cig (left panels).
Fig. 4: Respiratory tract (RT) retention of nicotine after use of E-cig and C-cig and its association with Cmax of brain nicotine accumulation following E-cig vapor inhalation.


  1. Jerzyński T, Stimson GV, Shapiro H, Król G. Estimation of the global number of e-cigarette users in 2020. Harm Reduct J. 2021;18:109.

    Article  Google Scholar 

  2. Abrams DB, Glasser AM, Pearson JL, Villanti AC, Collins LK, Niaura RS. Harm minimization and tobacco control: reframing societal views of nicotine use to rapidly save lives. Annu Rev Pubic Health. 2018;39:193–213.

    Article  Google Scholar 

  3. Farsalinos K. Electronic cigarettes: an aid in smoking cessation, or a new health hazard? Ther Adv Respir Dis. 2018;12:1753465817744960–60.

    Article  Google Scholar 

  4. Benowitz NL. Clinical pharmacology of nicotine: implications for understanding, preventing, and treating tobacco addiction. Clin Pharm Ther. 2008;83:531–41.

    CAS  Article  Google Scholar 

  5. Carter LP, Stitzer ML, Henningfield JE, O’Connor RJ, Cummings KM, Hatsukami DK. Abuse liability assessment of tobacco products including potential reduced exposure products. Cancer Epidemiol, Biomark Prev. 2009;18:3241–62.

    Article  Google Scholar 

  6. Henningfield JE, Keenan RM. Nicotine delivery kinetics and abuse liability. J Consult Clin Psychol. 1993;61:743–50.

    CAS  Article  Google Scholar 

  7. Goldenson NI, Buchhalter AR, Augustson EM, Rubinstein ML, Henningfield JE. Abuse liability assessment of the JUUL system in four flavors relative to combustible cigarette, nicotine gum and a comparator electronic nicotine delivery system among adult smokers. Drug Alcohol Depend. 2020;217:108395.

    CAS  Article  Google Scholar 

  8. Molander L, Lunell E, Andersson SB, Kuylenstierna F. Dose released and absolute bioavailability of nicotine from a nicotine vapor inhaler. Clin Pharm Ther. 1996;59:394–400.

    CAS  Article  Google Scholar 

  9. Hajek P, Pittaccio K, Pesola F, Myers Smith K, Phillips-Waller A, Przulj D. Nicotine delivery and users’ reactions to Juul compared with cigarettes and other e-cigarette products. Addiction. 2020;115:1141–48.

    Article  Google Scholar 

  10. St Helen G, Havel C, Dempsey DA, Jacob P 3rd, Benowitz NL. Nicotine delivery, retention and pharmacokinetics from various electronic cigarettes. Addiction 2016;111:535–44.

    Article  Google Scholar 

  11. Vansickel AR, Eissenberg T. Electronic cigarettes: effective nicotine delivery after acute administration. Nicotine Tob Res. 2013;15:267–70.

    CAS  Article  Google Scholar 

  12. Solingapuram Sai KK, Zuo Y, Rose JE, Garg PK, Garg S, Nazih R, et al. Rapid brain nicotine uptake from electronic cigarettes. J Nucl Med. 2020;61:928–30.

    Article  Google Scholar 

  13. Wall A, Roslin S, Borg B, McDermott S, Walele T, Nahde T, et al. E-cigarette aerosol deposition and disposition of [(11)C]nicotine using positron emission tomography: a comparison of nicotine uptake in lungs and brain using two different nicotine formulations. Pharmaceuticals (Basel). 2022;15:367.

    CAS  Article  Google Scholar 

  14. Zuo Y, Mukhin AG, Garg S, Nazih R, Behm FM, Garg PK, et al. Sex-specific effects of cigarette mentholation on brain nicotine accumulation and smoking behavior. Neuropsychopharmacology. 2015;40:884–92.

    CAS  Article  Google Scholar 

  15. Rose JE, Mukhin AG, Lokitz SJ, Turkington TG, Herskovic J, Behm FM, et al. Kinetics of brain nicotine accumulation in dependent and nondependent smokers assessed with PET and cigarettes containing 11C-nicotine. Proc Natl Acad Sci USA. 2010;107:5190–5.

    CAS  Article  Google Scholar 

  16. Polosa R, Morjaria JB, Caponnetto P, Caruso M, Campagna D, Amaradio MD, et al. Persisting long term benefits of smoking abstinence and reduction in asthmatic smokers who have switched to electronic cigarettes. Disco Med. 2016;21:99–108.

    Google Scholar 

  17. Farsalinos KE, Romagna G, Tsiapras D, Kyrzopoulos S, Voudris V. Evaluation of electronic cigarette use (vaping) topography and estimation of liquid consumption: implications for research protocol standards definition and for public health authorities’ regulation. Int J Environ Res Public Health. 2013;10:2500–14.

    Article  Google Scholar 

  18. Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO. The fagerström test for nicotine dependence: a revision of the fagerström tolerance questionnaire. Br J Addict. 1991;86:1119–27.

    CAS  Article  Google Scholar 

  19. Foulds J, Veldheer S, Yingst J, Hrabovsky S, Wilson SJ, Nichols TT, et al. Development of a questionnaire for assessing dependence on electronic cigarettes among a large sample of ex-smoking E-cigarette users. Nicotine Tob Res. 2015;17:186–92.

    Article  Google Scholar 

  20. Zuo Y, Garg PK, Nazih R, Garg S, Rose JE, Murugesan T, et al. A programmable smoke delivery device for PET imaging with cigarettes containing (11)C-nicotine. J Neurosci Methods. 2017;283:55–61.

    CAS  Article  Google Scholar 

  21. Halldin C, Någren K, Swahn CG, Långström B, Nybäck H. (S)- and (R)-[11C]nicotine and the metabolite (R/S)-[11C]cotinine. Preparation, metabolite studies and in vivo distribution in the human brain using PET. Int J Rad Appl Instrum B. 1992;19:871–80.

    CAS  Article  Google Scholar 

  22. Benowitz NL, Hukkanen J, Jacob P, 3rd. Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol. 2009;192:29–60.

  23. Bergström M, Nordberg A, Lunell E, Antoni G, Långström B. Regional deposition of inhaled 11C-nicotine vapor in the human airway as visualized by positron emission tomography. Clin Pharm Ther. 1995;57:309–17.

    Article  Google Scholar 

  24. Macklin KD, Maus AD, Pereira EF, Albuquerque EX, Conti-Fine BM. Human vascular endothelial cells express functional nicotinic acetylcholine receptors. J Pharm Exp Ther. 1998;287:435–9.

    CAS  Google Scholar 

  25. Gotts JE, Jordt SE, McConnell R, Tarran R. What are the respiratory effects of e-cigarettes? BMJ. 2019;366:l5275.

    Article  Google Scholar 

  26. Arredondo J, Chernyavsky AI, Marubio LM, Beaudet AL, Jolkovsky DL, Pinkerton KE, et al. Receptor-mediated tobacco toxicity: regulation of gene expression through alpha3beta2 nicotinic receptor in oral epithelial cells. Am J Pathol. 2005;166:597–613.

    CAS  Article  Google Scholar 

  27. Báez-Pagán CA, Delgado-Vélez M, Lasalde-Dominicci JA. Activation of the macrophage α7 nicotinic acetylcholine receptor and control of inflammation. J Neuroimmune Pharm. 2015;10:468–76.

    Article  Google Scholar 

  28. Stepanov I, Fujioka N. Bringing attention to e-cigarette pH as an important element for research and regulation. Tob Control. 2015;24:413–4.

    Article  Google Scholar 

  29. Lunell E, Bergström M, Antoni G, Långström B, Nordberg A. Nicotine deposition and body distribution from a nicotine inhaler and a cigarette studied with positron emission tomography. Clin Pharm Ther. 1996;59:593–4.

    CAS  Article  Google Scholar 

  30. David G, Parmentier EA, Taurino I, Signorell R. Tracing the composition of single e-cigarette aerosol droplets in situ by laser-trapping and Raman scattering. Sci Rep. 2020;10:7929.

    CAS  Article  Google Scholar 

  31. Leventhal AM, Madden DR, Peraza N, Schiff SJ, Lebovitz L, Whitted L, et al. Effect of exposure to e-cigarettes with salt vs free-base nicotine on the appeal and sensory experience of vaping: a randomized clinical trial. JAMA Netw Open. 2021;4:e2032757.

    Article  Google Scholar 

  32. Rose JE, Behm FM, Westman EC, Johnson M. Dissociating nicotine and nonnicotine components of cigarette smoking. Pharm Biochem Behav. 2000;67:71–81.

    CAS  Article  Google Scholar 

  33. Rose JE, Tashkin DP, Ertle A, Zinser MC, Lafer R. Sensory blockade of smoking satisfaction. Pharm Biochem Behav. 1985;23:289–93.

    CAS  Article  Google Scholar 

Download references


We thank Sandra Norona, Allison Fulp, and Jonathan Richardson for assistance in data acquisition.


Research reported in this publication was supported by the National Institute on Drug Abuse of the National Institutes of Health under Award Number R01DA044756. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations



All authors contributed to drafting the work or revising it critically for important intellectual content, gave final approval of the version to be published; and provided an agreement to be accountable for all aspects of the work. In addition: YZ provided contributions to the conception, the data acquisition, analysis and interpretation, and wrote the manuscript draft; AGM - the study concept and design, data acquisition, analysis and interpretation, and the project supervision; HB and JDM - data analysis and contributions to data acquisition and interpretation; AM provided contributions to the study concept and design; JER provided contributions to the study concept and data interpretation; KKSS provided contributions to the study conception, data acquisition and the project supervision.

Corresponding author

Correspondence to Alexey G. Mukhin.

Ethics declarations

Competing interests

AGM discloses grants from the National Institute on Drug Abuse and consulting for Rose Research Center LLC on the project funded by Philip Morris International, outside the submitted work. JER discloses grants from the National Institute on Drug Abuse, research support from Foundation for a Smoke-Free World, Philip Morris International, Altria, JUUL Labs, consulting with Revive pharmaceuticals, and consulting and patent purchase agreement with Philip Morris International, related to smoking cessation and tobacco harm reduction. All other authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zuo, Y., Mukhin, A.G., Berg, H. et al. Comparison of brain nicotine uptake from electronic cigarettes and combustible cigarettes. Neuropsychopharmacol. 47, 1939–1944 (2022).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


Quick links