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Comparison of brain nicotine accumulation from traditional combustible cigarettes and electronic cigarettes with different formulations

Neuropsychopharmacology volume 49, pages 740–746 (2024)Cite this article

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Abstract

Rapid brain accumulation is critical for the acute reinforcing effects of nicotine. Although nicotine formulation (free-base vs. protonated or salt) in electronic cigarette (E-cig) liquid affects user satisfaction, its impact on brain nicotine accumulation (BNA) from E-cig use has not been evaluated in comparison with traditional combustible cigarettes (C-cigs) using a within-subjects design. BNA was directly assessed with 29 adult dual users (13 females) of E-cigs and C-cigs, using [11C]nicotine and positron emission tomography (PET). Participants underwent two 15-min upper body (from chest to head) scanning sessions during which they inhaled a single puff of [11C]nicotine-labeled vapor from E-cigs with free-base nicotine or C-cig smoke in a randomized order. Seventeen of them also went through another session during which they inhaled from E-cigs with nicotine salt. A full-body scan was also conducted at each session to measure total absorbed dose of [11C]nicotine. Mean maximum nicotine concentration (Cmax) in brain following inhalation of free-base nicotine E-cig vapor was 19% and 15% lower relative to C-cig smoke and nicotine salt E-cig vapor (ps = 0.014 and 0.043, respectively). The Cmax values did not differ significantly between the C-cig and nicotine salt E-cig. Mean values of time to the maximum concentration (Tmax) were not significantly different between the two types of E-cig, but they were 64% and 40% longer than that for C-cig smoking (ps = 0.0005 and 0.004, respectively). Mean Cmax with C-cigs and free-base nicotine E-cigs were greater in females relative to males and correlated with T1/2 of lung nicotine clearance and participants’ pack-years. These results suggest that while E-cigs with free-base nicotine formulation can deliver nicotine rapidly to the brain, those with nicotine salt formulation are capable of even more efficient brain nicotine delivery closely resembling combustible cigarettes. Therefore, nicotine formulation or pH in E-liquid should be considered in evaluation of E-cigs in terms of abuse liability and potential in substituting for combustible cigarettes.

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Fig. 1: Average fitted brain nicotine accumulation and lung nicotine washout curves (±SEM) after inhalation of a single puff of vapor from Halo (n = 29) and JUUL (n = 17) E-cig liquids and single puff of smoke from a Capri conventional cigarette (n = 29).
Fig. 2: Kinetic parameters (mean ± SEM) of brain nicotine accumulation and lung nicotine washout after inhalation of a single puff of Halo and JUUL E-cig vapor and Capri conventional cigarettes in dual users (n = 17).
Fig. 3: Kinetic parameters (mean ± SEM) of brain nicotine accumulation and lung nicotine washout after inhalation of a single puff of Halo E-cig vapor and Capri conventional cigarettes in male (n = 16) and female dual users (n = 13).

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The data underlying this article will be shared on reasonable request to the corresponding author.

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Acknowledgements

We thank Sandra Norona, Allison Fulp, Freda Lynn Crawford and Joseph Bottoms for assistance in data acquisition.

Funding

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.

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Author notes

  1. These authors contributed equally: Yantao Zuo, Kiran Kumar Solingapuram Sai.

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Duke University Scholl of Medicine, Durham, NC, 27705, USA

    Yantao Zuo, Aeva Jazic, Jed E. Rose & Alexey G. Mukhin

  2. Department of Radiological Sciences, Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, NC, 27157, USA

    Kiran Kumar Solingapuram Sai & Avinash H. Bansode

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Contributions

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; KKSS provided contributions to the study conception, data acquisition and the project supervision: AJ—data analysis and contributions to data acquisition and interpretation; AHB provided contributions to data acquisition and interpretation; JER provided contributions to the study concept and data interpretation; AGM—the study concept and design, data acquisition, analysis and interpretation, and the project supervision.

Corresponding author

Correspondence to Alexey G. Mukhin.

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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 Client Services, JUUL Labs, Otsuka Pharmaceutical, Swedish Match North America, Nicotine BRST LLC; consulting with JT International, SA; and consulting and patent purchase agreement with Philip Morris International for nicotine inhalation system patents, final payment 2014; patent applications filed for bupropion/zonisamide and related drug combinations. All other authors declare no competing interests.

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Zuo, Y., Solingapuram Sai, K.K., Jazic, A. et al. Comparison of brain nicotine accumulation from traditional combustible cigarettes and electronic cigarettes with different formulations. Neuropsychopharmacol. 49, 740–746 (2024). https://doi.org/10.1038/s41386-024-01800-x

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