Effects of immediate versus gradual nicotine reduction in cigarettes on biomarkers of biological effects

Dorothy K. Hatsukami, Xianghua Luo, Alisa K. Heskin, Mei Kuen Tang, Steven G. Carmella, Joni Jensen, Jason D. Robinson, Ryan Vandrey, David J. Drobes, Andrew A. Strasser, Mustafa al'Absi, Scott Leischow, Paul M. Cinciripini, Joseph Koopmeiners, Joshua Ikuemonisan, Neal L. Benowitz, Eric C. Donny, Stephen S. Hecht

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Aim: A previous study showed significantly greater reductions in number of cigarettes smoked and biomarkers of toxicant and carcinogen exposure in smokers assigned to immediate reduction of nicotine in cigarettes to very low levels versus gradually over time or continued smoking of normal nicotine content cigarettes. This study examines the effects of these approaches on selected biomarkers associated with harmful biological effects. Design: Three-arm, randomized controlled trial. Setting: Ten United States academic institutional sites. Participants: Daily smokers uninterested in quitting smoking with a mean age of 45.1 [standard deviation (SD) = 13.4)] years and smoking 17.1 (SD = 8.5) cigarettes/day; 43.9% (549 of 1250) female; 60.6% (758 of 1250) white ethnicity. Interventions: (1) Smoking cigarettes where nicotine content was immediately reduced to very low levels (n = 503); (2) smoking cigarettes where nicotine content was gradually reduced, with dose changes occurring monthly (n = 498); and (3) continued smoking with normal nicotine content cigarettes (n = 249). Measurements: Smokers were assessed at baseline while smoking their usual brand cigarettes, and again at 4, 8, 12, 16 and 20 weeks. Outcomes were areas under the concentration time curve (AUC) for the period of study of biomarkers of inflammation, oxidative stress and hematological parameters. Findings: No consistent significant differences were observed across groups (Bayes factors showing data to be insensitive), with the only exception being red blood cell size variability, which was observed to be lower in the immediate versus gradual nicotine reduction [mean difference = −0.11; 95% confidence interval (CI) = –0.18, −0.04, P = 0.004] and normal nicotine control groups (mean difference = − 0.15, 95% CI = –0.23, −0.06, P = 0.001). Conclusion: It remains unclear whether switching to very low nicotine cigarettes leads to a short-term reduction in biomarkers of tobacco-related harm.

Original languageEnglish (US)
Pages (from-to)1824-1833
Number of pages10
Issue number10
StatePublished - Oct 8 2019

Bibliographical note

Funding Information:
This study was funded by National Institute on Drug Abuse and Food and Drug Administration grant U54DA031659. All mass spectrometry was conducted in the Analytical Biochemistry Shared Resource of the Masonic Cancer Center, supported in part by National Cancer Institute Cancer Center Support grant P30CA07759. REDCap (Research Electronic Data Capture) services were provided by grant UL1TR000114 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health. Clinical services at the University of Minnesota site were provided by grant UL1TR002494 from the Clinical Translational Science Award of the National Institutes of Health. We are grateful to the staff, students and investigators who implemented the study and Kathy Longley for her many years of service and contributions to preparing this paper. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health or the Food and Drug Administration.

© 2019 Society for the Study of Addiction.


  • Biomarkers of biological effects
  • hematological parameters
  • immediate versus gradual nicotine reduction
  • inflammation
  • oxidative stress
  • reduced nicotine content cigarettes


Dive into the research topics of 'Effects of immediate versus gradual nicotine reduction in cigarettes on biomarkers of biological effects'. Together they form a unique fingerprint.

Cite this