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Cited by 118Smoking Behavior and CessationSubstance Abuse Treatment and OutcomesNicotinic Acetylcholine Receptors Study

Effect of Cytisine vs Varenicline on Smoking Cessation: A Randomized Clinical Trial

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Courtney, Ryan J., McRobbie, Hayden, Tutka, Piotr, Weaver, Natasha A., Petrie, Dennis, Mendelsohn, Colin P., Shakeshaft, Anthony, Talukder, Saki +15 more·2021·JAMA
DOI 10.1001/jama.2021.7621PMC PMC8261608
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Abstract

Importance: Cytisine is more effective than placebo and nicotine replacement therapy for smoking cessation. However, cytisine has not been tested against the most effective smoking cessation medication, varenicline, which is associated with adverse events known to lead to discontinuation of therapy. Objective: To examine whether standard cytisine treatment (25 days) was at least as effective as standard varenicline treatment (84 days) for smoking cessation. Design, Setting, and Participants: This noninferiority, open-label randomized clinical trial with allocation concealment and blinded outcome assessment was undertaken in Australia from November 2017 through May 2019; follow-up was completed in January 2020. A total of 1452 Australian adult daily smokers willing to make a quit attempt were included. Data collection was conducted primarily by computer-assisted telephone interview, but there was an in-person visit to validate the primary outcome. Interventions: Treatments were provided in accordance with the manufacturers' recommended dosage: cytisine (n = 725), 1.5-mg capsules taken 6 times daily initially then gradually reduced over the 25-day course; varenicline (n = 727), 0.5-mg tablets titrated to 1 mg twice daily for 84 days (12 weeks). All participants were offered referral to standard telephone behavioral support. Main Outcomes and Measures: The primary outcome was 6-month continuous abstinence verified using a carbon monoxide breath test at 7-month follow-up. The noninferiority margin was set at 5% and the 1-sided significance threshold was set at .025. Results: Among 1452 participants who were randomized (mean [SD] age, 42.9 [12.7] years; 742 [51.1%] women), 1108 (76.3%) completed the trial. Verified 6-month continuous abstinence rates were 11.7% for the cytisine group and 13.3% for the varenicline group (risk difference, -1.62% [1-sided 97.5% CI, -5.02% to ∞]; P = .03 for noninferiority). Self-reported adverse events occurred less frequently in the cytisine group (997 events among 482 participants) compared with the varenicline group (1206 events among 510 participants) and the incident rate ratio was 0.88 (95% CI, 0.81 to 0.95; P = .002). Conclusions and Relevance: Among daily smokers willing to quit, cytisine treatment for 25 days, compared with varenicline treatment for 84 days, failed to demonstrate noninferiority regarding smoking cessation. Trial Registration: anzctr.org.au Identifier: ACTRN12616001654448.

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  • Cytisine is a plant-based alkaloid, is also a partial agonist of the α4β2 nicotinic receptor, and has comparable effectiveness to varenicline.

    “Cytisine, a plant- based alkaloid, is also a partial agonist of the α 4 β 2 nicotinic receptor, and has comparable effectiveness to varen icline 184 .”

    From Substance use disorders: a comprehensive update of classification, epidemiology, neurobiology, clinical aspects, treatment and prevention (2023) · cites this paper as [184]

    The Abstract identifies cytisine as a plant-based alkaloid and, like varenicline, a selective partial agonist at nicotinic acetylcholine receptors; it does not specify the α4β2 subtype for cytisine. The Key Points and Abstract report 11.7% versus 13.3% six-month abstinence, but the trial failed to demonstrate noninferiority, so the claim of comparable effectiveness overstates its finding. (LLM, conf=0.90)

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Cites

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5 of the 33 references couldn’t be matched to a known paper.

Research works printed but not linked: 7

  1. Tutka P, Vinnikov D, Courtney RJ, Benowitz NL. Cytisine for nicotine addiction treatment. Addiction. 2019;114(11):1951-1969.
  2. Thomas D, Farrell M, McRobbie H, et al. The effectiveness, safety and cost-effectiveness of cytisine versus varenicline for smoking cessation in an Australian population. Addiction. 2019;114(5): 923-933.
  3. West R, Hajek P, Stead L, Stapleton J. Outcome criteria in smoking cessation trials. Addiction. 2005; 100(3):299-303.
  4. US Food and Drug Administration. Non-inferiority clinical trials to establish effectiveness; guidance for industry; availability. Fed Regist. 2016;81(216):78605-78606.
  5. Nides M, Oncken C, Gonzales D, et al. Smoking cessation with varenicline, a selective α4β2 nicotinic receptor partial agonist. Arch Intern Med. 2006;166(15):1561-1568.
  6. Clarke A, Price KL, Lummis S. Cytisine's lower potency at 5-HT3 receptors may explain its lower incidence of nausea and vomiting than varenicline. Presented at: Society for Research on Nicotine and Tobacco; September 17-18, 2020; European online conference.
  7. Boland VC, Mattick RP, McRobbie H, et al. "I'm not strong enough; I'm not good enough. I can't do this, I'm failing. Int J Equity Health. 2017;16 (1):196.

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Authors
Courtney, R. J., McRobbie, H., Tutka, P., Weaver, N. A., Petrie, D., Mendelsohn, C. P., Shakeshaft, A., Talukder, S., Macdonald, C., Thomas, D., Kwan, B. C. H., Walker, N., Gartner, C., Mattick, R. P., Paul, C., Ferguson, S. G., Zwar, N. A., Richmond, R. L., Doran, C. M., Boland, V. C., Hall, W., West, R., & Farrell, M.
Affiliations
  • UNSW Sydney (AU)
  • University of Rzeszów (PL)
  • University of Newcastle Australia (AU)
  • Monash University (AU)
  • No affiliation
  • Hunter Medical Research Institute (AU)
  • University of Auckland (NZ)
  • The University of Queensland (AU)
  • University of Tasmania (AU)
  • Bond University (AU)
  • Central Queensland University (AU)
  • University College London (GB)
Corresponding author
Courtney, Ryan J.
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2021-07-06
Volume
326
Issue
1
Pages
56
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2021.7621
PMC
PMC8261608
OpenAlex
W3179416241
Cited by
118
References
33
Citations by year
2026: 17 · 2025: 15 · 2024: 26 · 2023: 31 · 2022: 25 · 2021: 4
FWCI
13.51
Type
journal article
Language
en
Open access
Locations
  • JAMA (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UTAS Research Repository (acceptedVersion)
  • Bond University Research Portal (Bond University) (submittedVersion, other-oa)
  • Figshare (submittedVersion)
  • NOVA (University of Newcastle Australia) (submittedVersion)
  • JAMA Network Open
Funders
  • University of Nebraska Medical Center
  • Australian Government
  • University of New South Wales
  • National Institute of Allergy and Infectious Diseases (R01AI083188)
Topics
  • Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
  • Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Keywords
cytisine, varenicline, smoking cessation, non-inferiority, continuous abstinence, nicotine replacement therapy, adverse events, tobacco dependence, carbon monoxide breath test, daily smokers, treatment discontinuation, nicotine withdrawal symptoms, nicotine self-administration, nicotine sensitivity
MeSH terms
Varenicline, Smoking Cessation Agents, Quinolizidine Alkaloids, Adult, Alkaloids, Azocines, Dreams, Female, Humans, Male, Middle Aged, Nausea, Quinolizines, Smoking Cessation, Treatment Outcome

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