Written by Babatunde Carew
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Cytisinicline, given for 6 or 12 weeks with behavioral support, significantly increased smoking cessation rates and reduced nicotine cravings compared to placebo.
Turning over a new leaf – plant-based smoking cessation?
It’s well established that smoking cessation aids significantly improve quit rates. However, there remains a need for new and accessible options, particularly given the high cost of varenicline. Cytisinicline, a plant-derived agent with a similar mechanism of action to varenicline, has been used in parts of Europe for decades but is not yet FDA-approved in the U.S.
This phase 3, randomized, double-blind, placebo-controlled trial (ORCA-3) evaluated the effectiveness and safety of cytisinicline for tobacco cessation. A total of 792 adult smokers (≥10 cigarettes/day, motivated to quit) were randomized to receive cytisinicline (3 mg TID) for 6 weeks, 12 weeks, or placebo; all participants also received behavioral support. At end-of-treatment, biochemically verified abstinence was significantly higher in the cytisinicline groups (14.8% for 6-week, 30.3% for 12-week) compared to placebo (6.0% and 9.4%, respectively). Cytisinicline also led to greater sustained abstinence through 24 weeks and significantly reduced nicotine craving. Limitations include the short follow-up period and the lack of comparison to established therapies such as varenicline, bupropion, or nicotine replacement.
How does this change my practice?
Cytisinicline appears to be a promising option, and may even be effective for vaping cessation. However, some things remain to be seen. We need to see how it measures up to established smoking cessation aids rather than placebo in future studies. The TID dosing may affect real-world adherence compared to varenicline or bupropion, though its plant-based nature could appeal to patients seeking more “natural” alternatives. All that said, if cytisinicline gains FDA approval and proves to be more cost-effective than varenicline, it could emerge as a go-to smoking cessation aid.
Pro-tip: If Varenicline is cost prohibitive for a patient who smokes, try the costplusdrugs formulary, where a month’s supply can run from around 20-30 dollars.
Source
Cytisinicline for Smoking Cessation: The ORCA Phase 3 Replication Randomized Clinical Trial. JAMA Intern Med. 2025 Jun 1;185(6):648-655. doi: 10.1001/jamainternmed.2025.0628. PMID: 40257755
