Cytisine for smoking cessation: A systematic review and meta-analysis suggesting potential benefits of extended treatment protocols

Background and AimsCytisine is an effective and affordable smoking cessation aid, but traditional 25-day tapering regimens may be suboptimal. We aimed to determine the optimal treatment duration and dosing pattern for cytisine through systematic review and meta-analysis of placebo-controlled trials. DesignSystematic review and meta-analysis following PRISMA guidelines (PROSPERO:CRD420251055773). We searched PubMed, CENTRAL, and Embase from inception to May 14, 2025. SettingSeven randomized controlled trials conducted in Pakistan, Thailand, Kyrgyzstan, United Kingdom, Italy, and United States. Participants3,847 adult smokers aged [&ge;]15 years (1,916 cytisine; 1,931 placebo). Mean age ranged from 38-57 years, with 24-70% female participation across studies. InterventionsCytisine monotherapy compared with placebo. Treatment durations included traditional 25-day (4 studies), 6-week (3 studies), and 12-week regimens (3 studies). Dosing patterns were categorized as declining-dose or fixed-dose throughout treatment. MeasurementsPrimary outcome was biochemically-verified continuous abstinence at [&ge;]24 weeks. Secondary outcomes included severe adverse events. We calculated risk ratios using random-effects models and explored heterogeneity through pre-specified subgroup analyses. FindingsOverall, cytisine significantly increased quit rates (RR=2.99, 95% CI: 1.78-5.00, p<0.001) with substantial heterogeneity (I2=88.2%). Subgroup analysis by duration revealed: 25-day regimens RR=2.00 (95% CI: 0.96-4.17, I2=78.9%), 6-week regimens RR=3.36 (95% CI: 2.51-4.49, I2=0%), and 12-week regimens RR=3.77 (95% CI: 2.92-4.88, I2=0%). Fixed-dose regimens (RR=3.71, 95% CI: 2.73-5.05, I2=0%) outperformed declining-dose regimens (RR=2.57, 95% CI: 1.31-5.04, I2=93.8%). Meta-regression showed a positive trend in the duration-response relationship ({beta}=0.069, p=0.217), though not statistically significant. The number needed to treat improved from 20 (25-day) to 6 (12-week regimen). Severe adverse events showed a small increase (RR=1.12, 95% CI: 1.01-1.24), with better tolerability in extended regimens. ConclusionsTwelve-week fixed-dose cytisine regimens nearly double the effectiveness of traditional 25-day protocols while maintaining favorable safety. These findings support updating clinical guidelines to recommend extended fixed-dose cytisine as standard care, offering an affordable alternative to varenicline with comparable efficacy.