Background and Aims Cytisine 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.

Design Systematic review and meta-analysis following PRISMA guidelines (PROSPERO:CRD420251055773). We searched PubMed, CENTRAL, and Embase from inception to May 14, 2025.

Setting Seven randomized controlled trials conducted in Pakistan, Thailand, Kyrgyzstan, United Kingdom, Italy, and United States.

Participants 3,847 adult smokers aged ≥15 years (1,916 cytisine; 1,931 placebo). Mean age ranged from 38-57 years, with 24-70% female participation across studies.

Interventions Cytisine 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.

Measurements Primary outcome was biochemically-verified continuous abstinence at ≥24 weeks. Secondary outcomes included severe adverse events. We calculated risk ratios using random-effects models and explored heterogeneity through pre-specified subgroup analyses.

Findings Overall, 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 (β=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.

Conclusions Twelve-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.

The authors have declared no competing interest.

This study did not receive any funding

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