Tobacco use disorder (TUD) remains a leading cause of preventable mortality, and existing pharmacotherapies yield 12-month abstinence rates below 30%. As cannabis legalization expands, approximately 18-22% of people who use tobacco report concurrent cannabis use, yet the impact of co-use on cessation outcomes and the therapeutic potential of endocannabinoid system (ECS) modulation remain unclear. We conducted a translational systematic review and meta-analysis following PRISMA 2020 guidelines, searching Ovid MEDLINE, Embase, APA PsycInfo, and Web of Science through January 2026 (PROSPERO: CRD420250652724). Three study categories were eligible: observational studies of cannabis co-use and cessation outcomes; preclinical studies of cannabinoid modulators on nicotine-related behaviors; and human experimental studies of ECS-targeted interventions. Of 4,869 records screened, 52 studies met inclusion criteria. Meta-analysis of 18 observational studies (N=229,630) revealed that cannabis use was associated with 35% lower odds of achieving tobacco smoking cessation (OR=0.65; 95% CI: 0.55-0.78; p<0.0001; I²=88.1%). Preclinical evidence (15 studies) demonstrated that CB1 receptor antagonists robustly reduced nicotine self-administration and reinstatement, while cannabidiol (CBD) attenuated both nicotine intake and withdrawal without affecting food reinforcement. Clinical translation of CB1 receptor inverse agonists failed due to psychiatric adverse effects, but CBD showed promise by reducing cigarette consumption by 40%, reversing attentional bias to smoking cues, and alleviating withdrawal severity. These findings distinguish naturalistic cannabis exposure from potentially beneficial targeted ECS modulation, and support CBD as a promising candidate for adequately powered tobacco cessation trials.

Dr. De Aquino has received research support from Jazz Pharmaceuticals and Ananda Scientific and has served as a paid consultant for Boehringer Ingelheim. The remaining authors declare no conflict of interest.

This work was supported by the grant K23DA052682 from the National Institute on Drug Abuse (NIDA) to Dr. De Aquino. The other authors received no specific funding for this work.

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Funding: This work was supported by the grant K23DA052682 from the National Institute on Drug Abuse (NIDA) to Dr. De Aquino. The other authors received no specific funding for this work.

Competing Interests: Dr. De Aquino has received research support from Jazz Pharmaceuticals and Ananda Scientific and has served as a paid consultant for Boehringer Ingelheim. The remaining authors declare no conflict of interest.

All data generated or analyzed during this study are included in this published article and its supplementary information files. The raw data used for meta-analyses are available from the corresponding author upon reasonable request.