ABSTRACT Tobacco use is the leading cause of preventable death and disease in the United States. The majority of smokers report the desire to quit smoking; however only 3-5% of unaided quit attempts are successful; highlighting the need for TUD treatments. Currently, there are only three classes of FDA-approved pharmacotherapies for smoking cessation. While these medications have shown effectiveness in increasing abstinence during randomized clinical trials, the benefit of using such treatments decreases over the course of a year, and long-term quit rates rarely exceed 30%. Thus, innovations in treatment approaches are needed to reach further reductions in tobacco use. Δ9-Tetrahydrocannabivarin (Δ9-THCV) is a phytocannabinoid, which is thought to be a CB1 receptor antagonist and partial CB2 receptor agonist. Δ9-THCV has shown initial promise as a novel therapeutic for nicotine dependence and addictive disorders. Evidence from several animal models indicates that THCV reduces nicotine self-administration, reduces cue- and nicotine-induced relapse-like behavior, and improves nicotine withdrawal symptoms. The proposed study consists of a randomized, double- blind, counter-balanced, crossover human laboratory study of Δ9-Tetrahydrocannabivarin (Δ9-THCV) for daily smokers. A total of 32 daily smokers will complete two outpatient study visits after 5 days underΔ9-THCV and matched placebo, during which they will undergo a Smoking Lapse task to assess: (a) the ability to resist smoking, (b) cigarette smoking self-administration, (c) subjective craving, (d) withdrawal, and (e) subjective effects of nicotine. This study will test the initial efficacy of Δ9-THCV, which is essential for understanding the clinical potential of this naturally occurring cannabinoid as a treatment for smoking cessation. Given the wide prevalence cigarette use and the high acceptability of naturally-occurring products, such as cannabinoids, as therapeutic agents, the proposed study has the potential to be transformative in uncovering the therapeutic benefits of Δ9-THCV.