This study will randomize 32 non-treatment-seeking individuals who smoke cigarettes daily into a randomized, crossover, double-blind, placebo-controlled study testing the safety, tolerability, and initial efficacy of Δ9-tetrahydrocannabivarin (Δ9-THCV).

The objective of this study is to examine the safety, tolerability, and initial efficacy of Δ9-tetrahydrocannabivarin (Δ9-THCV) in daily smokers. We will randomize 32 non-treatment-seeking adults who smoke cigarettes daily (50% female) into a randomized, double-blind, placebo-controlled, counter-balanced, within-subject human laboratory study of Δ9-THCV (10 mg oral) and matched placebo. Specifically, participants will complete two 5-day outpatient medication periods, with a 14-day washout period in between, during which they will receive either Δ9-THCV or placebo in a counter-balanced order, such that all participants will complete both medication conditions across the study. Following each 5-day medication period, participants will complete a laboratory study visit during which they will undergo the McKee Smoking Lapse Task to assess the ability to resist smoking, cigarette self-administration, craving, withdrawal, and subjective effects of nicotine. Total study participation will be approximately 4 weeks.

Inclusion Criteria:

1. Be between the ages of 21 and 65;
2. Smoke 10 or more combustible cigarettes per day;
3. Have fewer than 3 months of smoking abstinence in the past year;
4. Has self-reported ≥10 lifetime uses of cannabis products;
5. Have self-reported recent (past 3-month) use of cannabis products;
6. Agree to abstain from all other cannabinoid use during the study;
7. Agree to abstain from all other medication use during the study, other than methods of birth control as listed in inclusion criteria for female participants;
8. Agree to one of the following methods of birth control (if female), unless she or partner are surgically sterile: oral contraceptives, Contraceptive sponge, patch, double barrier, intrauterine contraceptive device, etonogestrel implant, medroxyprogesterone acetate contraceptive injection, hormonal vaginal contraceptive ring, complete abstinence from sexual intercourse.

Exclusion Criteria:

1. Have current (last 12 months) DSM-5 diagnosis of substance use disorder for any psychoactive substances other than nicotine;
2. Have a lifetime DSM-5 diagnosis of schizophrenia, bipolar disorder, or any other psychotic disorder;
3. Have a score of 3 or greater on the Columbia Suicide Severity Rating Scale (C-SSRS) at screening or anytime during study participation;
4. Have a positive urine screen for any substances, including cannabis
5. Have a breathalyzer reading above 0.000 g/dl;
6. Be pregnant, nursing, or planning to become pregnant while taking part in the study;
7. Have a medical condition that may interfere with safe study participation;
8. Have clinically significant abnormalities on the EKG;
9. Have evidence of renal impairment, defined by an eGFR value of <90 ml/min;
10. Have evidence of hepatic impairment, defined by a score of ≥5 points on the Child-Pugh assessment of liver function;
11. Exceed Grade 2 laboratory or vital sign abnormalities, based on FDA Guidance Document "Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials";
12. Have past month use of cannabis or cannabis products;
13. Have past month use of electronic nicotine delivery system (ENDS);
14. Have use of any medications (other than methods of birth control as listed in inclusion criteria for female participants) within 14 days or 5 half-lives (whichever is longer) prior to study drug administration, and throughout the study, including medication for smoking cessation, any prescription, OTC, dietary supplements, herbal products, or vitamins;
15. Have any other circumstances that, in the opinion of the investigators, would not be a good fit for study participation.