Currently, ∼17% of patients entering drug treatment has a diagnosis of Cannabis Use Disorder (CUD), yet few achieve sustained abstinence. Using an inpatient human laboratory model of CUD, we have shown that among daily cannabis smokers: (1) tobacco cigarette smokers have markedly higher rates of cannabis relapse in the laboratory relative to those who do not use tobacco (61% vs 15%), paralleling clinical evidence that tobacco and cannabis smokers have poorer CUD treatment outcome, (2) those who had their first tobacco cigarette prior to age 16 had higher rates of cannabis relapse after 7-days of tobacco cessation relative to those starting cigarettes at > 16 years (55% vs 21%), despite no differences in other tobacco- or cannabis-severity characteristics. When we compare cannabis relapse rates in this study as compared to our earlier study using closely similar procedures, we find that for those who started smoking cigarettes at > 16 years of age, 7 days of tobacco cessation was associated with rates of cannabis relapse as low as those seen in non-cigarette smokers. Yet for those who started smoking tobacco cigarettes earlier (<16 years of age), 7 days of tobacco cessation appeared to have no impact; cannabis relapse rates matched those seen in ongoing cigarette smokers. Thus, the age of first tobacco cigarette is a robust predictor of cannabis relapse following short-term tobacco cessation. It may be that the more intractable cannabis smokers (those initiating tobacco use early) require a longer period of tobacco cessation to impact cannabis relapse than later-onset tobacco/cannabis smokers. In mice, daily nicotine administration enhanced the abuse-related behavioral effects of stimulants and alcohol, and nicotine abstinence for 14 days reversed these effects. The objective of this renewal application is to test both the duration of smoking cessation prior to cannabis abstinence and age of tobacco onset on cannabis relapse. We will compare the effects of 7- and 21-days of tobacco cessation on cannabis relapse (assessed both in the laboratory and the natural ecology) in daily cigarette-smoking, cannabis smokers, with half the participants in each group initiating tobacco cigarette smoking early (<16 years) and the other half later (>16 years). Blood measures of histone acetylation will be collected at study onset and following 14 days of confirmed tobacco abstinence. We hypothesize that (1) later-onset tobacco smokers will have significantly lower cannabis relapse rates than early-onset tobacco smokers after 7- but not 21 days of tobacco cessation, (2) histone acetylation will decrease as a function of tobacco cessation. To date, clinical studies with cannabis and tobacco smokers have had patients quit both drugs concurrently, and have not reduced cannabis relapse. No studies to our knowledge have tested tobacco cessation prior to cannabis treatment, yet this may be a more effective approach to achieving long-term cannabis abstinence. The outcome...