At this time, when 1 in 16 youth in the U.S. report daily cannabis use, research needs to identify and characterize individuals who are particularly vulnerable to start using cannabis and to accelerate to problem use. This competing renewal examines the effects of a lifetime history of tobacco smoking on early and later stages of cannabis involvement from a genetically informed perspective. The first phase of funding investigated the comorbidity between cannabis and tobacco involvement. Across 44 peer-reviewed publications, we identified the importance of shared genetic and environmental influences, the independent role of inhalation as a common route of administration and the emerging significance of cannabis withdrawal as a phenotype of clinical relevance. In this renewal, we focus on further understanding how tobacco smoking, which typically precedes cannabis use, modifies the course of cannabis involvement, from the earliest stages of opportunity to use cannabis to problematic stages of withdrawal and dependence. Keeping our genetically informed focus, we also conduct one the first studies of genomic influences on these early and late stages of cannabis involvement and building on our important finding of genetic overlap between tobacco smoking and various stages of cannabis involvement, we examine the extent to which peer drug use and traumatic life events moderate this relationship. This research is motivated by three important observations: (i) far too little is known of the etiology f cannabis involvement, including early stages such as initial reactions and later stages, such as withdrawal; (ii) tobacco smoking is a clear and particularly potent risk factor for cannabis involvement; and importantly, (iii) rates of cannabis use in the United States are on the rise, especially among youth, which begs further research in this area that can inform prevention and intervention efforts. Recognizing the need for a fine-grained study of cannabis involvement in the context of tobacco smoking, using two large twin datasets and a sample of non-twin siblings (N=9106), which include an extensive assessment of cannabis and tobacco involvement, as well as a rich array of covariates, including peer drug use and traumatic environments and candidate gene data, we examine: (a) whether tobacco smoking modifies the earliest stages of cannabis involvement including first opportunity to use cannabis, initial reactions to cannabis and other behaviors related to first use; (b) whether tobacco smoking alters severity and nature of cannabis withdrawal symptomatology and of other dependence and abuse criteria; (c) whether variants in endocannabinoid genes (CNR1, CNR2, FAAH and MAGL) exert a stronger influence on these early and later stages of cannabis involvement in tobacco smokers; and (d) whether the genetic overlap between tobacco smoking and cannabis involvement is moderated by peer drug use and traumatic life events. In summary, results from this renewal will be pivotal in informing prevention, intervention and treatment strategies that evolve to tackle these growing rates of cannabis use by recognizing the important contributions of tobacco smoking to its etiology. PUBLIC HEALTH RELEVANCE: This renewal focuses on the examination of the influence of tobacco smoking on early and later stages of cannabis involvement and investigates genetic influences on cannabis involvement in the context of tobacco smoking. As rates of cannabis use rise in youth, it is critical to identify factors that exacerbate the course of cannabis involvemen. Our study aims to identify the mechanisms by which tobacco smoking may modify the etiology of cannabis involvement and thus, contribute to future prevention, intervention and treatment efforts.