This CCC model has been most extensively applied to smoking and nicotine dependence27 and more recently to cannabis28,29. The results for nicotine demonstrate a moderate role of genetic factors in smoking initiation, a clear set of genes for nicotine dependence that ‘come on line’ only with smoking initiation (which could reflect changes in gene expression or physiology such that genes serving other functions now affect risk for nicotine dependence) and a moderate to strong relationship between these two stages. The genetic risk for smoking initiation is more highly correlated with the genetic risk for progression to nicotine dependence than many neurobiologists might think. Furthermore, shared environment (for example, rates of smoking in peers) typically affects smoking initiation but not the progression from initiation to dependence. Likewise, genetic risk for symptoms of cannabis abuse also ‘come on line’ conditional on cannabis initiation. Moreover, an extended version of the CCC model that includes ‘upstream’ environmental risk factors has shown that risk of cannabis initiation and subsequent progression to cannabis abuse can be explained, in part, by environmental factors influencing cannabis availability28. One
