Although tribes differ with regard to the use of alcohol and drugs, the U.S. Indian Health Service has cited substance abuse as one of the most urgent health problems facing Native Americans. Morbidity and mortality rates attributable to alcohol and drugs among certain segments of the Native American population are at epidemic levels. Survey data suggest that American Indian youths’ use of drugs is generally higher than any other ethnic group particularly for marijuana. Despite the devastating impact that alcohol and drugs has had in some tribes, how and why substance abuse is more prevalent in some Native American communities remains unclear. It appears from studies in the majority population that approximately 50-60% of the variance for drug dependence may be explained by genetic/biological factors. The overall objective of the research plan is to enhance understanding of the neurobehavioral risk factors for, and consequences of, marijuana use and use disorders in reservation dwelling Indians indigenous to San Diego county. A 33% lifetime prevalence rate for marijuana dependence, based on DSM IV, has been found in the currently assessed population. In addition to the already high rates of use and abuse, initiation of marijuana use during adolescence is particularly malignant for Mission Indians. Our current data demonstrate that Mission Indian adolescent users are highly significantly more likely to develop marijuana dependence when compared to young adults. Additionally, data are converging from a number of human and animal studies to suggest that adolescence, like the peri-natal period, is an epoch of high brain vulnerability to the toxic effects of drug exposure due to rapidly changing brain development. Thus, during adolescence drugs may be both more addicting and more neurotoxic, a combination that makes drug abuse particularly dangerous for adolescents. Studies are proposed in this application aimed at finding identifiable neurobiological (EEG, ERPs, candidate gene polymorphisms (FAAH, CNR1) and/or behavioral cognitive (neuropsychological measures of subjective effects) markers for those Native American youth who progress from marijuana use to abuse, and to dependence. As well as identify any long-term neuroadaptive changes in Mission Indians after repeated adolescent marijuana exposure as indexed by MRI, EEG, ERPs, neuropsyhchological and behavioral functioning. We believe these studies will not only allow for the indentification of factors associated with risk for and consequences of marijuana dependence in these tribes but eventually should also guide the development of prevention and intervention programs.