PROJECT SUMMARY The goal of this project is to index individual resistance to psychoactive substance use (SU) during adolescence and use the indices to identify factors influencing resistance into early middle adulthood (30-40 years old), with a special focus on potentially modifiable factors. One possible cause for the limited success in reducing SU is a focus on factors that elevate risk for rather than resistance to SU. Although the risk and resistance aspects of liability to a disorder are symmetric, the respective factors are not. Factors enhancing resistance may more readily translate into prevention and treatment strategies. In addition, “environmental” variables, which are more likely to be modifiable than the genetic ones, may be confounded by the genetic influences. Failure to account for this confounding could hinder the detection of resistance factors. We address these limitations by measuring liability to SU/SUD in childhood/adolescence using previously collected and harmonizable data from the Virginia Twin Study of Adolescent and Behavioral Development (VTSABD; 1,214 twin pairs) and Minnesota Twin and Family Study (1,382 twin pairs), and assessing potential resistance factors. Long-term SU phenotype will be verified in a new wave of VTSABD data collection, where participants will be 30-50 years old. Aim 1. Develop continuous indices of resistance to SU and estimate genetic and environmental contributions to their variation. Two indices of SU resistance will be derived using a validated measure of childhood SU liability (Transmissible Liability Index) and SUD diagnosis in the same individuals as adults (verified in new Wave 7 SU data) to select psychological items measured in earlier waves. Two resistance indices will be generated via item response theory analysis: High Outset Resistance (based on items differentiating between low and average childhood SU liability) and High Realized Resistance (based on items distinguishing high and average childhood SU liability). Aim 2. Identify novel factors that have the highest probability of enhancing resistance to substance use. These factors will be sourced as most impactful on decisions related to substance use, using a Concept Mapping approach and existing data. Aim 3. Evaluate developmental trajectories of the resistance indices and SU outcomes while determining how these trajectories vary across levels of resistance factors. This will detail the influence of childhood/adolescent resistance on SU across the life course. This project will produce detail on potentially modifiable factors that can be targeted to reduce the likelihood of SU and addiction.