Project Summary Methamphetamine dependence is a widespread problem that crosses socioeconomic boundaries and causes substantial medical morbidity and economic burden. This project uses genetics and neuroimaging techniques to investigate the neurobiology of addiction to methamphetamine as it relates to the TAAR1 trace amine receptor. We hypothesize that individuals with a common TAAR1 genetic variant (v288v) will have a blunted response to methamphetamine on tests of attention and cognitive control as well as on striato-limbic resting state functional connectivity (RSFC). SA 1. Determine the influence of htaar1 common variant (CV) vs. wild type (WT) genotype on RSFC and craving in chronic MUD. SA 2: Determine the effect of acute oral MA or placebo (PBO) administration on the interaction of htaar1 CV vs. WT genotype on RSFC, craving, cognitive control, attention and subjective experience in MUD. This project will consent and enroll up to 100 subjects who will be screened for TAAR1 genotype and placed into one of two groups: one which will include subjects who are wild type (WT) for the TAAR1 gene and those who are either homozygous or heterozygous for the CV, v288v. Others will be screened out of the study. A partner lab will determine genotype so that study staff and subjects will be blinded to genotype. Subjects will be administered methamphetamine and placebo in a blinded, randomized manner over two visits and evaluated with resting state fMRI, subjective effects and behavioral tasks. RSFC comparisons of meth versus placebo and comparisons of WT versus CV groups will be evaluated.