The primary objectives of Component 8 are to test key aspects of our unique theoretical model focused on neuroimmune mechanisms contributing to methamphetamine (MA) induced neuropsychiatric impairments, and to test our central hypothesis that immunomodulatory agents can promote brain healing and neuropsychiatric recovery following chronic MA dependence by reducing neuroinflammation and by addressing hyper-reactivity to neuroantigen. Specific Aim 1 - In humans, to identify peripheral immune factors most significantly impacted by chronic MA dependence and which correspond with MA induced neuropsychiatric impairments. Peripheral blood mononuclear cells (PBMCs) will be collected from humans who are non-dependent, actively using, and in early remission from MA dependence. Gene expression array analyses will be conducted to identify immune factors that are differentially expressed across groups and which correspond with cognitive and psychiatric symptom measures. Results will be compared with similar gene expression data collected from MA and saline exposed mice in Component 9. Specific Aim 2 - In humans, to fully characterize the effects of chronic MA dependence on peripheral immune cell function as measured by in vitro reactivity to neuroantigens and other antigens, and to characterize the relationship between MA induced neuropsychiatric impairment and altered peripheral immunoreactivity. PBMCs will be collected from humans who are non-dependent, actively using, and in early remission from MA dependence followed by stimulation with neuroantigens and other antigens, immune factor detection assays and cell proliferation experiments. Specific Aim 3 - In mice, to evaluate the therapeutic activity of one novel immunotherapy, [multiple antigenic (Ag) peptide (MAP)], in reducing MA induced neuropsychiatric impairments, central nervous system (CNS) injury, neuroinflammation, and trafficking of neuroantigen-reactive immune cells from the periphery to the CNS. Following saline versus repeated MA exposure, mice will be treated with MAP versus vehicle followed by memory and anxiety tests and brain and spleen collection and analysis.