Although cytochrome P450-2D6 (CYP2D6) is the primary enzyme responsible for methamphetamine (meth) metabolism, no work has been conducted outside of our group on its role in meth-related brain dysfunction. Our preliminary data with a small sample suggests that genetic differences coding for the activity of CYP2D6 are associated with differential vulnerability to neurocognitive problems in meth users. Individuals with genotypes corresponding to diminished metabolism seem to incur less neuropsychological impairment than those with normal metabolism. This is an intriguing finding, as it implicates the metabolic products of methamphetamine in brain injury. It also suggests that certain individuals are at increased risk of meth-related brain problems. Our group has described additive negative effects of meth, HIV, and hepatitis C (HCV) on brain function. There is evidence that liver disease, such as in HCV, as well as HIV, may alter CYP2D6 activity such that the genotype does not always correspond with the actual metabolic activity phenotype. Additionally, serotonin reuptake inhibitors for depression, which are very widely prescribed, are also substrates and inhibitors of CYP2D6 and thus may affect methamphetamine metabolism if taken concurrently. Finally, the antiretroviral ritonavir, used to boost the majority of cART regimens, is also a CYP2D6 inhibitor, and there are reports in the literature of prolonged psychoactive drug effects in HIV patients taking this medicine. As a first step in understanding whether CYP2D6 variants truly contribute to brain dysfunction associated with meth, we propose to generate CYP2D6 genotypes to replicate the small study referenced above with a large sample, and perform deep data analysis to understand the complexities that may mitigate the relationship between drug metabolism and cognitive outcomes. To do this, we propose to leverage an incredible resource in the form of stored samples that are accompanied by extensive clinical characterization collected from a number of projects funded by NIDA and NIMH over the past 15 years, which likely constitute the largest collection of well- characterized methamphetamine dependent cases available anywhere. Findings could lead to pharmacologic interventions to reduce brain injury as well as inform treatment choices for meth users with HIV or HCV infection.