Methamphetamine (METH) is a potent psychostimulant that disrupts cognitive and neurobiological functions in brain regions such as the prefrontal cortex (PFC) and hippocampus. Chronic METH use leads to altered synaptic plasticity, neuroinflammation, and mitochondrial dysfunction, contributing to methamphetamine use disorder (MUD). This study investigates gene expression changes following long-access intravenous METH self-administration in a rodent model. RNA sequencing (RNA-Seq) was conducted on PFC and hippocampal tissue to identify differentially expressed genes (DEGs) between METH-treated and control groups. We identified 41 DEGs in the PFC and 32 in the hippocampus, many involved in synaptic plasticity, immune response, and energy metabolism. Key findings included downregulation of mitochondrial function genes and upregulation of genes related to neural development and extracellular matrix organization, highlighting the profound transcriptional effects of METH. As a proof-of-concept, we explored individual gene expression variability in relation to economic demand for METH. Rats exhibiting higher demand showed distinct molecular profiles, including upregulation of genes linked to neural signaling and transcription regulation, such as