Up to 46% of chronic methamphetamine users develop psychotic symptoms, creating an urgent need for therapeutic interventions that address the underlying neurobiological damage. Current treatments remain limited, leaving many patients with persistent cognitive deficits and anxiety disorders that severely impact quality of life. New preclinical research reveals that cannabidiol operates through a previously unrecognized mechanism involving sigma-1 receptors to restore mitochondrial function in brain regions critical for memory and emotional regulation. The study demonstrates that 40 mg/kg CBD administration significantly reduced anxiety-like behaviors and cognitive impairments in methamphetamine-exposed mice. Network pharmacology analysis identified the sigma-1 receptor pathway as a key target, with CBD directly binding to these receptors and preventing the cascade of mitochondrial dysfunction that drives psychotic symptoms. Molecular dynamics simulations and surface plasmon resonance confirmed this direct interaction, while cellular studies showed CBD's ability to reduce neuronal damage, normalize calcium levels, and restore mitochondrial membrane potential in hippocampal tissue. This finding represents a significant advance in understanding how plant-derived compounds can target specific receptor systems to reverse drug-induced neurological damage. The sigma-1 receptor pathway has emerged as a promising therapeutic target across multiple psychiatric conditions, and this research provides the first detailed mechanistic evidence for CBD's neuroprotective effects in methamphetamine toxicity. However, the translation from animal models to human clinical applications remains uncertain, particularly regarding optimal dosing and long-term safety profiles in vulnerable populations with substance use disorders.