Towards precision psychiatry for cannabis use disorder: integrating endocannabinoid neurobiology, genetics, and therapeutic innovation

Abstract Cannabis use disorder (CUD) is a prevalent and chronic psychiatric condition characterized by impaired control over cannabis use, craving, withdrawal symptoms, and continued use despite negative consequences, potentially impairing social and occupational function. Despite increasing legalization and rising global prevalence, no pharmacotherapies are currently approved for CUD, highlighting an important unmet clinical need. Emerging evidence implicates dysregulation of the endocannabinoid system (ECS), particularly CB 1 receptor signaling and endocannabinoid metabolism, within cortico-striatal and stress-responsive circuits involved in addiction. Large-scale genomic studies further reveal polygenic vulnerability involving loci such as FOXP2 , NPTX1 , CHRNA2 , and PDE4B , suggesting the involvement of neurodevelopmental, glutamatergic, nicotinic, and neuroimmune mechanisms in CUD susceptibility. Together, these findings provide a biologically grounded framework for both therapeutic development and future patient stratification. Early-phase clinical trials of fatty acid amide hydrolase (FAAH) inhibitors, signaling-specific CB 1 modulators such as AEF0117, cannabidiol (CBD), and selected repurposed agents demonstrate proof-of-concept that mechanism-based interventions can attenuate withdrawal, craving, and cannabis reinforcement. Accumulating evidence also indicates substantial heterogeneity in CUD vulnerability and treatment response, influenced by factors including biological sex, age, psychiatric comorbidities, and patterns of cannabis use. Collectively, current findings support a biologically informed framework for therapeutic development and highlight the importance of understanding CUD heterogeneity. Continued integration of endocannabinoid, genetic, and clinical factors may facilitate future patient stratification, guide mechanism-based therapeutic development, and advance precision psychiatry research in CUD.