Breaking the cycle: a systematic review of neurobiological mechanisms and psychotherapeutic innovations in ketamine addiction.

This systematic review synthesizes current evidence on non-prescribed ketamine use, emphasizing its neurobiological impacts and psychotherapeutic interventions. Patterns of misuse demonstrate the complex interplay of neurobiological, socio-economic, demographic and psychological factors with adolescents, women and polysubstance users identified as high-risk groups. Neurobiological findings highlight prefrontal-limbic dysconnectivity, maladaptive neuroplasticity alongside hypothalamic-pituitary-adrenal (HPA) axis dysregulation as central mechanisms underlying this addiction. The review evaluates the comparative efficacy of psychotherapies whilst proposing an innovative framework that aligns therapeutic timing with neuroplastic recovery phases. Emerging evidence identifies biomarkers, e.g., brain-derived neurotrophic factor (BDNF) and heart rate variability (HRV), as promising tools for guiding personalized and phase-specific interventions. Gaps in research include the limited representation of low-resource settings and insufficient longitudinal data on biomarker integration and therapy sequencing. Recommendations propose a comprehensive neurobiologically informed model which carefully integrates digital platforms, culturally tailored strategies and biomarkers to enhance treatment outcomes.