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

Non-prescribed ketamine use involves complex interactions of neurobiological, socioeconomic, demographic, and psychological factors, with adolescents, women, and polysubstance users at higher risk. Neurobiological mechanisms include prefrontal-limbic dysconnectivity, maladaptive neuroplasticity, and HPA axis dysregulation. Psychotherapies show varying efficacy, and an innovative framework aligns therapeutic timing with phases of neuroplastic recovery. Biomarkers such as BDNF and HRV may guide personalized interventions. Research gaps include limited representation of low-resource settings and insufficient longitudinal data. A comprehensive neurobiologically informed model integrating digital platforms, culturally tailored strategies, and biomarkers is recommended to improve treatment outcomes.

Study at a glance

Abstract

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.