Novel psychoactive substances and psychosis: A comprehensive systematic review of epidemiology, clinical features, neurobiology, and treatment.

BACKGROUND: Novel psychoactive substances (NPS) have shown increasing prevalence worldwide, yet their relationship with psychotic disorders remains incompletely characterized despite growing clinical concern.

OBJECTIVE: To systematically evaluate the epidemiological evidence, clinical characteristics, neurobiological mechanisms, vulnerability factors, and management approaches for NPS-associated psychosis.

METHODS: A comprehensive systematic review following PRISMA guidelines was conducted across five major databases from January 2005 through December 2022. Quality assessment was performed using the Newcastle-Ottawa Scale and Joanna Briggs Institute checklist. Of 684 initially identified records, 85 studies met inclusion criteria, comprising case reports/series (n = 38), retrospective cohort studies (n = 25), cross-sectional studies (n = 10), case-control studies (n = 7), experimental studies (n = 3), and prospective cohort studies (n = 2).

RESULTS: Epidemiological evidence consistently suggested higher psychosis risk with NPS compared to traditional substances (OR 4.4-5.2 for synthetic cannabinoids versus cannabis). Distinctive clinical profiles emerged: synthetic cannabinoid-induced "spiceophrenia" featured visual hallucinations (73-84 %), agitation (79-91 %), and anxiety (62-76 %); cathinone-induced psychosis presented with extreme agitation (81-94 %) and stereotyped behaviors (47-63 %); phenethylamine-induced states showed perceptual disturbances including synesthesia (37-54 %). Neurobiological investigations indicated different mechanisms across substance classes. Key vulnerability factors included pre-existing psychiatric conditions, adolescent exposure, and polysubstance use.

CONCLUSION: NPS use is associated with elevated psychosis risk and distinctive clinical presentations across substance classes. Standardized assessment approaches and rigorous longitudinal investigations are needed to better establish causality, refine substance-specific treatment protocols, and develop targeted prevention strategies.