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

Abstract

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.