Clinical Management of Synthetic-Cannabinoid-Induced Psychosis: A Systematic Review of Treatment Strategies and Outcomes

Background: Synthetic cannabinoid receptor agonists (SCRAs, commercially known as “Spice”) have become a leading cause of substance-induced psychosis worldwide. These compounds show strong associations not only with acute psychotic episodes but also, in a subset of patients, with persistent or relapsing psychotic disorders, patterns that raise concern about progression to schizophrenia. Yet clinicians still lack clear, evidence-based guidance, and the optimal management of SCRA-induced psychosis remains inadequately defined. Methods: We carried out a systematic search of PubMed, Scopus, and Web of Science on 2 April 2025, identifying 35 primary studies that together describe roughly 4600 clinical presentations (≈77% male; mean age: 24.7 years). Results: Across diverse settings a convergent three-step pharmacological strategy emerged. First, rapid tranquillization with parenteral benzodiazepines consistently controlled severe agitation and autonomic instability. Second, when florid psychosis persisted beyond 30–60 min, clinicians introduced a second-generation antipsychotic—most commonly olanzapine, risperidone, or aripiprazole—often at doses exceeding those used for primary psychoses. Third, for the minority of refractory or relapse-prone cases, escalation to long-acting injectable formulations or low-dose clozapine achieved symptom control, even at plasma levels below those required in treatment-resistant schizophrenia. Although the evidence base consists largely of uncontrolled clinical descriptions, across studies, a recurrent clinical pattern was observed: initial benzodiazepines for agitation, followed by antipsychotics when psychosis persisted and escalation to clozapine or long-acting injectables in refractory cases. This approach appears to be associated with symptom improvement, although the certainty of the evidence is low to very low. Conclusions. Prospective, comparative studies are urgently needed to refine dosing, directly compare antipsychotic classes, and evaluate emerging cannabinoid-modulating interventions.