{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T13:29:34Z","timestamp":1781530174407,"version":"3.54.1"},"reference-count":75,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T00:00:00Z","timestamp":1758067200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background: Synthetic cannabinoid receptor agonists (SCRAs, commercially known as \u201cSpice\u201d) 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 (\u224877% 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\u201360 min, clinicians introduced a second-generation antipsychotic\u2014most commonly olanzapine, risperidone, or aripiprazole\u2014often 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.<\/jats:p>","DOI":"10.3390\/brainsci15091006","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T13:03:02Z","timestamp":1758114182000},"page":"1006","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinical Management of Synthetic-Cannabinoid-Induced Psychosis: A Systematic Review of Treatment Strategies and Outcomes"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3832-1398","authenticated-orcid":false,"given":"Alessio","family":"Mosca","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Imaging and Clinical Sciences, \u201cG. d\u2019 Annunzio\u201d University, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6810-1540","authenticated-orcid":false,"given":"Stefania","family":"Chiappini","sequence":"additional","affiliation":[{"name":"Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9EU, UK"},{"name":"School of Medicine, UniCamillus International University of Medical Sciences, Via di S. Alessandro 8, 00131 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2431-0460","authenticated-orcid":false,"given":"Andrea","family":"Miuli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Imaging and Clinical Sciences, \u201cG. d\u2019 Annunzio\u201d University, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2484-245X","authenticated-orcid":false,"given":"Clara","family":"Cavallotto","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Imaging and Clinical Sciences, \u201cG. d\u2019 Annunzio\u201d University, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4164-3040","authenticated-orcid":false,"given":"Mauro","family":"Pettorruso","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Imaging and Clinical Sciences, \u201cG. d\u2019 Annunzio\u201d University, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7292-2341","authenticated-orcid":false,"given":"Giovanni","family":"Martinotti","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Imaging and Clinical Sciences, \u201cG. d\u2019 Annunzio\u201d University, 66100 Chieti, Italy"},{"name":"Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9EU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4178-5401","authenticated-orcid":false,"given":"Fabrizio","family":"Schifano","sequence":"additional","affiliation":[{"name":"Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9EU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.coph.2021.02.008","article-title":"The e-psychonaut drugs\u2019 psychopharmacology","volume":"57","author":"Schifano","year":"2021","journal-title":"Curr. 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