The Cannabis-Psychosis Spectrum: Clinical Manifestations, Conversion Risk, and Therapeutic Strategies

Abstract

Cannabis-induced psychosis (CIP) represents a significant public health concern in the context of increasing global cannabis use and potency. This review synthesizes current evidence on the epidemiology, neurobiological mechanisms, clinical features, and treatment approaches for cannabis-induced psychotic disorders. Recent epidemiological data indicate rising incidence rates of CIP, with estimates ranging from 2.7 to 6.1 per 100,000 person-years in recent studies. The neurobiological mechanisms involve complex interactions between Δ9-tetrahydrocannabinol (THC) and the endocannabinoid system, affecting dopaminergic, GABAergic, and glutamatergic neurotransmission. Clinical manifestations typically include acute onset of paranoid delusions and hallucinations, often distinguishable from primary psychotic disorders by their temporal relationship to cannabis use and relatively preserved insight. Treatment remains challenging, with limited evidence-based guidelines, though second-generation antipsychotics and benzodiazepines show efficacy. The conversion rate to schizophrenia-spectrum disorders ranges from 33-50%, highlighting the importance of early identification and intervention. This review emphasizes the need for improved diagnostic criteria, treatment protocols, and prevention strategies as cannabis legalization continues worldwide.

Keywords

cannabis-induced psychosis / THC / cannabinoids / schizophrenia / epidemiology / neurobiology

References

[1] Peacock, A.; Leung, J.; Larney, S.; et al. Global statistics on alcohol, tobacco and illicit drug use:2017 status report. Addiction 2018, 113, 1905-1926.

[2] United Nations Office on Drugs and Crime.World Drug Report 2022; Sales No. E.22.XI.8; United Nations publication:New York, NY, USA, 2022.

[3] Freeman, T.P.; Groshkova, T.; Cunningham, A.; et al. Increasing potency and price of cannabis in Europe, 2006-2016. Addiction 2019, 114, 1015-1023.

[4] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed.; American Psychiatric Association: Washington, DC, USA, 2022.

[5] Hjorthøj, C.; Posselt, C.M.; Nordentoft, M. Development over time of the population-attributable risk fraction for cannabis use disorder in schizophrenia in Denmark. JAMA Psychiatry 2021, 78, 1013-1019.

[6] Arendt, M.; Rosenberg, R.; Foldager, L.; et al. Cannabis-induced psychosis and subsequent schizophrenia-spectrum disorders: Follow-up study of 535 incident cases. Br. J. Psychiatry 2005, 187, 510-515.

[7] Di Forti, M.; Quattrone, D.; Freeman, T.P.; et al. The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI): A multicentre case-control study. Lancet Psychiatry 2019, 6, 427-436.

[8] Schoeler, T.; Ferris, J.; Winstock, A.R. Rates and correlates of cannabis-associated psychotic symptoms in over 230,000 people who use cannabis. Transl. Psychiatry 2022, 12, 369.

[9] Chesney, E.; McGuire, P.; Freeman, T.P.; et al. Assessing cannabis use in people with psychosis. Cannabis Cannabinoid Res. 2024, 9, 49-58.

[10] Kucerova, J.; Tabiova, K.; Drago, F.; et al. Therapeutic potential of cannabinoids in schizophrenia. Recent Pat. CNS Drug Discov. 2014, 9, 13-25.

[11] Marco, E.M.; García-Gutiérrez, M.S.; Bermúdez-Silva, F.J.; et al. Endocannabinoid system and psychiatry: In search of a neurobiological basis for detrimental and potential therapeutic effects. Front. Behav. Neurosci. 2011, 5, 63.

[12] Pertwee, R.G. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br. J. Pharmacol. 2008, 153, 199-215.

[13] Skosnik, P.D.; Krishnan, G.P.; O’Donnell, B.F. The effect of cannabis use on neurocognition in people with schizophrenia: A systematic review. Schizophr. Res. 2016, 185, 142-147.

[14] Soares, V.P.; Campos, A.C. Evidences for the anti-panic actions of cannabidiol. Curr. Neuropharmacol. 2017, 15, 291-299.

[15] Lubman, D.I.; Cheetham, A.; Yücel, M. Cannabis and adolescent brain development. Pharmacol. Ther. 2015, 148, 1-16.

[16] Raver, S.M.; Haughwout, S.P.; Keller, A. Adolescent cannabinoid exposure permanently suppresses cortical oscillations in adult mice. Neuropsychopharmacology 2013, 38, 2338-2347.

[17] Hajos, N.; Katona, I.; Naiem, S.S.; et al. Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations. Eur. J. Neurosci. 2008, 12, 3239-3249.

[18] Skosnik, P.D.; Krishnan, G.P.; O’Donnell, B.F. The effect of cannabis use and schizotypy on electroencephalogram resting state networks. PsychiatryRes. Neuroimaging 2012, 202, 111-116.

[19] Caspi, A.; Moffitt, T.E.; Cannon, M.; et al. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: Longitudinal evidence of a gene X environment interaction. Biol. Psychiatry 2005, 57, 1117-1127.

[20] Grewal, R.S.; George, T.P. Cannabis-induced psychosis: A review. Psychiatr. Times 2020, 37, 13-15.

[21] Rentero, D.; Arias, F.; Sánchez-Romero, S.; et al. Cannabis-induced psychotic disorder and schizophrenia with cannabis use: Clinical differences and treatment outcomes. Eur. Psychiatry 2021, 64, S488-S489.

[22] Ricci, V.; Ceci, F.; Di Carlo, F.; et al. First episode psychosis with and without the use of cannabis and synthetic cannabinoids: Psychopathology, global functioning and suicidal ideation and antipsychotic effectiveness. Psychiatry Res. 2023, 320, 115053. https://doi.org/10.1016/j.psychres.2023.115053.

[23] Martinotti, G.; Chiappini, S.; Mosca, A.; et al. Atypical Antipsychotic Drugs in Dual Disorders: Current Evidence for Clinical Practice. Curr. Pharm. Des. 2022, 28, 2241-2259. https://doi.org/10.2174/1381612828666220623092853.

[24] Ricci, V.; Ciavarella, M.C.; Marrangone, C.; et al. Modern perspectives on psychoses: Dissociation, automatism, and temporality across exogenous and endogenous dimensions. Front. Psychiatry 2025, 16, 1543673. https://doi.org/10.3389/fpsyt.2025.1543673.

[25] Martinotti, G.; Di Forti, M. Cannabis use and psychosis: Evidence and new clinical features of a new epidemic. Eur. Neuropsychopharmacol. 2025, 91, 45-46. https://doi.org/10.1016/j.euroneuro.2024.11.007.

[26] Caton, C.L.; Hasin, D.S.; Shrout, P.E.; et al. Risk factors for homelessness among indigent urban adults with no history of psychotic illness: A case-control study. Am. J. Public Health 2005, 95, 1020-1025.

[27] Rubio, G.; Martínez-Gras, I.; Manzanares, J. Modulation of impulsivity by topiramate: Implications for the treatment of alcohol dependence. J. Clin. Psychopharmacol. 2012, 32, 584-585.

[28] Rabin, R.A.; Zakzanis, K.K.; George, T.P. The effects of cannabis use on neurocognition in schizophrenia: A meta-analysis. Schizophr. Res. 2017, 185, 142-147.

[29] Baldacchino, A.; Hughes, Z.; Kehoe, M.; et al. Cannabis psychosis and paranoia. In Handbook of Cannabis and Related Pathologies; Academic Press: Cambridge, MA, USA 2012; pp. 295-308.

[30] Gorelick, D.A. Pharmacological treatment of cannabis-related disorders: A narrative review. CNS Drugs 2016, 30, 777-791.

[31] Martinotti, G.; De Risio, L.; Vannini, C.; et al. Substance-related exogenous psychosis: A postmodern syndrome. CNS Spectr. 2021, 26, 84-91. https://doi.org/10.1017/S1092852920001479.

[32] Pisanu, A.; Acquas, E.; Fenu, S.; et al. Real world clinical outcomes of treatment of cannabis-induced psychosis and prevalence of cannabis-related primary psychosis: A retrospective study. BMC Psychiatry 2024, 24, 494.

[33] Ricci, V.; De Berardis, D.; Maina, G. Third-Generation Antipsychotics and Lurasidone in the Treatment of Substance-Induced Psychoses: A Narrative Review. Healthcare 2024, 12, 339. https://doi.org/10.3390/healthcare12030339.

[34] Aggarwal, M.; Chand, P.; Srivastava, S.; et al. Cannabis induced psychosis and subsequent psychiatric disorders. Asian J. Psychiatry 2017, 30, 180-184.

[35] Nielsen, S.; Gowing, L.; Sabioni, P.; et al. Pharmacotherapies for cannabis dependence. Cochrane Database Syst. Rev. 2019, 1, CD008940.

[36] Mason, B.J.; Crean, R.; Goodell, V.; et al. A proof-of-concept randomized controlled study of gabapentin: Effects on cannabis use, withdrawal and executive function deficits in cannabis-dependent adults. Neuropsychopharmacology 2012, 37, 1689-1698.

[37] Gray, K.M.; Sonne, S.C.; McClure, E.A.; et al. A randomized placebo-controlled trial of N-acetylcysteine for cannabis use disorder in adults. Drug Alcohol Depend. 2017, 177, 249-257.

[38] Batalla, A.; Janssen, H.; Gangadin, S.S.; et al. The potential of cannabidiol as a treatment for psychosis and addiction: Who benefits most? A systematic review. J. Clin. Med. 2019, 8, 1058.

[39] Leweke, F.M.; Piomelli, D.; Pahlisch, F.; et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl. Psychiatry 2012, 2, e94.

[40] Wall, M.B.; Pope, R.; Freeman, T.P.; et al. Dissociable effects of cannabis with and without cannabidiol on the human brain’s resting-state functional connectivity. J. Psychopharmacol. 2019, 33, 822-830.

[41] Niemi-Pynttäri, J.A.; Sund, R.; Putkonen, H.; et al. Substance-induced psychoses converting into schizophrenia: A register-based study of 18,478 Finnish inpatient cases. J. Clin. Psychiatry 2013, 74, e94-e99.

[42] Starzer MS, K.; Nordentoft, M.; Hjorthøj, C. Rates and predictors of conversion to schizophrenia or bipolar disorder following substance-induced psychosis. Am. J. Psychiatry 2018, 175, 343-350.

[43] Crocker, C.E.; Emsley, J.; Tibbo, P.G. Mental health adverse events with cannabis use diagnosed in the Emergency Department: What are we finding now and are our findings accurate? Front. Psychiatry 2023, 14, 1093081.