Antipsychotic Potential of Opioids: Rethinking Substance-Induced Psychosis and Treatment Stratification
Abstract
1. Introduction
2. The Opioid Exception in Substance-Induced Psychosis
3. Psychosis Associated with Methadone Withdrawal
4. Psychosis Associated with Buprenorphine Withdrawal
5. Psychosis Associated with Heroin and Other Prescription Opioid Withdrawal
6. Psychosis Associated with Opioid Intoxication
7. Mechanistic Hypotheses: Opioid Modulation of Psychosis
8. Clinical Observations from the Pisa School of Addiction Medicine
9. Therapeutic Implications: A New Role for Antipsychotics in Dual Diagnosis
10. Conclusions and Recommendations
- In patients with opioid use and comorbid psychosis,
- Carefully assess the temporal association between opioid withdrawal and the onset of psychotic symptoms;
- Prioritize the reinstatement or optimization of opioid agonist therapy (e.g., consider switching from buprenorphine to methadone when appropriate);
- Reserve antipsychotic treatment for persistent symptoms. In adherent patients, clozapine may be considered. Otherwise, second- or third-generation antipsychotics with partial D2 agonism or rapid D2 dissociation profiles are preferable.
- In patients with primary psychotic disorders and no opioid involvement,
- Consider clozapine in compliant patients under appropriate medical supervision. Alternatively, initiate treatment with second- or third-generation antipsychotics, taking into account their receptor binding profiles and side-effect burden.
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Wilson, L.; Szigeti, A.; Kearney, A.; Clarke, M. Clinical characteristics of primary psychotic disorders with concurrent substance abuse and substance-induced psychotic disorders: A systematic review. Schizophr. Res. 2018, 197, 78–86. [Google Scholar] [CrossRef] [PubMed]
- Fiorentini, A.; Cantu, F.; Crisanti, C.; Cereda, G.; Oldani, L.; Brambilla, P. Substance-Induced Psychoses: An Updated Literature Review. Front. Psychiatry 2021, 12, 694863. [Google Scholar] [CrossRef]
- DeQuardo, J.R.; Carpenter, C.F.; Tandon, R. Patterns of substance abuse in schizophrenia: Nature and significance. J. Psychiatr. Res. 1994, 28, 267–275. [Google Scholar] [CrossRef] [PubMed]
- A.P.A. Schizophrenia spectrum and other psychotic disorders. In Diagnostic and Statistical Manual of Mental Disorders; American Psychiatric Association Publishing: Washington, DC, USA, 2013; Volume 5. [Google Scholar]
- Maremmani, A.G.I.; Rovai, L.; Rugani, F.; Bacciardi, S.; Dell’Osso, L.; MAremmani, I. Substance abuse and psychosis. The strange case of opioid. Eur. Rev. Med. Pharmacol. Sci. 2014, 18, 287–302. [Google Scholar] [PubMed]
- Lozano-Lopez, M.T.; Gamonal-Limcaoco, S.; Casado-Espada, N.; Aguilar, L.; Vicente-Hernandez, B.; Grau-Lopez, L.; Alvarez-Navares, A.; Roncero, C. Psychosis after buprenorphine, heroin, methadone, morphine, oxycodone, and tramadol withdrawal: A systematic review. Eur. Rev. Med. Pharmacol. Sci. 2021, 25, 4554–4562. [Google Scholar] [CrossRef] [PubMed]
- Pinho, M.; Martins, D.O.; Coutinho, F. Methadone Withdrawal-Related Psychosis in a Patient with Hormone-Dependent Breast Cancer: A Case Report. Cureus 2023, 15, e51240. [Google Scholar] [CrossRef]
- Cobo, J.; Ramos, M.M.; Pelaez, T.; Garcia, G.; Marsal, F. Psychosis related to methadone withdrawal. Acta Neuropsychiatr. 2006, 18, 50–51. [Google Scholar] [CrossRef]
- Oke, O.; Sekh, M.B.; Johnson, B.O.; Adeyemo, S. Methadone Withdrawal-Induced Psychosis: A Case Report. Cureus 2024, 16, e55256. [Google Scholar] [CrossRef]
- Levinson, I.; Galynker, I.I.; Rosenthal, R.N. Methadone withdrawal psychosis. J. Clin. Psychiatry 1995, 56, 73–76. [Google Scholar] [CrossRef]
- Brizer, D.A.; Hartman, N.; Sweeney, J.; Millman, R.B. Effect of methadone plus neuroleptics on treatment-resistant chronic paranoid schizophrenia. Am. J. Psychiatry 1985, 142, 1106–1107. [Google Scholar] [CrossRef]
- Lin, Y.; Zhang, A.D.; Sun, C.F.; White, J.B.; Qi, A.; Farrell, J.A.; Trestman, R.L.; Martin, R.K.; Kablinger, A.S. New-Onset Psychotic Symptoms Following Abrupt Buprenorphine/Naloxone Discontinuation in a Female Patient with Bipolar Disorder: A Case Report. Psychopharmacol. Bull. 2022, 52, 72–80. [Google Scholar]
- Navkhare, P.; Kalra, G.; Saddichha, S. Possible Psychosis Associated with Buprenorphine Withdrawal. J. Clin. Psychopharmacol. 2017, 37, 748–749. [Google Scholar] [CrossRef] [PubMed]
- Weibel, S.; Mallaret, M.; Bennouna-Greene, M.; Bertschy, G. A case of acute psychosis after buprenorphine withdrawal: Abrupt versus progressive discontinuation could make a difference. J. Clin. Psychiatry 2012, 73, e756. [Google Scholar] [CrossRef] [PubMed]
- Karila, L.; Berlin, I.; Benyamina, A.; Reynaud, M. Psychotic symptoms following buprenorphine withdrawal. Am. J. Psychiatry 2008, 165, 400–401. [Google Scholar] [CrossRef] [PubMed]
- Schmauss, C.; Yassouridis, A.; Emrich, H.M. Antipsychotic effect of buprenorphine in schizophrenia. Am. J. Psychiatry 1987, 144, 1340–1342. [Google Scholar] [CrossRef] [PubMed]
- Sharma, S.; Kumar, P.; Singh, R.; Sidhu, G.S.; Shah, K. Psychotic Symptoms in Heroin Withdrawal: A Case Report. Cureus 2021, 13, e12620. [Google Scholar] [CrossRef]
- Freye, E.; Levy, J. Acute abstinence syndrome following abrupt cessation of long-term use of tramadol (Ultram): A case study. Eur. J. Pain. 2000, 4, 307–311. [Google Scholar] [CrossRef] [PubMed]
- Senay, E.C.; Adams, E.H.; Geller, A.; Inciardi, J.A.; Munoz, A.; Schnoll, S.H.; Woody, G.E.; Cicero, T.J. Physical dependence on Ultram (tramadol hydrochloride): Both opioid-like and atypical withdrawal symptoms occur. Drug Alcohol. Depend. 2003, 69, 233–241. [Google Scholar] [CrossRef] [PubMed]
- Rajabizadeh, G.; Kheradmand, A.; Nasirian, M. Psychosis following Tramadol Withdrawal. Addict. Health 2009, 1, 58–61. [Google Scholar]
- Casado-Espada, N.M.; Martin, C.; De La Iglesia-Larrad, J.I.; De Alarcon, R.; Fombellida, C.I.; Fernandez-Martin, L.C.; Roncero, C. Psychotic symptoms following oxycodone withdrawal, case report and update. Eur. Rev. Med. Pharmacol. Sci. 2019, 23, 6315–6320. [Google Scholar] [CrossRef]
- Aiyer, R.; Jain, V.; Bhatia, A.; Mekinulov, B.; Gungor, S. Rare presentation of intrathecal morphine withdrawal psychosis. Pain Manag. 2017, 7, 171–173. [Google Scholar] [CrossRef]
- Tumenta, T.; Thanju, A.; Perera, P.; Kallikkadan, J.; Fouron, P.; Olupona, T. Opioid-Induced Psychosis in a Patient with Sickle Cell Disease. Cureus 2021, 13, e15557. [Google Scholar] [CrossRef]
- Dhanabalan, A.; Saveen, S.; Singh, C.; Ramasamy, R.; Raveendran, K. Opioid-Induced Hallucinations: A Case Report. Cureus 2024, 16, e74915. [Google Scholar] [CrossRef]
- Powell, D.H. A pilot study of occasional heroin users. Arch. Gen. Psychiatry 1973, 28, 586–594. [Google Scholar] [CrossRef] [PubMed]
- Khantzian, E.J.; Mack, J.E.; Schatzberg, A.F. Heroin use as an attempt to cope: Clinical observations. Am. J. Psychiatry 1974, 131, 160–164. [Google Scholar] [CrossRef] [PubMed]
- McKenna, G.J. Methadone and opiate drugs: Psychotropic effect and self-medication. Ann. N. Y. Acad. Sci. 1982, 398, 44–55. [Google Scholar] [CrossRef] [PubMed]
- Gold, M.S.; Donabedian, R.K.; Dillard, M., Jr.; Slobetz, F.W.; Riordan, C.E.; Kleber, H.D. Antipsychotic effect of opiate agonists. Lancet 1977, 2, 398–399. [Google Scholar] [CrossRef]
- Abi-Dargham, A. Relevance of the Kappa Dynorphin System to Schizophrenia and Its Therapeutics. J. Psychiatr. Brain Sci. 2021, 6, e210015. [Google Scholar] [CrossRef]
- Adler, M.W. Multiple opiate receptors and their different ligand profiles. Ann. N. Y. Acad. Sci. 1982, 398, 340–351. [Google Scholar] [CrossRef] [PubMed]
- Ros-Cucurull, E.; Miquel, L.; Franco, M.Q.; Casas, M. Reduction of psychotic symptoms during the use of exogenous opiates. Heroin Addict. Relat. Clin. Probl. 2012, 14, 57–58. [Google Scholar]
- Lone, B.B.; Jan, N.; Kousar, M.U.; Bhat, F.R.; Rather, Y.H.; Rasool, U. A study of predictors of retention to naltrexone maintenance therapy in patients with opioid use disorder: A prospective study. Middle East Curr. Psychiatry 2024, 31, 61. [Google Scholar] [CrossRef]
- Maremmani, I.; Pacini, M.; Pani, P.P.; Popovic, D.; Romano, A.; Maremmani, A.G.I.; Deltito, J.; Perugi, G. Use of “Street Methadone” in Italian Heroin Addicts Presenting for Opioid Agonist Treatment. J. Addict. Dis. 2009, 28, 382–388. [Google Scholar] [CrossRef] [PubMed]
- Maremmani, A.G.I.; Bacciardi, S.; Rovai, L.; Rugani, F.; Dell’Osso, L.; Maremmani, I. Natural history of addiction in psychotic heroin addicted patients at their first Agonist Opioid Treatment. Addict. Disord. Their Treat. 2012, 12, 31–39. [Google Scholar] [CrossRef]
- Maremmani, A.G.I.; Dell’Osso, L.; Pacini, M.; Popovic, D.; Rovai, L.; Torrens, M.; Perugi, G.; Maremmani, I. Dual diagnosis and chronology of illness in 1090 treatment seeking Italian heroin dependent patients. J. Addict. Dis. 2011, 30, 123–135. [Google Scholar] [CrossRef] [PubMed]
- Khantzian, E.J. The self-medication hypothesis of addictive disorders: Focus on heroin and cocaine dependence. Am. J. Psychiatry 1985, 142, 1259–1264. [Google Scholar] [CrossRef]
- Pacini, M.; Maremmani, I. Methadone reduces the need for antipsychotic and antimanic agents in heroin addicts hospitalized for manic and/or acute psychotic episodes. Heroin Addict. Relat. Clin. Probl. 2005, 7, 43–48. [Google Scholar]
- Maremmani, A.G.; Rugani, F.; Bacciardi, S.; Rovai, L.; Massimetti, E.; Gazzarrini, D.; Dell’Osso, L.; Maremmani, I. Differentiating between the course of illness in bipolar 1 and chronic-psychotic heroin-dependent patients at their first agonist opioid treatment. J. Addict. Dis. 2015, 34, 43–54. [Google Scholar] [CrossRef]
- Maremmani, A.G.I.; Rovai, L.; Pani, P.P.; Pacini, M.; Lamanna, F.; Rugani, F.; Schiavi, E.; Dell’Osso, L.; Maremmani, I. Do methadone and buprenorphine have the same impact on psychopathological symptoms of heroin addicts? Ann. Gen. Psychiatry 2011, 10, 17. [Google Scholar] [CrossRef]
- Ceraso, A.; Lin, J.J.; Schneider-Thoma, J.; Siafis, S.; Tardy, M.; Komossa, K.; Heres, S.; Kissling, W.; Davis, J.M.; Leucht, S. Maintenance treatment with antipsychotic drugs for schizophrenia. Cochrane Database Syst. Rev. 2020, 8, CD008016. [Google Scholar] [CrossRef]
- Maremmani, A.G.I.; Pani, P.P.; Rovai, L.; Bacciardi, S.; Rugani, F.; Dell’Osso, L.; Pacini, M.; Maremmani, I. The effects of agonist opioids on the psychopathology of opioid dependence. Heroin Addict. Relat. Clin. Probl. 2013, 15, 47–56. [Google Scholar]
- Rovai, L.; Maremmani, A.G.I.; Pacini, M.; Pani, P.P.; Rugani, F.; Lamanna, F.; Schiavi, E.; Mautone, S.; Dell’Osso, L.; Maremmani, I. Negative dimension in psychiatry. Amotivational syndrome as a paradigm of negative symptoms in substance abuse. Riv. Psichiatr. 2013, 48, 1–9. [Google Scholar] [CrossRef]
- Malandain, L.; Leygues, M.; Thibaut, F. Antipsychotic drug dose in real-life settings results from a Nationwide Cohort Study. Eur. Arch. Psychiatry Clin. Neurosci. 2022, 272, 583–590. [Google Scholar] [CrossRef] [PubMed]
- Wobrock, T.; Soyka, M. Pharmacotherapy of patients with schizophrenia and substance abuse. Expert Opin. Pharmacother. 2009, 10, 353–367. [Google Scholar] [CrossRef] [PubMed]
- Seeman, P. Clozapine, a fast-off-D2 antipsychotic. ACS Chem. Neurosci. 2014, 5, 24–29. [Google Scholar] [CrossRef] [PubMed]
- Temmingh, H.S.; Williams, T.; Siegfried, N.; Stein, D.J. Risperidone versus other antipsychotics for people with severe mental illness and co-occurring substance misuse. Cochrane Database Syst. Rev. 2018, 1, CD011057. [Google Scholar] [CrossRef]
- Skryabin, V.Y.; Vinnikova, M.A.; Ezhkova, E.V.; Titkov, M.S.; Bulatova, R.A. Atypical antipsychotics in the treatment of patients with a dual diagnosis of schizophrenia spectrum disorders and substance use disorders: The results of a randomized comparative study. J. Addict. Dis. 2021, 39, 513–525. [Google Scholar] [CrossRef]
- Saklad, S.R. Graphic representation of pharmacology: Development of an alternative model. Ment. Health Clin. 2017, 7, 201–206. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef]
- Rafizadeh, R.; Danilewitz, M.; Bousman, C.A.; Mathew, N.; White, R.F.; Bahji, A.; Honer, W.G.; Schutz, C.G. Effects of clozapine treatment on the improvement of substance use disorders other than nicotine in individuals with schizophrenia spectrum disorders: A systematic review and meta-analysis. J. Psychopharmacol. 2023, 37, 135–143. [Google Scholar] [CrossRef]
- Rafizadeh, R.; Frankow, L.; Mahmood, H.; Poonia, S.; Mathew, N.; Danilewitz, M.; Bousman, C.A.; Honer, W.G.; Schutz, C.G. Association of clozapine treatment and rate of methamphetamine or amphetamine relapses and abstinence among individuals with concurrent schizophrenia spectrum and amphetamine use disorder: A retrospective cohort study. J. Psychopharmacol. 2023, 37, 1040–1048. [Google Scholar] [CrossRef]
- Brunette, M.F.; Drake, R.E.; Xie, H.; McHugo, G.J.; Green, A.I. Clozapine use and relapses of substance use disorder among patients with co-occurring schizophrenia and substance use disorders. Schizophr. Bull. 2006, 32, 637–643. [Google Scholar] [CrossRef]
- Baldacara, L.; Ramos, A.; Castaldelli-Maia, J.M. Managing drug-induced psychosis. Int. Rev. Psychiatry 2023, 35, 496–502. [Google Scholar] [CrossRef] [PubMed]
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Maremmani, A.G.I.; Della Rocca, F.; Bacciardi, S.; Carbone, M.G.; Maremmani, I. Antipsychotic Potential of Opioids: Rethinking Substance-Induced Psychosis and Treatment Stratification. J. Clin. Med. 2025, 14, 5596. https://doi.org/10.3390/jcm14155596
Maremmani AGI, Della Rocca F, Bacciardi S, Carbone MG, Maremmani I. Antipsychotic Potential of Opioids: Rethinking Substance-Induced Psychosis and Treatment Stratification. Journal of Clinical Medicine. 2025; 14(15):5596. https://doi.org/10.3390/jcm14155596
Chicago/Turabian StyleMaremmani, Angelo G. I., Filippo Della Rocca, Silvia Bacciardi, Manuel Glauco Carbone, and Icro Maremmani. 2025. "Antipsychotic Potential of Opioids: Rethinking Substance-Induced Psychosis and Treatment Stratification" Journal of Clinical Medicine 14, no. 15: 5596. https://doi.org/10.3390/jcm14155596
APA StyleMaremmani, A. G. I., Della Rocca, F., Bacciardi, S., Carbone, M. G., & Maremmani, I. (2025). Antipsychotic Potential of Opioids: Rethinking Substance-Induced Psychosis and Treatment Stratification. Journal of Clinical Medicine, 14(15), 5596. https://doi.org/10.3390/jcm14155596