Opioids and psychosis: a narrative review of a paradoxical relationship

Introduction: The relationship between opioids and psychosis appears to differ from that observed with other psychoactive substances. While stimulants, cannabinoids and hallucinogens are well-recognized precipitants of substance-induced psychosis, opioid-related psychotic phenomena seem to be less frequent and clinically heterogeneous. Concurrently, several reports describe psychotic symptoms emerging after abrupt opioid withdrawal or discontinuation of opioid agonist treatment, raising the hypothesis that opioid signalling may exert antipsychotic-like modulation in selected contexts. A more nuanced understanding of opioid–psychosis interactions is warranted, as this relationship may have important implications for both pathophysiology and clinical management.

Aims: To explore the relationship between opioids and psychosis, with particular emphasis on the paradoxical emergence of psychotic symptoms during opioid withdrawal and the possible antipsychotic-like effects of opioid agonism.

Methods: A narrative review of the literature was conducted using PubMed and Google Scholar, with search terms including “opioids”, “psychosis”, “opioid withdrawal”, “methadone”, and “buprenorphine”. Thirteen papers published between 1995 and 2025 were selected by the authors according to their relevance to opioid-related psychotic symptoms, withdrawal-associated psychosis, opioid use in patients with psychotic disorders, and neurobiological links between the endogenous opioid system and psychosis.

Results: Although the available literature was limited and heterogeneous, the evidence suggested a paradoxical relationship between opioids and psychosis. Psychotic symptoms during opioid exposure appeared to be relatively uncommon and were more often described in medically complex contexts. In contrast, several reports pointed to the emergence or exacerbation of psychotic symptoms following abrupt opioid withdrawal or discontinuation of opioid agonist treatment. In some of these cases, symptom improvement was observed after reintroduction of the opioid agonist, suggesting a possible modulatory effect of opioid signalling in susceptible individuals. Studies addressing co-occurring psychotic disorders and opioid use disorder further supported the clinical relevance of this association, particularly by suggesting greater treatment complexity and poorer retention outcomes in dual-diagnosis populations. Neurobiological literature implicated the endogenous opioid system, particularly kappa-opioid receptor signalling, in mechanisms related to dopaminergic regulation, salience processing and stress responsivity. The findings support the hypothesis that opioids may occupy a distinct and atypical position among substances associated with psychosis. However, the available evidence remains limited and insufficient to draw definitive causal inferences or to guide clinical practice.

Conclusions: The available evidence supports a complex and potentially paradoxical relationship between opioids and psychosis. In some instances, opioid withdrawal or discontinuation of opioid agonist treatment appears to be associated with the emergence of psychotic symptoms, while reintroduction of the agonist may coincide with clinical improvement. However, the available evidence is still largely based on case reports and narrative data, and remains insufficient to support any therapeutic antipsychotic role for opioids. To clarify the causality of this association and to determine its clinical relevance in the management of substance use and psychotic disorders, further systematic and mechanistic research is needed.

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