| Summary: | <b>Background:</b> The present retrospective observational study aims to identify differences in clinical features and peripheral biomarkers among patients affected by substance-induced psychotic disorder (SIPD) according to the primary substance of abuse. <b>Methods:</b> A sample of 218 patients was divided into three groups according to the type of consumed substance: alcohol, cannabis, and psychostimulants. The three groups were compared using one-way analyses of variance (ANOVAs) for continuous variables and χ<sup>2</sup> tests for qualitative variables. After excluding the alcohol-induced psychotic disorder group, the same analyses were repeated. The statistically significant variables from these subsequent analyses were included in a binary logistic regression model to confirm their reliability as predictors of cannabis- or psychostimulant-induced psychotic disorder. <b>Results:</b> Psychotic cannabis abusers were younger (<i>p</i> < 0.01), with illness onset at an earlier age (<i>p</i> < 0.01). Alcohol consumers presented a longer duration of illness (<i>p</i> < 0.01), more frequent previous hospitalizations (<i>p</i> = 0.04) and medical comorbidities (<i>p</i> < 0.01), and higher mean Modified Sad Persons Scale scores (<i>p</i> < 0.01). Finally, psychostimulant abusers had a higher frequency of lifetime history of poly-substance use disorders (<i>p</i> < 0.01). A binary logistic regression analysis revealed that higher mean Brief Psychiatric Rating Scale scores (<i>p</i> < 0.01) and higher sodium (<i>p</i> = 0.012) and hemoglobin (<i>p</i> = 0.040) plasma levels were predictors of cannabis misuse in SIPD patients. <b>Conclusions:</b> Different clinical factors and biochemical parameters con be associated with SIPD according to the main substance of abuse, thus requiring specific management by clinicians.
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