Background: The notion that substance use can induce symptoms of depression and anxiety is influential in clinical practice, however questions remain about the empirical support for this hypothesis. Methods: We analysed mental health and substance dependence screening records for 280 outpatients in addictions treatment. Item-level data for depression (PHQ-9), anxiety (GAD-7), severity of dependence (SDS) and self-reported weekly substance use were studied using factor analysis and correlations. Symptom-level associations between substance use and psychological distress symptoms were examined after controlling for underlying levels of psychopathology. Results: We obtained a two-factor solution accounting for approximately 48 % of total variance. Depression and anxiety symptoms loaded onto a single psychopathology factor. Severity of dependence (SDS) and substance use measures loaded onto a distinct but correlated factor. After controlling for latent levels of psychopathology, the only remaining symptom-level associations were impaired concentration linked to cannabis use and irritability linked to alcohol use. Dependence (SDS) was prominently associated with depressive rumination, and negatively correlated with residual anxiety symptoms related to substance use (e.g., craving). Conclusions: Overall, this analysis supports a psychological understanding of comorbidity; with dependence, craving, negative reinforcement and rumination as key variables.