Factors Associated with Reduced Clinical Response in Adult ADHD: The Role of Alcohol and Cannabis Use Disorders and Autism Spectrum Disorder

Background: Attention-Deficit/Hyperactivity Disorder (ADHD) in adulthood is frequently associated with complex psychiatric comorbidity, including high rates of Substance Use Disorders (SUDs), which may influence treatment outcomes. Although pharmacological treatments are effective for core ADHD symptoms, real-world response remains heterogeneous, and the contribution of specific substance-related and neurodevelopmental factors to treatment response is not fully understood. Methods: This retrospective observational study examined a real-world cohort of 67 adults with ADHD treated pharmacologically in a specialized outpatient setting. ADHD was diagnosed according to DSM-5-TR criteria using the Diagnostic Interview for ADHD in Adults (DIVA-5). Autism spectrum disorder (ASD) was recorded based on documented pre-existing specialist diagnoses and confirmed clinically at baseline. Psychiatric comorbidities and substance use disorders, including alcohol and cannabis use disorders, were assessed according to DSM-5-TR criteria. Clinical response was defined using the Clinical Global Impression–Improvement scale (CGI-I; responders = scores 1–3). Exploratory binary logistic regression analyses were used to identify clinical factors associated with treatment response. Given the limited sample size, revised multivariable models were specified parsimoniously on the basis of a priori clinical relevance. Results: At follow-up, 48 of 67 patients (71.6%) met criteria for clinical response. In revised parsimonious multivariable models, alcohol use disorder (OR ≈ 0.08–0.10, p = 0.010–0.026) and cannabis use disorder (OR ≈ 0.20–0.24, p = 0.014–0.028) were consistently associated with reduced odds of clinical response. Autism spectrum disorder showed a descriptive trend toward lower response rates but did not retain statistical significance after adjustment (p ≈ 0.11–0.15). Conclusions: In adults with ADHD treated in routine clinical practice, alcohol and cannabis use disorders were associated with a reduced likelihood of achieving clinically meaningful improvement under routine pharmacological care, whereas autism spectrum disorder showed a trend toward lower response that was not stable enough to support firm conclusions. These findings should be considered exploratory given the retrospective design, limited sample size, and lack of systematic treatment exposure measures.