Synthetic cannabinoids (SC) have become increasingly popular in the last few years, especially among adolescents. Given ADHD is overrepresented in patients with substance use across adolescents compared to the general population, the current study aims were two-fold: i) examine structural brain network topology in SC users compared to healthy controls and, ii) examine the influence of ADHD on network topology in SC users. Diffusion-weighted magnetic resonance imaging scans were acquired from 27 SC users (14 without ADHD and 13 with ADHD combined type) and 13 controls. Structural networks were examined using network-based statistic and connectomic analysis. We found that SC users without ADHD had significantly weaker connectivity compared to controls in bilateral hemispheres, most notably in edges connecting the left parietal and occipital regions. In contrast, SC users with ADHD showed stronger structural connectivity compared to controls. In addition, adolescent SC users with ADHD, but not without ADHD, displayed reduced network organization, indicated by lower clustering coefficient and modularity, suggesting that poor structural network segregation and preserved structural network integration. These results suggest that comorbidity of ADHD and substance dependence may show different structural connectivity alterations than substance use alone. Therefore, future connectivity studies in the substance use population should account for the presence of ADHD in their samples, which may be associated with disparate connectivity profiles.