Rationale and Objectives <p>Cannabis is often consumed in polysubstance contexts, yet research comparing its isolated use to polydrug use is limited. Such comparisons are essential for understanding substance-specific versus interactive effects on brain activity. This study investigates how cannabis-only and polydrug use relate to alterations in resting-state EEG functional connectivity, using the Directed Transfer Function (DTF) to assess frequency-specific information flow in the brain.</p> Methods <p>Three age- and sex-matched groups were studied: individuals with cannabis-only use (n=27), polydrug use (n=29), and non-drug-using controls (n=30). Resting-state EEG was recorded under eyes-open and eyes-closed conditions. DTF was applied to quantify directed connectivity and frequency-dependent propagation of neural signals across brain regions.</p> Results <p>Individuals with cannabis-only use exhibited localized changes in neural propagation, particularly in frontal areas and within theta, beta, and gamma bands, while alpha-band activity remained relatively stable. In contrast, individuals with polydrug use showed more widespread and complex alterations in connectivity, including reduced alpha activity and increased frontal and prefrontal engagement, suggesting heightened excitation and possible compensatory mechanisms.</p> Conclusions <p>This study is the first to characterize frequency-specific EEG connectivity patterns associated with cannabis and polydrug use. The findings highlight the importance of studying substance use patterns and considering cannabis within a polysubstance context. A longitudinal study is needed to assess the effects of use duration, frequency, and dosage.</p>