Analysis of 733 Canadian adults (average age 30.6) reveals that specific two-substance combinations produce distinct mental health effects, with cannabis-nicotine users showing 2.58-point higher anxiety scores and nearly 6-point lower positive mental health measures compared to non-users. The alcohol-nicotine pairing similarly decreased positive mental health by 3.7 points, while single-substance use showed no significant associations. These findings challenge the assumption that polysubstance effects scale linearly with quantity. Instead, the data suggests certain combinations create synergistic impacts on mental wellness that exceed what individual substances produce alone. The cannabis-nicotine pattern appears particularly problematic, potentially reflecting shared neurochemical pathways that amplify anxiety responses. This Canadian cohort study adds nuance to substance use research by demonstrating that combination patterns matter more than total number of substances consumed. The observational design limits causal inference, and the study focused only on regular users (weekly or daily), missing occasional use patterns. For young adults managing multiple substances, these results suggest prioritizing reduction of specific high-risk combinations rather than blanket cessation approaches.