Analysis of 733 Montreal young adults (average age 30.6) revealed that combining cannabis with nicotine produces significantly worse mental health outcomes than using either substance alone or abstaining entirely. The cannabis-nicotine pairing was associated with 2.58-point increases in anxiety symptoms and nearly 6-point reductions in positive mental health scores, representing the most detrimental combination examined. This finding challenges the common assumption that polysubstance effects simply scale with the number of substances used. Instead, the research demonstrates that specific combinations create unique risk profiles, with cannabis-nicotine showing particularly pronounced negative synergy. The alcohol-nicotine combination also reduced positive mental health measures, though without the anxiety amplification seen with cannabis-nicotine. These patterns suggest that nicotine may act as a mental health catalyst when combined with other substances, potentially through shared neurochemical pathways involving dopamine and GABA systems. For harm reduction strategies, the results indicate that dual-use prevention programs should prioritize cannabis-nicotine combinations over simply reducing overall substance frequency. The observational design limits causal inference, but the specificity of combination effects points toward genuine pharmacological interactions rather than confounding factors.