The COVID-19 pandemic has led to unprecedented challenges globally, impacting various aspects of daily life, including education. This study examines the effects of the pandemic on stress levels and substance use among Italian medical students. Two independent surveys were conducted: 388 medical students were interviewed before the epidemic, and 222 medical students a year after the COVID-19 epidemic began. Results revealed significant changes in stress levels, with a reduction in mild stress and an increase in severe stress during the post-pandemic period, rising from 23% (95% CI: 19%-28%) to 46% (95% CI: 39%-52%). While tobacco smoking prevalence remained stable (25% vs 27%), the proportion of students exhibiting high levels of nicotine dependence increased (3.64%) compared to the period before the pandemic (1.80%). Alcohol consumption rates remained consistent (66%), with no significant differences in the distribution of risky alcohol consumption between the two periods (<em>p</em> = 0.535). Surprisingly, there was a significant decrease in cannabis use post-pandemic (16% vs 6%), though problematic use among users persisted (49% vs 46%). Multivariable analysis confirmed associations between stress and tobacco smoking (AdjOR = 1.98, 95% CI: 1.11-3.53; <em>p</em> = 0.020), as well as alcohol consumption (AdjOR = 1.71, 95% CI: 1.01-2.89; <em>p</em> = 0.047). Furthermore, male students were more likely to engage in alcohol (AdjOR = 2.16, 95% CI: 1.47-3.19; <em>p</em> < 0.001) and cannabis use (AdjOR = 1.79, 95% CI: 1.07-3.00; <em>p</em> = 0.027). The study highlighted the complex interplay between stress and substance use among medical students, underscoring the importance of targeted interventions to address stress-related substance use and support the well-being of medical students, particularly in the context of the COVID-19 pandemic. Further research should explore longitudinal trends and the effectiveness of interventions in mitigating stress-related substance use among this vulnerable population.
