The global impact of the COVID-19 pandemic on mental health and substance use behaviors has sparked extensive research efforts. The COMET-G international study, organized by the Department of Medicine and the Rectorate of the Aristotle University of Thessaloniki in collaboration with the World Psychiatric Association, delved into these issues. Running from March 2020 to April 2021, the study collected responses from 55,589 individuals across 40 countries. Through a comprehensive questionnaire, participants provided insights into their mental state, attitudes toward the pandemic, and the resultant changes in their personal and daily lives. Findings revealed, among other things, significant patterns of change in substance use, with notable correlations between reduced usage and the severity of lockdown measures among non-binary individuals. Mental health history emerged as a strong predictor of substance use changes, with influences from anxiety disorders, depression, and self-harm. Additionally, family and social dynamics, including economic expectations and household composition, significantly shaped substance use behaviors during lockdowns. Given these findings, the development of comprehensive approaches targeting the adverse effects of the pandemic on individual behaviors and general welfare is crucial.