Abstract
Syndemic theory posits that multiple, interconnected health behaviors-such as substance use, anxiety, depression, sexual risk behaviors, and societal or social stressors-interact synergistically within specific populations, particularly in those who face social disadvantage. These health behaviors are not isolated, but are shaped and exacerbated by social, economic, and environmental factors. Using data from the 2021 Youth Risk Behavior Surveillance System (N = 17,232), this cross-sectional study examined how the co-occurrence of substance use, mental health challenges, sexual risk behaviors, and COVID-19 pandemic-related stress creates different risk profiles among adolescents. Latent class analysis (LCA) results identified five distinct profiles of behavioral health risks: Class 1 (Complex high-risk), Class 2 (Moderate risk experimenters), Class 3 (Recent polysubstance use/Covid distress), Class 4 (Low-risk/COVID distress), and Class 5 (Low-risk). COVID distress referred to pandemic-related anxiety or stress. Higher-risk classes were characterized by recent substance use, engagement in condomless sex and having multiple partners, and psychological distress. Females, sexual minority adolescents, older-aged adolescents, and racially/ethnically marginalized groups were disproportionately represented in high-risk classes. The co-occurrence of substance, mental health challenges, and sexual risk behaviors reflects underlying structural and social inequities. By applying a syndemic lens, this study highlights the need for integrated, culturally responsive and contextually appropriate interventions, alongside early prevention and systemic policy changes to promote positive adolescent health.