Mechanisms of cortisol - Substance use development associations: Hypothesis generation through gene enrichment analysis

There are many theories about the mechanisms of associations between hypothalamic-pituitary-adrenal (HPA) function (indexed by cortisol) and substance use. However, the potential for genes that contribute to both HPA function and substance use to confound the association (e.g., genetic confounding) has largely been ignored. We explore the potential role of genetics in cortisol-substance use associations, build a conceptual framework placing theories and mechanisms for how cortisol and substance use are related into a developmental progression, and develop new hypotheses based on our findings. We conclude that the relationship between cortisol function and substance use is complex, occurs at multiple levels of analysis, and is bidirectional at multiple phases of the substance use progression. Additionally, there is potential for genetic confounding in cortisol-substance use associations, and thus a need for genetically informed designs to investigate how and why cortisol function is associated with substance use phenotypes from initiation through disorder. Gene-environment interplay and developmental context are likely to impact the effectiveness of prevention and intervention efforts to reduce substance use problems.