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.

关于下丘脑-垂体-肾上腺（HPA）功能（以皮质醇为指标）的关联机制的理论有很多。然而，同时影响HPA功能和物质使用的基因混淆该关联的潜力（例如，遗传混淆）被忽略了。我们探讨了遗传学在皮质醇-物质使用关联中的潜在作用，建立了一个概念框架，将皮质醇和物质使用与发展进程相关的理论和机制放入其中，并根据我们的发现提出了新的假设。我们得出的结论是，皮质醇功能与物质使用之间的关系很复杂，发生在多个分析级别，并且在物质使用进展的多个阶段是双向的。此外，皮质醇-物质使用关联中存在潜在的遗传混淆，因此需要进行遗传知情的设计，以研究皮质醇功能如何以及为什么从开始到发生紊乱都与物质使用表型相关联。基因-环境的相互作用和发展背景可能会影响预防和干预措施减少药物使用问题的有效性。