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

Highlights

• Cortisol is associated with substance use (SU) phenotypes across the SU progression.

• Associations are observed at multiple levels, from intra-cellular to psychological.

• Associations of cortisol and SU across the SU progression are often bi-directional.

• There is potential for some genetic confounding in cortisol-SU associations.

• Genetically informed designs are critically needed to test cortisol-SU associations.

Abstract

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.

Introduction

Substance use costs the American public more than $740 billion/year (National Institute on Drug Abuse [NIDA], 2017). Addiction has its origins in adolescence: 90% of those addicted began using during adolescence, and over $80 billion/year is spent on underage drinking and juvenile justice costs related to adolescent substance use (The National Center on Addiction and Substance Abuse [CASA], 2011). Understanding biological mechanisms underlying the progression of substance use from initiation through disorder is of key importance for prevention and intervention efforts, as substance use disorders are biologically-based (e.g., Conrod and Nikolaou, 2016; Grunberg, 1994; Kreek et al., 2005). One important biological mechanism often studied in relation to substance use is cortisol reactivity to environmental cues. The steroid hormone cortisol has been a major focus of research in biological and psychological sciences because of its important regulatory role in maintaining homeostasis in the face of stressors (Del Giudice et al., 2011; Doom and Gunnar, 2013; Gunnar and Quevedo, 2007). Cortisol reactivity to environmental stressors has been linked with emotional and behavioral problems across the lifespan that are risk factors for developing substance use problems (Alink et al., 2008; Dickerson and Kemeny, 2004; Doom and Gunnar, 2013; Marceau et al., 2015). Generally, decreased stress reactivity has also been directly linked to substance use and related phenotypes at many stages of the progression to substance use disorder (see, e.g., Lovallo, 2006; Sinha, 2011; Stephens and Wand, 2012 for review), with several theoretical explanations for these associations (detailed below). The purpose of this review is to integrate theory and hypotheses about the mechanisms of association between cortisol reactivity to environmental cues and substance use, leveraging known information about the genes associated with each phenotype to clarify potential mechanisms of association.