Early life stress and substance use disorders: The critical role of adolescent substance use

Highlights

• Early life stress (ELS) is related to adolescent substance use/disorders (SUDs).

• ELS and substance use are associated with brain changes that increase risk for SUDs.

• Adolescent substance use may be an intermediate step in the path from ELS to SUDs.

• Intervention during adolescence may effectively reduce substance use following ELS.

Abstract

Early life stress (ELS) is a well-established risk factor for many psychiatric and medical disorders, including substance use disorders (SUDs). The relationship between ELS and SUDs is complex and there are likely multiple pathways from ELS to adverse substance use outcomes. The association between ELS and substance use emerges in adolescence. Adolescence is a critical period in development during which substance exposure markedly increases risk for SUDs. Therefore, this review focuses on the literature supporting the hypothesis that ELS increases risk for the development of SUDs through its influence on adolescent substance use. We discuss studies substantiating the role of ELS in adolescent substance use and explore how internalizing and externalizing psychopathology may be antecedents of substance use in adolescence. We examine clinical work suggesting ELS sculpts the Hypothalamic-Pituitary-Adrenal (HPA) Axis and developing brain—particularly subcortical brain regions that underlie stress response, mesocorticolimbic brain systems associated with reward sensitivity, and prefrontal regions that underlie executive control—in a way that increases risk for adolescent substance use and SUDs. We further explore how substance use during adolescence alters structure and function of these same systems, and how brain changes following ELS and adolescent substance use may independently, additively, or interactively contribute to risk for addiction. We conclude by discussing how the current literature can inform interventions aimed at reducing risk for SUDs in individuals with a history of ELS.

Introduction

Early life stress (ELS)—defined as childhood maltreatment (sexual, physical, and emotional abuse and physical and emotional neglect) and household dysfunction—is highly prevalent. Fifty-three percent of adults have experienced ELS prior to the age of 18 (Green et al., 2010). ELS is a major public health concern and increases risk for a wide range of psychiatric and medical illnesses (Nemeroff, 2016, Lippard and Nemeroff, 2020), including substance use disorders (SUDs) (Kirsch et al., 2020). The landmark Adverse Childhood Experiences (ACE) study (N = 17,337) found number of ACEs ‘dose-dependently’ related to greater risk for alcoholism and drug abuse. ACEs were associated with 65% of population attributable risk for alcoholism, 50% for drug abuse, and 78% for intravenous drug use (Dube et al., 2003a). Anda et al. (2006) also demonstrated a graded relationship between ELS and risk for alcohol use disorders; individuals having experienced four or more categories of ELS possessed a 7.2-fold increase in risk for developing an alcohol use disorder (Anda et al., 2006). This relationship has since been replicated by a large number of retrospective cross-sectional studies (Enoch, 2011). Prospective, longitudinal studies have also emerged, and have begun to establish the temporality of this association (Shin et al., 2009; Skeer et al., 2009; Kisely et al., 2020a; Kisely et al., 2020b). Decades of preclinical work also supports an association between ELS and SUDs, thereby strengthening inferences about the causality of this relationship (Higley et al., 1991; Kosten et al., 2000; Huot et al., 2001; Kosten et al., 2004; Kosten et al., 2006; Vazquez et al., 2006; Moffett et al., 2007).

ELS impacts each stage of the addiction cycle, from compulsive drug seeking and use, to loss of control over limiting intake, and to the emergence of negative emotional states (Kirsch et al., 2020). ELS has been associated with an earlier onset of addiction and a more pernicious illness course marked by increased risk of relapse and poor treatment response. Patients with a SUD and a history of ELS remain abstinent for shorter periods of time (Greenfield et al., 2002), relapse more often (Heffner et al., 2011, Van Dam et al., 2014a), and are less adherent to treatment (Jaycox et al., 2004), compared to patients with a SUD and no history of ELS. The association between ELS and increased risk for SUDs is observed across a broad range of substances of abuse, including alcohol, cannabis, nicotine, opioids, and cocaine (Le Moal and Koob, 2007; Sinha, 2008; Pilowsky et al., 2009; Enoch, 2011; Garami et al., 2019). Despite this significant public health concern, the exact mechanisms by which ELS is translated into risk for SUDs is not entirely understood. A wealth of literature supports the hypothesis that ELS shapes neurobiological development in a way that increases risk for addiction (Andersen and Teicher, 2009). Indeed, ELS-related neurobiological differences are strikingly similar to those observed in individuals with SUDs. The pathway from ELS to SUDs, however, is complex and likely mediated and moderated by a plethora of internal and external factors.

The current review focuses on evidence supporting the hypothesis that ELS increases risk for the development of SUDs through its influence on adolescent substance use. The association between ELS and substance use emerges in early adolescence (Tonmyr et al., 2010; Brajović et al., 2019)—a vulnerable period during which exposure to substances of abuse is more likely to increase risk for SUDs (Orlando et al., 2004; King and Chassin, 2007). As a high proportion of individuals with ELS are exposed to substances of abuse during this vulnerable window, adolescent substance use may be a critical intermediate step in the pathway from ELS to SUDs. We discuss the literature substantiating the relationship between ELS and adolescent substance use and explore psychological and neurobiological pathways by which ELS may confer risk for adolescent substance use. We further examine how substance use during the adolescent period may uniquely increase risk for the development of SUDs. We conclude by discussing future areas of research and opportunities for intervention aimed at reducing risk for the development of SUDs following ELS through intervention during adolescence.