Stress modulates illness-course of substance use disorders: a translational review

Abstract

Childhood trauma and post-childhood chronic/repeated stress could increase the risk of a substance use disorder by affecting five stages of addiction illness-course: (a) initial experimentation with substances; (b) shifting from experimental to regular use; (c) escalation from regular use to abuse or dependence; (d) motivation to quit; and (e) risk of (re-)lapse. We reviewed the human literature on relationships between stress and addiction illness-course. We explored per illness-course stage: (i) whether childhood trauma and post-childhood chronic/repeated stress have comparable effects and (ii) whether effects cut across classes of substances of abuse. We further discuss potential underlying mechanisms by which stressors may affect illness-course stages for which we relied on evidence from studies in animals and humans. Stress and substances of abuse both activate stress and dopaminergic motivation systems, and childhood trauma and post-childhood stressful events are more chronic and occur more frequently in people who use substances. Stressors increase risk to initiate early use potentially by affecting trait-like factors of risk-taking, decision making, and behavioral control. Stressors also accelerate transition to regular use potentially due to prior effects of stress on sensitization of dopaminergic motivation systems, cross-sensitizing with substances of abuse, especially in people with high trait impulsivity who are more prone to sensitization. Finally, stressors increase risk for abuse and dependence, attenuate motivation to quit, and increase relapse risk potentially by intensified sensitization of motivational systems, by a shift from positive to negative reinforcement due to sensitization of the amygdala by corticotropin releasing factor, and by increased sensitization of noradrenergic systems. Stress generally affects addiction illness-course across stressor types and across classes of substances of abuse.

Keywords: HPA axis; addiction; impulsivity; norepinephrine; risk-taking; sensitization; stress; trauma.

Figure 1

Stages associated with the illness-course of addiction, definitions or each stage, and topics discussed in this review per illness-course stage.

Figure 2

Model on how stressors may affect substance initiation or initial experimentation. Stressors affect HPA and SAM axes, which can increase risk-taking, and impair decision making and behavioral control. At particular risk are people with trait-like high risk-taking, impaired decision making, poor behavioral control or high impulsivity, increased stress reactivity, or elevated emotional distress with a belief that substances diminish negative affect.

Figure 3

Model of how stressors, in conjunction with initial irregular substance use, may affect progression from experimentation to regular use. Repeated stress can cross-sensitize motivational systems to the motivating effects of substances of abuse, which can be further sensitized by irregular substance use (right side of picture). This might operate in parallel with effects of stress on trait-like factors (left side of figure). People with high trait impulsivity, who are more prone to sensitization, may be at particular risk.

Figure 4

Model of how stressors, in conjunction with chronic or repeated substance use, may affect progression from regular use to abuse or dependence. Repeated activation of stress or motivational systems by stress and substances of abuse can (right side of figure) (1) intensify sensitization of motivational systems and enhance reactivity to and attentional bias for drug-related information; (2) increase HPA axis activation during acute withdrawal instead of substance intake and shift use from positively to negatively reinforcing; (3) increase sensitivity or reactivity of noradrenergic mechanisms and increase emotional distress to stress, impair control mechanisms, and enhance attentional bias or cue reactivity. These effects might operate in parallel with the effects of stress on trait-like factors (left side of figure). People with high trait impulsivity, who are more prone to sensitization, may be at particular risk.

Figure 5

Hypothesized relationships between no stress (black line), low stress (gray line), and high stress (red line) on risk and latency of escalation. High stress relates to early onset and increased risk of (rapid) escalation to a substance use disorder (early onset and steeper risk-latency slope), whereas no stress relates to later onset and low risk to transition to problematic substance use or to a substance use disorder (later onset and shallow risk-latency slope). Effects of stress on risk and latency may follow those on level of sensitization of motivational systems and age of people (text in green).

Figure 6

Full model of how stressors and substance use may affect progression from experimentation to dependence and relapse. (A) Childhood trauma or chronic/repeated post-childhood stressful events (as well as substances) activate, and change activation patterns of the HPA and SAM axis. (B) Stress affects trait-like factors (elevating risk-taking, impaired decision making, and behavioral control) or sensitization mechanisms (dopaminergic motivation, amygdalar CRF, and norepinephrine), predisposing people to use substances. (C) Stress effects on trait-like factors can result in first-time use of a substance. (D) Stress and irregular, repeated, or chronic substance use can affect sensitization mechanisms. (E) Sensitization (in conjunction with stress effects on trait-like factors) can result in escalation to regular use, abuse/dependence, and lapse/relapse. People with trait-like high risk-taking, impaired decision making, poor behavioral control or high impulsivity, increased stress reactivity, or elevated emotional distress with a belief that substances diminish negative affect, are at particular risk.