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Stress has long been associated with substance misuse and substance use disorders (SUDs). The past two decades have seen a surge in research aimed at understanding the underlying mechanisms driving this association. This Review introduces a multilevel “adaptive stress response” framework, encompassing a stress baseline, acute reaction, and recovery with return-to-homeostasis phase that occurs at varying response times and across domains of analysis. It also discusses evidence showing the disruption of this adaptive stress response in the context of chronic and repeated stressors, trauma, adverse social and drug-related environments, as well as with acute and chronic drug misuse and with drug withdrawal and abstinence sequelae. Subjective, cognitive, peripheral, and neurobiological disruptions in the adaptive stress response phases and their link to inflexible, maladaptive coping; increased craving; relapse risk; and maintenance of drug intake are also presented. Finally, the prevention and treatment implications of targeting this “stress pathophysiology of addiction” are discussed, along with specific aspects that may be targeted in intervention development to rescue stress-related alterations in drug motivation and to improve SUD treatment outcomes.

Relapse is a highly prevalent phenomenon in addiction. This paper examines the new research on identifying biological factors that contribute to addiction relapse risk. Prospective studies examining relapse risk are reviewed, and clinical, biological, and neural factors that predict relapse risk are identified. Clinical factors, patient-related factors, and subjective and behavioral measures such as depressive symptoms, stress, and drug craving all predict future relapse risk. Among biological measures, endocrine measures such as cortisol and cortisol/corticotropin (ACTH) ratio as a measure of adrenal sensitivity and serum brain-derived neurotrophic factor were also predictive of future relapse risk. Among neural measures, brain atrophy in the medial frontal regions and hyperreactivity of the anterior cingulate during withdrawal were identified as important in drug withdrawal and relapse risk. Caveats pertaining to specific drug abuse type and phase of addiction are discussed. Finally, significant implications of these findings for clinical practice are presented, with a specific focus on determining biological markers of relapse risk that may be used to identify those individuals who are most at risk of relapse in the clinic. Such markers may then be used to assess treatment response and develop specific treatments that will normalize these neural and biological sequelae so as to significantly improve relapse outcomes.

Our society is experiencing more stress than ever before, leading to both negative psychiatric and physical outcomes. Chronic stress is linked to negative long-term health consequences, raising the possibility that stress is related to accelerated aging. In this study, we examine whether resilience factors affect stress-associated biological age acceleration. Recently developed “epigenetic clocks” such as GrimAge have shown utility in predicting biological age and mortality. Here, we assessed the impact of cumulative stress, stress physiology, and resilience on accelerated aging in a community sample (N = 444). Cumulative stress was associated with accelerated GrimAge (P = 0.0388) and stress-related physiologic measures of adrenal sensitivity (Cortisol/ACTH ratio) and insulin resistance (HOMA). After controlling for demographic and behavioral factors, HOMA correlated with accelerated GrimAge (P = 0.0186). Remarkably, psychological resilience factors of emotion regulation and self-control moderated these relationships. Emotion regulation moderated the association between stress and aging (P = 8.82e−4) such that with worse emotion regulation, there was greater stress-related age acceleration, while stronger emotion regulation prevented any significant effect of stress on GrimAge. Self-control moderated the relationship between stress and insulin resistance (P = 0.00732), with high self-control blunting this relationship. In the final model, in those with poor emotion regulation, cumulative stress continued to predict additional GrimAge Acceleration even while accounting for demographic, physiologic, and behavioral covariates. These results demonstrate that cumulative stress is associated with epigenetic aging in a healthy population, and these associations are modified by biobehavioral resilience factors.

Although the feeling of stress is ubiquitous, the neural mechanisms underlying this affective experience remain unclear. Here, we investigate functional hippocampal connectivity throughout the brain during an acute stressor and use machine learning to demonstrate that these networks can specifically predict the subjective feeling of stress. During a stressor, hippocampal connectivity with a network including the hypothalamus (known to regulate physiological stress) predicts feeling more stressed, whereas connectivity with regions such as dorsolateral prefrontal cortex (associated with emotion regulation) predicts less stress. These networks do not predict a subjective state unrelated to stress, and a nonhippocampal network does not predict subjective stress. Hippocampal networks are consistent, specific to the construct of subjective stress, and broadly informative across measures of subjective stress. This approach provides opportunities for relating hypothesis-driven functional connectivity networks to clinically meaningful subjective states. Together, these results identify hippocampal networks that modulate the feeling of stress. Although the feeling of being stressed is ubiquitous and clinically significant, the underlying neural mechanisms are unclear. Using a novel predictive modeling approach, the authors show that functional hippocampal networks specifically and consistently predict the feeling of stress.

Recent stressors may increase the risk of alcohol misuse. However, the number and duration of recent stress, whether social support (SS) moderates these effects, and whether this differs for men and women, are unclear. This cross-sectional study examined the effects of these factors on alcohol use severity, amount, and frequency in 462 community adult women and men. Linear regression (controlling for sex, age, and education) indicated that more stressful life events and longer stress duration were associated with a greater probability of any alcohol use and greater alcohol use severity as measured by the Alcohol Use Disorder Identification Test (AUDIT). More stressful events were associated with a greater amount of alcohol consumption. Longer stress duration also interacted with sex and SS to predict AUDIT scores, such that high SS, only for men, predicted a higher AUDIT score, but higher stress duration predicted AUDIT scores for women, regardless of SS score. More stress events with high social support predicted a greater alcohol use amount, only in men. Current findings demonstrate that significant impacts of the number and duration of recent stressors increase the risk of alcohol intake and severity. Furthermore, SS uniquely promotes drinking in men, suggesting male-specific increased alcohol risk. Future work would benefit from further disentangling whether these effects stem from certain types of SS (i.e., emotional, financial, practical) or if these effects were due to the nature of the social interactions (i.e., drinking buddies). Moreover, future work should continue to explore the multifaceted nature of stress as well as consider how sex and SS impact alcohol use.

Males and females with alcohol dependence have distinct mental health and cognitive problems. Animal models of addiction postulate that the underlying neurobiological mechanisms are partially distinct, but there is little evidence of sex differences in humans with alcohol dependence as most neuroimaging studies have been conducted in males. We examined hippocampal and amygdala subregions in a large sample of 966 people from the ENIGMA Addiction Working Group. This comprised 643 people with alcohol dependence (225 females), and a comparison group of 323 people without alcohol dependence (98 females). Males with alcohol dependence had smaller volumes of the total amygdala and its basolateral nucleus than male controls, that exacerbated with alcohol dose. Alcohol dependence was also associated with smaller volumes of the hippocampus and its CA1 and subiculum subfield volumes in both males and females. In summary, hippocampal and amygdalar subregions may be sensitive to both shared and distinct mechanisms in alcohol-dependent males and females.

Background Psychological stress and physical activity (PA) are believed to be reciprocally related; however, most research examining the relationship between these constructs is devoted to the study of exercise and/or PA as an instrument to mitigate distress. Objective The aim of this paper was to review the literature investigating the influence of stress on indicators of PA and exercise. Methods A systematic search of Web of Science, PubMed, and SPORTDiscus was employed to find all relevant studies focusing on human participants. Search terms included “stress”, “exercise”, and “physical activity”. A rating scale (0–9) modified for this study was utilized to assess the quality of all studies with multiple time points. Results The literature search found 168 studies that examined the influence of stress on PA. Studies varied widely in their theoretical orientation and included perceived stress, distress, life events, job strain, role strain, and work–family conflict but not lifetime cumulative adversity. To more clearly address the question, prospective studies ( n  = 55) were considered for further review, the majority of which indicated that psychological stress predicts less PA (behavioral inhibition) and/or exercise or more sedentary behavior (76.4 %). Both objective (i.e., life events) and subjective (i.e., distress) measures of stress related to reduced PA. Prospective studies investigating the effects of objective markers of stress nearly all agreed (six of seven studies) that stress has a negative effect on PA. This was true for research examining (a) PA at periods of objectively varying levels of stress (i.e., final examinations vs. a control time point) and (b) chronically stressed populations (e.g., caregivers, parents of children with a cancer diagnosis) that were less likely to be active than controls over time. Studies examining older adults (>50 years), cohorts with both men and women, and larger sample sizes ( n  > 100) were more likely to show an inverse association. 85.7 % of higher-quality prospective research (≥7 on a 9-point scale) showed the same trend. Interestingly, some prospective studies (18.2 %) report evidence that PA was positively impacted by stress (behavioral activation). This should not be surprising as some individuals utilize exercise to cope with stress. Several other factors may moderate stress and PA relationships, such as stages of change for exercise. Habitually active individuals exercise more in the face of stress, and those in beginning stages exercise less. Consequently, stress may have a differential impact on exercise adoption, maintenance, and relapse. Preliminary evidence suggests that combining stress management programming with exercise interventions may allay stress-related reductions in PA, though rigorous testing of these techniques has yet to be produced. Conclusions Overall, the majority of the literature finds that the experience of stress impairs efforts to be physically active. Future work should center on the development of a theory explaining the mechanisms underlying the multifarious influences of stress on PA behaviors.

High levels of stress and individual differences in acute stress responses are important predictors of chronic illness. This study examined the effects of stress and Alcohol Use Disorder (AUD) on heart rate variability (HRV) using the Yale Pain Stress Test (YPST), adapted from the well-established Cold Pressor Test (CPT). The YPST characterized three key (time periods) phases of the cardiovascular stress response to repeated trials of a pain-stress versus no pain-stress control condition: pre-stress baseline, acute reactivity, and recovery, using HRV as a physiological marker. Participants included 24 individuals who engaged in social drinking and 21 participants with AUD, all recruited from the Greater New Haven area. They were screened for psychiatric or medical conditions and other substance use disorders using DSM-5 criteria. Results showed significant main effects of stress condition and time across HRV metrics. While no significant three-way interaction among time period, condition, and drinking group was observed, there were significant condition × time period effects and group × condition effects. Participants with AUD exhibited lower high-frequency (HF) and low-frequency (LF) HRV during stress exposure compared to the recovery phase. They also showed a less dynamic LF/HF ratio during stress relative to social drinking controls, suggesting greater sympathetic dominance. In contrast, participants who engaged in social drinking displayed autonomic flexibility across time periods. Findings suggest that individuals with AUD experience blunted autonomic reactivity and reduced HRV recovery following stress, highlighting diminished physiological flexibility potentially indicating risk for long-term stress-related chronic diseases. The results underscore the importance of evaluating autonomic function in clinical care and recovery planning for individuals with AUD.

Stress is an important factor known to increase alcohol and drug relapse risk. This paper examines the stress-related processes that influence addiction relapse. First, individual patient vignettes of stress- and cue-related situations that increase drug seeking and relapse susceptibility are presented. Next, empirical findings from human laboratory and brain-imaging studies that are consistent with clinical observations and support the specific role of stress processes in the drug-craving state are reviewed. Recent findings on differences in stress responsivity in addicted versus matched community social drinkers are reviewed to demonstrate alterations in stress pathways that could explain the significant contribution of stress-related mechanisms on craving and relapse susceptibility. Finally, significant implications of these findings for clinical practice are discussed, with a specific focus on the development of novel interventions that target stress processes and drug craving to improve addiction relapse outcomes.

Active coping underlies a healthy stress response, but neural processes supporting such resilient coping are not well-known. Using a brief, sustained exposure paradigm contrasting highly stressful, threatening, and violent stimuli versus nonaversive neutral visual stimuli in a functional magnetic resonance imaging (fMRI) study, we show significant subjective, physiologic, and endocrine increases and temporally related dynamically distinct patterns of neural activation in brain circuits underlying the stress response. First, stress-specific sustained increases in the amygdala, striatum, hypothalamus, midbrain, right insula, and right dorsolateral prefrontal cortex (DLPFC) regions supported the stress processing and reactivity circuit. Second, dynamic neural activation during stress versus neutral runs, showing early increases followed by later reduced activation in the ventrolateral prefrontal cortex (VLPFC), dorsal anterior cingulate cortex (dACC), left DLPFC, hippocampus, and left insula, suggested a stress adaptation response network. Finally, dynamic stress-specific mobilization of the ventromedial prefrontal cortex (VmPFC), marked by initial hypoactivity followed by increased VmPFC activation, pointed to the VmPFC as a key locus of the emotional and behavioral control network. Consistent with this finding, greater neural flexibility signals in the VmPFC during stress correlated with active coping ratings whereas lower dynamic activity in the VmPFC also predicted a higher level of maladaptive coping behaviors in real life, including binge alcohol intake, emotional eating, and frequency of arguments and fights. These findings demonstrate acute functional neuroplasticity during stress, with distinct and separable brain networks that underlie critical components of the stress response, and a specific role for VmPFC neuroflexibility in stress-resilient coping.