Chronic stress, drug use, and vulnerability to addiction

Sinha, Rajita

doi:10.1196/annals.1441.030

Cited by 1,904Neurotransmitter Receptor Influence on BehaviorStress Responses and CortisolSubstance Abuse Treatment and Outcomes

Chronic stress, drug use, and vulnerability to addiction

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Sinha, Rajita·2008·Annals of the New York Academy of Sciences

DOI 10.1196/annals.1441.030PMC PMC2732004

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Abstract

Stress is a well‐known risk factor in the development of addiction and in addiction relapse vulnerability. A series of population‐based and epidemiological studies have identified specific stressors and individual‐level variables that are predictive of substance use and abuse. Preclinical research also shows that stress exposure enhances drug self‐administration and reinstates drug seeking in drug‐experienced animals. The deleterious effects of early life stress, child maltreatment, and accumulated adversity on alterations in the corticotropin releasing factor and hypothalamic‐pituitary‐adrenal axis (CRF/HPA), the extrahypothalamic CRF, the autonomic arousal, and the central noradrenergic systems are also presented. The effects of these alterations on the corticostriatal‐limbic motivational, learning, and adaptation systems that include mesolimbic dopamine, glutamate, and gamma‐amino‐butyric acid (GABA) pathways are discussed as the underlying pathophysiology associated with stress‐related risk of addiction. The effects of regular and chronic drug use on alterations in these stress and motivational systems are also reviewed, with specific attention to the impact of these adaptations on stress regulation, impulse control, and perpetuation of compulsive drug seeking and relapse susceptibility. Finally, research gaps in furthering our understanding of the association between stress and addiction are presented, with the hope that addressing these unanswered questions will significantly influence new prevention and treatment strategies to address vulnerability to addiction.

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Anxiety and depression are known to increase the risk of relapse in substance use.
“two emotions known to increase the risk of relapse in substance use (115, 116).”
From Mobile intervention for individuals with psychosis, dual disorders, and their common comorbidities: A literature review (2019) · cites this paper as [116]
In “Stress-Induced Reinstatement of Drug Seeking and Relapse” (page unavailable), the paper associates negative mood with alcohol relapse outcomes and discusses anxiety in stress-related relapse. It does not establish that depression increases substance-use relapse risk; its reference to depression concerns relapse to major depression, not substance use. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Stress is a common risk factor of both chemical addictions and behavioral addictions.
“Stress was considered to be a common risk factor of both chemical addictions [e.g., drug dependence; (42)] and behavioral addictions [e.g., excessive smartphone use; (43)].”
From COVID-19 stress and addictive social media use (SMU): mediating role of active use and social media flow (2021) · cites this paper as [42]
Given known linkages between stress and addiction, MBIs might ameliorate addictive behavior by attenuating stress reactivity and augmenting stress recovery.
“Given known linkages between stress and addiction [42, 43], MBIs might ameliorate addictive behavior by attenuating stress reactivity and augmenting stress recovery.”
From Mindfulness-based treatment of addiction: current state of the field and envisioning the next wave of research (2018) · cites this paper as [42]
Stress, negative affect, and pain provide interoceptive input that elicits drug use schemas and further dysregulates prefrontal control over automaticity, amplifying addictive behavior.
“Stress, negative affect, and pain provide additional interoceptive input to elicit drug use schemas and further dysregulate prefrontal control over automaticity,20–23 amplifying addictive behavior.24”
From Restructuring reward processing with Mindfulness‐Oriented Recovery Enhancement: novel therapeutic mechanisms to remediate hedonic dysregulation in addiction, stress, and pain (2016) · cites this paper as [24]
This link is an important concept in addiction and is hypothesized to mediate the relationship between early life stress and increased risk of substance use disorders.
“This is an important concept in the field of addiction (Burke and Miczek, 2014b; George et al., 2012; Sinha, 2008), that is hypothesized to mediate the relationship between ELS and increased risk of substance use disorders (Andersen and Teicher, 2009).”
From The effects of early life stress on reward processing (2018) · cites this paper as Sinha, 2008

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The role of urgency in maladaptive behaviors
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Psychological model for smoking behavior.
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The HPA axis and cocaine reinforcement
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Executive cognitive functioning and aggressive behavior in preadolescent boys at high risk for substance abuse/dependence.
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Chronic Daily Ethanol and Withdrawal: 1. Long-Term Changes in the Hypothalamo-Pituitary-Adrenal Axis
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Transition into adolescent problem drinking: the role of psychosocial risk and protective factors.
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The dopaminergic hyper-responsiveness of the shell of the nucleus accumbens is hormone-dependent
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Work Stress and Alcohol Effects: A Test of Stress-Induced Drinking
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Enhanced acquisition of cocaine self-administration in adult rats with neonatal isolation stress experience
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The role of self-control in early escalation of substance use: A time-varying analysis.
Wills, T. A., & Stoolmiller, M. (2002) · Journal of Consulting and Clinical Psychology · doi:10.1037/0022-006x.70.4.986 · Cited by 203 · see citing works
Maternal separation alters drug intake patterns in adulthood in rats
Moffett, M. C., Vicentic, A., Kozel, M. A., Plotsky, P. M., Francis, D. D., & Kuhar, M. J. (2006) · Biochemical Pharmacology · doi:10.1016/j.bcp.2006.08.003 · Cited by 200 · see citing works
Sex differences in vulnerability to drug self-administration.
Lynch, W. J. (2006) · Experimental and Clinical Psychopharmacology · doi:10.1037/1064-1297.14.1.34 · Cited by 199 · see citing works
Abnormal frontal activations related to decision-making in current and former amphetamine and opiate dependent individuals
Ersche, K. D., Fletcher, P. C., Lewis, S. J. G., Clark, L., Stocks-Gee, G., London, M., Deakin, J. B., Robbins, T. W., & Sahakian, B. J. (2005) · Psychopharmacology · doi:10.1007/s00213-005-2205-7 · Cited by 199 · see citing works
Suppression of the HPA Axis Stress‐Response: Implications for Relapse
Adinoff, B. H., Junghanns, K., Kiefer, F., & Krishnan‐Sarin, S. (2005) · Alcoholism Clinical and Experimental Research · doi:10.1097/01.alc.0000176356.97620.84 · Cited by 198 · see citing works
Craving predicts time to cocaine relapse: Further validation of the Now and Brief versions of the cocaine craving questionnaire
Paliwal, P., Hyman, S. M., & Sinha, R. (2007) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2007.10.002 · Cited by 197 · see citing works
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Initiation of substance use in early adolescence: The roles of pubertal timing and emotional distress.
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Initiation of substance use in early adolescence: the roles of pubertal timing and emotional distress
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Alcohol use, urinary cortisol, and heart rate variability in apparently healthy men: Evidence for impaired inhibitory control of the HPA axis in heavy drinkers
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Neural activity associated with stress-induced cocaine craving: a functional magnetic resonance imaging study
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[71]Riggs PD Whitmore EA Substance Use Disorders and Disruptive Behavior Disorders 1999 APA Press Washington, DC
[186]Everitt B Robbins TW Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat. Neurosci 2005 8 1481 1489 16251991

Sorted by citations

The Effects of Stress on Physical Activity and Exercise
Stults-Kolehmainen, M. A., & Sinha, R. (2014) · Sports Medicine · doi:10.1007/s40279-013-0090-5 · Cited by 1,192 · see citing works
Self-citation
Cognitive neuroscience of self-regulation failure
Heatherton, T. F., & Wagner, D. D. (2011) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2010.12.005 · Cited by 1,033 · see citing works
Impact of COVID-19 on Mental Health in Adolescents: A Systematic Review
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Stress and Obesity
Tomiyama, A. J. (2019) · Annual Review of Psychology · doi:10.1146/annurev-psych-010418-102936 · Cited by 695 · see citing works
“Changes in CRF, glucocorticoids including cortisol, and norepinephrine sensitize reward centers in the brain such as the nucleus accumbens and dorsal striatum, which increases the drive to eat these foods (Cottone et al. 2009, Sinha & Jastreboff 2013).”
BackgroundInfluential
Factors associated with Internet addiction among adolescents
Lam, L. T., Peng, Z.-W., Mai, J.-C., & Jing, J. (2009) · CyberPsychology & Behavior · doi:10.1089/cpb.2009.0036 · Cited by 531 · see citing works
Factors modulating neural reactivity to drug cues in addiction: a survey of human neuroimaging studies
Jasinska, A. J., Stein, E. A., Kaiser, J., Naumer, M. J., & Yalachkov, Y. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2013.10.013 · Cited by 513 · see citing works
Dynorphin, stress, and depression
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Sensitive periods of substance abuse: Early risk for the transition to dependence
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“Early life stress may also nduce a propensity towards habit formation (Schwabe and Wolf, 011; Sinha, 2008).”
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New findings on biological factors predicting addiction relapse vulnerability
Sinha, R. (2011) · Current Psychiatry Reports · doi:10.1007/s11920-011-0224-0 · Cited by 401 · see citing works
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The relationship between life stress and smartphone addiction on Taiwanese university student: A mediation model of learning self-efficacy and social self-efficacy
Chiu, S.-I. (2014) · Computers in Human Behavior · doi:10.1016/j.chb.2014.01.024 · Cited by 407 · see citing works
Effects of Adrenal Sensitivity, Stress- and Cue-Induced Craving, and Anxiety on Subsequent Alcohol Relapse and Treatment Outcomes
Sinha, R. (2011) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2011.49 · Cited by 368 · see citing works
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Stress and multiple memory systems: from ‘thinking’ to ‘doing’
Schwabe, L., & Wolf, O. T. (2013) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2012.12.001 · Cited by 355 · see citing works
Cumulative adversity and smaller gray matter volume in medial prefrontal, anterior cingulate, and insula regions
Ansell, E. B., Rando, K., Tuit, K., Guarnaccia, J., & Sinha, R. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.11.022 · Cited by 354 · see citing works
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Corticostriatal-limbic gray matter morphology in adolescents with self-reported exposure to childhood maltreatment
Edmiston, E. E. (2011) · Archives of Pediatrics & Adolescent Medicine · doi:10.1001/archpediatrics.2011.565 · Cited by 341 · see citing works
Modeling stress and drug craving in the laboratory: implications for addiction treatment development
Sinha, R. (2009) · Addiction Biology · doi:10.1111/j.1369-1600.2008.00134.x · Cited by 314 · see citing works
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Early-life stress, HPA axis adaptation, and mechanisms contributing to later health outcomes
Maniam, J., Antoniadis, C., & Morris, M. J. (2014) · Frontiers in Endocrinology · doi:10.3389/fendo.2014.00073 · Cited by 295 · see citing works
Mindfulness-based treatment of addiction: current state of the field and envisioning the next wave of research
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Interplay between the gut-brain axis, obesity and cognitive function
Agustí, A., García-Pardo, M. P., López-Almela, I., Campillo, I., Maes, M., Romaní-Pérez, M., & Sanz, Y. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00155 · Cited by 294 · see citing works
Interoception and drug addiction
Paulus, M. P., & Stewart, J. L. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.07.002 · Cited by 281 · see citing works
Global changes and factors of increase in caloric/salty food intake, screen use, and substance use during the early COVID-19 containment phase in the general population in France: survey study
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Diseases, Disorders, and Comorbidities of Interoception
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Investigations of HPA function and the enduring consequences of stressors in adolescence in animal models
McCormick, C. M., Mathews, I. Z., Thomas, C., & Waters, P. (2010) · Brain and Cognition · doi:10.1016/j.bandc.2009.06.003 · Cited by 276 · see citing works
The impact of sugar consumption on stress driven, emotional and addictive behaviors
Jacques, A., Chaaya, N., Beecher, K., Ali, S. A., Belmer, A., & Bartlett, S. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.05.021 · Cited by 271 · see citing works
Alcohol, stress, and glucocorticoids: From risk to dependence and relapse in alcohol use disorders
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“…responses that are associated with decreased prefrontal executive control over stress and reward systems, which may result in increased craving and a greater susceptibility to habit-based maladaptive coping, i.e., relapse to drinking behavior (Heinz et al., 2009; Seo and Sinha, 2014; Sinha, 2008a).”
Acute stress increases circulating anandamide and other N-acylethanolamines in healthy humans
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Banishing the Control Homunculi in Studies of Action Control and Behavior Change
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COVID-19 stress and addictive social media use (SMU): mediating role of active use and social media flow
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Role of addiction and stress neurobiology on food intake and obesity
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A transdiagnostic minority stress treatment approach for gay and bisexual men's syndemic health conditions
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Brief meditation training induces smoking reduction
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Neural Correlates of Stress- and Food Cue–Induced Food Craving in Obesity
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The effects of early life stress on reward processing
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“This is an important concept in the field of addiction (Burke and Miczek, 2014b; George et al., 2012; Sinha, 2008), that is hypothesized to mediate the relationship between ELS and increased risk of substance use disorders (Andersen and Teicher, 2009).”
Background
Perceived stress and mobile phone addiction in Chinese adolescents: A moderated mediation model
Liu, Q.-Q., Zhang, D.-J., Yang, X.-J., Zhang, C.-Y., Fan, C.-Y., & Zhou, Z.-K. (2018) · Computers in Human Behavior · doi:10.1016/j.chb.2018.06.006 · Cited by 201 · see citing works
Influence of stress associated with chronic alcohol exposure on drinking
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The Effect of Stress on Consumer Saving and Spending
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Social deprivation enhances VTA synaptic plasticity and drug-induced contextual learning
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Behavioral and emotional regulation and adolescent substance use problems: a test of moderation effects in a dual-process model
Wills, T. A., Pokhrel, P., Morehouse, E., & Fenster, B. (2011) · Psychology of Addictive Behaviors · doi:10.1037/a0022870 · Cited by 157 · see citing works
Adaptogenic and Anxiolytic Effects of Ashwagandha Root Extract in Healthy Adults: A Double-blind, Randomized, Placebo-controlled Clinical Study
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Neurobiology of opioid dependence in creating addiction vulnerability
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Psychological resilience can help combat the effect of stress on problematic social networking site usage
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Restructuring reward processing with Mindfulness‐Oriented Recovery Enhancement: novel therapeutic mechanisms to remediate hedonic dysregulation in addiction, stress, and pain
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Prenatal stress alters amygdala functional connectivity in preterm neonates
Scheinost, D., Kwon, S. H., Lacadie, C., Sze, G., Sinha, R., Constable, R. T., & Ment, L. R. (2016) · NeuroImage: Clinical · doi:10.1016/j.nicl.2016.08.010 · Cited by 130 · see citing works
Self-citation
Biological mechanisms underlying the relationship between stress and smoking: State of the science and directions for future work
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Self-citation
Ghrelin's role in the hypothalamic-pituitary-adrenal axis stress response: implications for mood disorders
Spencer, S. J., Emmerzaal, T. L., Kozicz, T., & Andrews, Z. B. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.10.021 · Cited by 129 · see citing works
Psychological and biological resilience modulates the effects of stress on epigenetic aging
Harvanek, Z. M., Fogelman, N., Xu, K., & Sinha, R. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01735-7 · Cited by 123 · see citing works
Self-citation
Oxytocin and Estrogen Receptor β in the Brain: An Overview
Acevedo-Rodriguez, A., Mani, S. K., & Handa, R. J. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00160 · Cited by 124 · see citing works
Extinction of instrumental (operant) learning: interference, varieties of context, and mechanisms of contextual control
Bouton, M. E. (2019) · Psychopharmacology · doi:10.1007/s00213-018-5076-4 · Cited by 118 · see citing works
Stress- and Glucocorticoid-Induced Priming of Neuroinflammatory Responses: Potential Mechanisms of Stress-Induced Vulnerability to Drugs of Abuse
Frank, M. G., Watkins, L. R., & Maier, S. F. (2011) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2011.01.005 · Cited by 116 · see citing works
“This facilitation of drug reward processes by stress has been the subject of numerous reviews (Briand and Blendy, 2010; Koob, 2009; Sinha, 2008) and need not be reviewed here.”
Background
Interactive Effects of Cumulative Stress and Impulsivity on Alcohol Consumption
Helen C., F., Keri L., B., Peihua, G., & Rajita, S. (2010) · Alcoholism: Clinical and Experimental Research · doi:10.1111/j.1530-0277.2010.01221.x · Cited by 106 · see citing works
Mindfulness meditation in the treatment of substance use disorders and preventing future relapse: neurocognitive mechanisms and clinical implications
Priddy, S. E., Howard, M. O., Hanley, A. W., Riquino, M. R., Friberg-Felsted, K., & Garland, E. L. (2018) · Substance Abuse and Rehabilitation · doi:10.2147/sar.s145201 · Cited by 101 · see citing works
Sex differences in behavioral and neural cross-sensitization and escalated cocaine taking as a result of episodic social defeat stress in rats
Holly, E. N., Shimamoto, A., DeBold, J. F., & Miczek, K. A. (2012) · Psychopharmacology · doi:10.1007/s00213-012-2846-2 · Cited by 98 · see citing works
Emotional self-control and dysregulation: A dual-process analysis of pathways to externalizing/internalizing symptomatology and positive well-being in younger adolescents
Wills, T. A., Simons, J. S., Sussman, S., & Knight, R. (2016) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2015.08.039 · Cited by 98 · see citing works
The effect of adverse rearing environments on persistent memories in young rats: removing the brakes on infant fear memories
Callaghan, B. L., & Richardson, R. (2012) · Translational Psychiatry · doi:10.1038/tp.2012.65 · Cited by 97 · see citing works
Cue-induced reactivity, cortisol response and substance use outcome in treated heroin dependent individuals
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Effects of anxiety and mood disorders on craving and substance use among patients with substance use disorder: An ecological momentary assessment study
Fatseas, M., Serre, F., Swendsen, J., & Auriacombe, M. (2018) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2018.03.008 · Cited by 89 · see citing works
Cumulative adversity sensitizes neural response to acute stress: association with health symptoms
Seo, D., Tsou, K. A., Ansell, E. B., Potenza, M. N., & Sinha, R. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2013.250 · Cited by 88 · see citing works
Self-citation
Multigenerational and transgenerational effects of paternal exposure to drugs of abuse on behavioral and neural function
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Emotional valence and context of social influences on drug abuse-related behavior in animal models of social stress and prosocial interaction
Neisewander, J. L., Peartree, N. A., & Pentkowski, N. S. (2012) · Psychopharmacology · doi:10.1007/s00213-012-2853-3 · Cited by 87 · see citing works
Examining perceived stress, childhood trauma and interpersonal trauma in individuals with drug addiction
Garami, J., Valikhani, A., Parkes, D., Haber, P., Mahlberg, J., Misiak, B., Frydecka, D., & Moustafa, A. A. (2019) · Psychological Reports · doi:10.1177/0033294118764918 · Cited by 87 · see citing works
Intranasal oxytocin selectively modulates social perception, craving, and approach behavior in subjects with alcohol use disorder
Mitchell, J. M., Arcuni, P. A., Weinstein, D., & Woolley, J. D. (2016) · Journal of Addiction Medicine · doi:10.1097/adm.0000000000000213 · Cited by 82 · see citing works
Sex differences of gray matter morphology in cortico-limbic-striatal neural system in major depressive disorder
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Shared and specific associations of substance use disorders on adverse outcomes: A national prospective study
Franco, S., Olfson, M., Wall, M. M., Wang, S., Hoertel, N., & Blanco, C. (2019) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2019.03.003 · Cited by 82 · see citing works
A neurobehavioral approach to addiction: implications for the opioid epidemic and the psychology of addiction
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Neural stress reactivity relates to smoking outcomes and differentiates between mindfulness and cognitive-behavioral treatments
Kober, H., Brewer, J. A., Height, K. L., & Sinha, R. (2017) · NeuroImage · doi:10.1016/j.neuroimage.2016.09.042 · Cited by 75 · see citing works
Self-citation
A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation
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Self-citation
Substance use outcomes for mindfulness based relapse prevention are partially mediated by reductions in stress: results from a randomized trial
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Influence of affective manipulations on cigarette craving: a meta-analysis: Affect manipulations and craving
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Drug Addiction and Stress-Response Genetic Variability: Association Study in African Americans: Stress-Response Genes and Drug Addiction
Levran, O., Randesi, M., Li, Y., Rotrosen, J., Ott, J., Adelson, M., & Jeanne Kreek, M. (2014) · Annals of Human Genetics · doi:10.1111/ahg.12064 · Cited by 62 · see citing works
Changes in Adolescents' Psychosocial Functioning and Well-Being as a Consequence of Long-Term COVID-19 Restrictions
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Adverse childhood experiences are associated with self-regulation and the magnitude of the error-related negativity difference
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Authors: Sinha, R.
Affiliations: Yale University (US)
Corresponding author: Sinha, Rajita
ORCID: Sinha, Rajita
Venue: Annals of the New York Academy of Sciences
Publisher: Wiley
Published: 2008-10
Volume: 1141
Issue: 1
Pages: 105-130
ISSN: 0077-8923 (ISSN-L)
1749-6632
DOI: 10.1196/annals.1441.030
PMC: PMC2732004
OpenAlex: W2043559838
Cited by: 1,904
References: 342
Citations by year: 2026: 129 · 2025: 122 · 2024: 120 · 2023: 136 · 2022: 156 · 2021: 143 · 2020: 176 · 2019: 114 · 2018: 150 · 2017: 109 · 2016: 103 · 2015: 97 · 2014: 83 · 2013: 73 · 2012: 66
FWCI: 3.50
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 22 d)
Locations: Annals of the New York Academy of Sciences (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (1ul1rr024925-01)
National Institute on Alcohol Abuse and Alcoholism (R01AA013892, R01-AA-13892)
National Institute on Drug Abuse (R01-DA18219, R01DA018219, P50-DA165556, PL1DA024859)
National Center for Research Resources (U01-RR24925, UL1-RR024925)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
Keywords: chronic stress, addiction vulnerability, early life stress, child abuse, corticotropin-releasing factor, hypothalamic-pituitary-adrenal axis, noradrenergic system, mesolimbic dopamine system, glutamate, GABA, self-administration, drug-seeking behavior, stress regulation, impulse control, compulsive drug seeking, substance use risk factors
MeSH terms: Arousal, Chronic Disease, Corticotropin-Releasing Hormone, Disease Susceptibility, Emotions, Female, Humans, Hypothalamo-Hypophyseal System, Limbic System, Male, Pituitary-Adrenal System, Reward, Self Medication, Illicit Drugs, Stress, Physiological, Stress, Psychological, Substance Withdrawal Syndrome, Sympathetic Nervous System, Neurotransmitter Agents, Substance-Related Disorders

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