Effects of Adrenal Sensitivity, Stress- and Cue-Induced Craving, and Anxiety on Subsequent Alcohol Relapse and Treatment Outcomes
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CONTEXT: Alcoholism is a chronic, relapsing illness in which stress and alcohol cues contribute significantly to relapse risk. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, increased anxiety, and high alcohol craving have been documented during early alcohol recovery, but their influence on relapse risk has not been well studied. OBJECTIVES: To investigate these responses in treatment-engaged, 1-month-abstinent, recovering alcohol-dependent patients relative to matched controls (study 1) and to assess whether HPA axis function, anxiety, and craving responses are predictive of subsequent alcohol relapse and treatment outcome (study 2). DESIGN: Experimental exposure to stress, alcohol cues, and neutral, relaxing context to provoke alcohol craving, anxiety, and HPA axis responses (corticotropin and cortisol levels and cortisol to corticotropin ratio) and a prospective 90-day follow-up outcome design to assess alcohol relapse and aftercare treatment outcomes. SETTING: Inpatient treatment in a community mental health center and hospital-based research unit. PARTICIPANTS: Treatment-engaged alcohol-dependent individuals and healthy controls. MAIN OUTCOME MEASURES: Time to alcohol relapse and to heavy drinking relapse. RESULTS: Significant HPA axis dysregulation, marked by higher basal corticotropin level and lack of stress- and cue-induced corticotropin and cortisol responses, higher anxiety, and greater stress- and cue-induced alcohol craving, was seen in the alcohol-dependent patients vs the control group. Stress- and cue-induced anxiety and stress-induced alcohol craving were associated with fewer days in aftercare alcohol treatment. High provoked alcohol craving to both stress and to cues and greater neutral, relaxed-state cortisol to corticotropin ratio (adrenal sensitivity) were each predictive of shorter time to alcohol relapse. CONCLUSIONS: These results identify a significant effect of high adrenal sensitivity, anxiety, and increased stress- and cue-induced alcohol craving on subsequent alcohol relapse and treatment outcomes. Findings suggest that new treatments that decrease adrenal sensitivity, stress- and cue-induced alcohol craving, and anxiety could be beneficial in improving alcohol relapse outcomes.
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The physiological reactivity elicited by stress cues may serve as a powerful catalyst for craving and subsequent relapse.
“and support the evidence that the physiological reactivity elicited by stress cues may serve as a powerful catalyst for craving and subsequent relapse (Sinha et al., 2011).”
From Cued for Risk: Evidence for an Incentive Sensitization Framework to Explain the Interplay between Stress and Anxiety, Substance Abuse, and Reward Uncertainty in Disordered Gambling Behavior (2019) · cites this paper as Sinha et al., 2011
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Zakiniaeiz, Y., Scheinost, D., Seo, D., Sinha, R., & Constable, R. T. (2016) · NeuroImage Clinical · doi:10.1016/j.nicl.2016.10.019 · Cited by 80 · see citing works
Self-citationA role for the peripheral immune system in the development of alcohol use disorders?
de Timary, P., Stärkel, P., Delzenne, N. M., & Leclercq, S. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.04.013 · Cited by 80 · see citing works
Substance use modulates stress reactivity: Behavioral and physiological outcomes
Fosnocht, A. Q., & Briand, L. A. (2016) · Physiology & Behavior · doi:10.1016/j.physbeh.2016.02.024 · Cited by 80 · see citing works
Affective vulnerability in substance use disorders
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Lu, Y.-L., & Richardson, H. N. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.06.053 · Cited by 78 · see citing works
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-citationGenetic influences on craving for alcohol
Arpana Agrawal, A., Wetherill, L. F., Bucholz, K. K., Kramer, J., Samuel Kuperman, C., Lynskey, M. T., Nürnberger, J. I., Schuckit, M. A., Tischfield, J. A., Edenberg, H. J., et al. (2012) · Addictive Behaviors · doi:10.1016/j.addbeh.2012.03.021 · Cited by 80 · see citing works
Regulation of Craving and Negative Emotion in Alcohol Use Disorder
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Transdiagnostic Connectome-Based Prediction of Craving
Garrison, K. A., Sinha, R., Potenza, M. N., Gao, S., Liang, Q., Lacadie, C., & Scheinost, D. (2023) · American Journal of Psychiatry · doi:10.1176/appi.ajp.21121207 · Cited by 68 · see citing works
Self-citationTreatment of Co-occurring Anxiety Disorders and Substance Use Disorders
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Hellberg, S. N., Levit, J. D., & Robinson, M. J. F. (2018) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.09.036 · Cited by 70 · see citing works
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“, 2009; Sinha & Li, 2007), and support the evidence that the physiological reactivity elicited by stress cues may serve as a powerful catalyst for craving and subsequent relapse (Sinha et al., 2011).”
The relationship between impulsivity and craving in alcohol dependent patients
Joos, L., Goudriaan, A. E., Schmaal, L., Witte, N. A. J. D., van den Brink, W., Sabbe, B., & Dom, G. (2012) · Psychopharmacology · doi:10.1007/s00213-012-2905-8 · Cited by 67 · see citing works
COVID-19 behavioral health and quality of life
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Computer-aided diagnosis of alcoholism-related EEG signals
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Future pharmacological treatments for substance use disorders
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Wemm, S., Larkin, C., Hermes, G., Tennen, H. A., & Sinha, R. (2019) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2019.107569 · Cited by 65 · see citing works
Self-citationTranslational opportunities in animal and human models to study alcohol use disorder
Nieto, S. J., Grodin, E. N., Aguirre, C. G., Izquierdo, A., & Ray, L. A. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01615-0 · Cited by 64 · see citing works
Xu, K., Seo, D., Hodgkinson, C. A., Hu, Y., Goldman, D. A., & Sinha, R. (2013) · Translational Psychiatry · doi:10.1038/tp.2013.62 · Cited by 63 · see citing works
Self-citationKarpyak, V. M., Biernacka, J. M., Geske, J. R., Abulseoud, O. A., Brunner, M. D., Chauhan, M., Hall‐Flavin, D. K., Lewis, K. A., Loukianova, L. L., Melnyk, G. J., et al. (2016) · Addiction · doi:10.1111/add.13386 · Cited by 65 · see citing works
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Hogarth, L., Hardy, L., Mathew, A. R., & Hitsman, B. L. (2018) · Experimental and Clinical Psychopharmacology · doi:10.1037/pha0000177 · Cited by 61 · see citing works
Brain Imaging Biomarkers to Predict Relapse in Alcohol Addiction
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Chronic childhood adversity and stages of substance use involvement in adolescents
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Gender Considerations in Addiction: Implications for Treatment
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Alcohol Effects on Stress Pathways
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Self-citationBrooks, A. T., López, M. M., Ranucci, A., Krumlauf, M., & Wallen, G. R. (2017) · Addictive Behaviors Reports · doi:10.1016/j.abrep.2017.08.002 · Cited by 58 · see citing works
Clay, J. M., & Parker, M. O. (2018) · Psychopharmacology · doi:10.1007/s00213-018-5027-0 · Cited by 60 · see citing works
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Association between a brief alcohol craving measure and drinking in the following week
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McReynolds, J. R., Doncheck, E. M., Li, Y., Vranjkovic, O., Graf, E. N., Ogasawara, D., Cravatt, B. F., Baker, D. L., Liu, Q.-S., Hillard, C. J., et al. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.09.024 · Cited by 55 · see citing works
Lovallo, W. R., Enoch, M., Acheson, A., Cohoon, A. J., Sorocco, K. H., Hodgkinson, C. A., Vincent, A. S., Glahn, D. C., & Goldman, D. A. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.101 · Cited by 54 · see citing works
Alcohol stress response dampening during imminent versus distal, uncertain threat.
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Kwako, L. E., George, D. T., Schwandt, M. L., Spagnolo, P. A., Momenan, R., Hommer, D. W., Diamond, C. A., Sinha, R., Shaham, Y., & Heilig, M. A. (2014) · Psychopharmacology · doi:10.1007/s00213-014-3665-4 · Cited by 54 · see citing works
Self-citationAlcohol and Prostate Cancer: Time to Draw Conclusions
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Neurobiology of alcohol seeking behavior
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A Rationale for Allopregnanolone Treatment of Alcohol Use Disorders: Basic and Clinical Studies
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Ramchandani, V. A., Stangl, B. L., Blaine, S. K., Plawecki, M. H., Schwandt, M. L., Kwako, L. E., Sinha, R., Cyders, M. A., O’Connor, S., & Zakhari, S. (2018) · Alcohol · doi:10.1016/j.alcohol.2018.06.001 · Cited by 49 · see citing works
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Self-citationNeuroplasticity and Predictors of Alcohol Recovery
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Fox, H. C., & Sinha, R. (2014) · Advances in pharmacology · doi:10.1016/b978-0-12-420118-7.00006-8 · Cited by 46 · see citing works
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Dopamine Response to Psychosocial Stress in Chronic Cannabis Users: A PET Study With [11C]-(+)-PHNO
Mizrahi, R., Suridjan, I., Kenk, M., George, T., Wilson, A., Houle, S., & Rusjan, P. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2012.232 · Cited by 48 · see citing works
The Corticotropin Releasing Factor Receptor 1 in Alcohol Use Disorder: Still a Valid Drug Target?
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Characterizing subjective responses to alcohol among adolescent problem drinkers.
Miranda, R., Monti, P. M., Ray, L. A., Padovano, H. T., Reynolds, E. K., Ramirez, J. J., Chun, T. H., Gwaltney, C. J., Justus, A. N., Tidey, J. W., et al. (2014) · Journal of Abnormal Psychology · doi:10.1037/a0035328 · Cited by 44 · see citing works
Peripheral and prefrontal stress system markers and risk of relapse in alcoholism
Blaine, S. K., Seo, D., & Sinha, R. (2015) · Addiction Biology · doi:10.1111/adb.12320 · Cited by 44 · see citing works
Self-citation
- Authors
- Sinha, R.
- Affiliations
- Yale University (US)
- Corresponding author
- Sinha, Rajita
- ORCID
- Sinha, Rajita
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2011-09-01
- Volume
- 68
- Issue
- 9
- Pages
- 942
- ISSN
- 0003-990X (ISSN-L)
- PMC
- PMC3668981
- OpenAlex
- W2065577847
- Cited by
- 368
- References
- 42
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 23 · 2023: 25 · 2022: 15 · 2021: 29 · 2020: 24 · 2019: 27 · 2018: 24 · 2017: 26 · 2016: 34 · 2015: 29 · 2014: 30 · 2013: 22 · 2012: 31
- FWCI
- 21.93
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (R01AA013892, R01-AA-13892)
- National Institute on Drug Abuse (P60DA005130, PL1DA024859)
- National Institute of Dental and Craniofacial Research (UL1DE019586)
- National Center for Research Resources (UL1RR024139)
- Topics
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Keywords
- alcohol relapse, alcoholism, HPA axis dysregulation, adrenal sensitivity, alcohol craving, alcohol cues, anxiety, cortisol, ACTH, alcohol recovery, predictors of relapse
- MeSH terms
- Adrenal Glands, Adrenocorticotropic Hormone, Adult, Alcoholism, Anxiety, Cues, Female, Humans, Hydrocortisone, Hypothalamo-Hypophyseal System, Male, Middle Aged, Pituitary-Adrenal System, Psychotherapy, Recurrence, Relaxation Therapy, Stress, Psychological, Case-Control Studies, Behavior, Addictive
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