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Neurobiologic Advances from the Brain Disease Model of Addiction
Open accessAbstract
This article reviews scientific advances in the prevention and treatment of substance-use disorder and related developments in public policy. In the past two decades, research has increasingly supported the view that addiction is a disease of the brain. Although the brain disease model of addiction has yielded effective preventive measures, treatment interventions, and public health policies to address substance-use disorders, the underlying concept of substance abuse as a brain disease continues to be questioned, perhaps because the aberrant, impulsive, and compulsive behaviors that are characteristic of addiction have not been clearly tied to neurobiology. Here we review recent advances in the neurobiology of addiction to clarify the link between addiction and brain function and to broaden the understanding of addiction as a brain disease. We review findings on the desensitization of reward circuits, which dampens the ability to feel pleasure and the motivation to pursue everyday activities; the increasing strength of conditioned responses and stress reactivity, which results in increased cravings for alcohol and other drugs and negative emotions when these cravings are not sated; and the weakening of the brain regions involved in executive functions such as decision making, inhibitory control, and self-regulation that leads to repeated relapse. We also review the ways in which social environments, developmental stages, and genetics are intimately linked to and influence vulnerability and recovery. We conclude that neuroscience continues to support the brain disease model of addiction. Neuroscience research in this area not only offers new opportunities for the prevention and treatment of substance addictions and related behavioral addictions (e.g., to food, sex, and gambling) but may also improve our understanding of the fundamental biologic processes involved in voluntary behavioral control. In the United States, 8 to 10% of people 12 years of age or older, or 20 to 22 million people, are addicted to alcohol or other drugs. 1 The abuse of tobacco, alcohol, and illicit drugs in the United States exacts more than $700 billion annually in costs related to crime, lost work productivity, and health care. 2-4 After centuries of efforts to reduce addiction and its related costs by punishing addictive behaviors failed to produce adequate results, recent basic and clinical research has provided clear evidence that addiction might be better considered and treated as an acquired disease of the brain (see Box 1 for definitions of substance-use disorder and addiction). Research guided by the brain disease model of addiction has led to the development of more effective methods of prevention and treatment and to more informed public health policies. Notable examples include the Mental Health Parity and Addiction Equity Act of 2008, which requires medical insurance plans to provide the same coverage for substance-use disorders and other mental illnesses that is provided for other illnesses, 5 and the proposed bipartisan Senate legislation that From the National Institute on Drug Abuse (N.D.V.) and the National Institute of Alcohol Abuse and Alcoholism (G.F.K.) — both in Bethesda, MD; and the Treatment Research Institute, Philadelphia (A.T.M.). Address reprint requests to Dr. Volkow at the National Institute on Drug Abuse, 6001 Executive Bld., Rm. 5274, Bethesda, MD 20892, or at nvolkow@ nida . nih . gov.
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“There is a growing consensus that SUDs, once developed, tend to be chronic disorders 161 , reflecting long- lasting changes in brain function 50,51 , that are exacerbated by the cumulative mental health and social consequences that they trigger.”
From Substance use disorders: a comprehensive update of classification, epidemiology, neurobiology, clinical aspects, treatment and prevention (2023) · cites this paper as [50]
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“The transition from controlled drug use into addiction mani fests itself in a repetitive cycle of intoxication, withdrawal and craving 49 , occurring along with a deterioration of mood that the addicted individual experiences as dysphoria/depression, anxi ety, irritability and anhedonia when not intoxicated 50 .”
From Substance use disorders: a comprehensive update of classification, epidemiology, neurobiology, clinical aspects, treatment and prevention (2023) · cites this paper as [50]
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“Animal models have shown that both ethanol intake and anticipation prompt dopamine release in the NAc, impacting the mesocorticolimbic system associated with craving, reward, and behavioral control”
From A Narrative Review of Current and Emerging Trends in the Treatment of Alcohol Use Disorder (2024) · cites this paper as [111]
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“emerging evidence has pointed out that addiction is in fact associated with structural and functional brain alterations, including deficits in reward, attention, memory and motivation mechanisms (3)”
From Addiction Psychotherapy: Going Beyond Self-Medication (2022) · cites this paper as [4]
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“Further research demonstrated the reciprocal nature of these neurobiological deficits, suggesting that they serve both as a cause for addiction, in predisposing individuals toward the onset of addiction, and as the effect of addiction, in further altering some neurobiological mechanisms, and even genetics, following intensive and prolonged intoxication (4).”
From Addiction Psychotherapy: Going Beyond Self-Medication (2022) · cites this paper as [4]
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“Case–control neuroimaging studies of the brain with high-resolution provide early evidence for altered brain integrity in brain regions with a high density of CB1 receptors in heavy cannabis users [75].”
From Cannabis, cannabinoids and health: a review of evidence on risks and medical benefits (2025) · cites this paper as [75]
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“The primary subcortical brain target is the nucleus accumbens (NAc) which is considered the center of the reward circuitry and heavily implicated in substance use and craving [18–22].”
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“CRH affects hormones involved in the stress response, including cortisol, and has been associated with the stress response and relapse to drug taking in animals39,40.”
From Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use (2019) · cites this paper as [40]
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Alizadehgoradel, J., Imani, S., Vahid, N., Vanderhasselt, M., Molaei, B., Salehinejad, M. A., Ahmadi, S., & Taherifard, M. (2021) · Clinical Psychopharmacology and Neuroscience · doi:10.9758/cpn.2021.19.4.653 · Cited by 29
Calabrese, S. K., Kalwicz, D. A., Modrakovic, D. X., Earnshaw, V. A., Edelman, E. J., Bunting, S. R., del Río‐González, A. M., Magnus, M., Mayer, K. H., Hansen, N. B., et al. (2021) · AIDS and Behavior · doi:10.1007/s10461-021-03495-3 · Cited by 28
“For example, a provider may believe a patient’s drug use will contribute to adherence challenges and compromise the patient’s ability to carry out responsibilities because the provider is aware of the potential biological effects of drug use on executive functioning [75], reasoning that would not necessarily detract f…”
BackgroundBiomarkers of the Endocannabinoid System in Substance Use Disorders
Navarrete, F., García‐Gutiérrez, M. S., Gasparyan, A., Navarro, D., Lopez‐Picon, F. R., Morcuende, Á., Femenía, T., & Manzanares, J. (2022) · Biomolecules · doi:10.3390/biom12030396 · Cited by 26
“These changes are linked to neuroplastic and morphological changes in the PFC glutamatergic neurons [18].”
BackgroundEmerging Drug Use Trends in Kelantan, Malaysia
Desrosiers, A., Chooi, W.-T., Zaharim, N. M., Ahmad, I., Yasin, M. A. M., Jaapar, S. Z. S., Schottenfeld, R. S., Vicknasingam, B. K., & Chawarski, M. C. (2016) · Journal of Psychoactive Drugs · doi:10.1080/02791072.2016.1185553 · Cited by 27
Gonzalez, D. A., Jia, T., Pinzón, J. H., Acevedo, S. F., Ojelade, S. A., Xu, B., Tay, N., Desrivières, S., Hernández, J. L., Banaschewski, T., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.112 · Cited by 27
Ethanol induces interferon expression in neurons via TRAIL: role of astrocyte-to-neuron signaling
Lawrimore, C. J., Coleman, L. G., & Crews, F. T. (2019) · Psychopharmacology · doi:10.1007/s00213-018-5153-8 · Cited by 27
Curing the broken brain model of addiction: Neurorehabilitation from a systems perspective
Wiers, R. W. H. J., & Verschure, P. F. M. J. (2020) · Addictive Behaviors · doi:10.1016/j.addbeh.2020.106602 · Cited by 31
Dying on Hospice in the Midst of an Opioid Crisis: What Should We Do Now?
Gabbard, J., Jordan, A. E., Mitchell, J., Corbett, M., White, P., & Childers, J. W. (2018) · American Journal of Hospice and Palliative Medicine® · doi:10.1177/1049909118806664 · Cited by 27
Stress as a Risk Factor for Substance Use Disorders: A Mini-Review of Molecular Mediators
Mukhara, D., Banks, M. L., & Neigh, G. N. (2018) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2018.00309 · Cited by 26
Liu, X., & Wang, S. (2021) · Psychiatry Research · doi:10.1016/j.psychres.2021.114241 · Cited by 26
Time Perception in Cocaine-Dependent Patients
Mioni, G., Sanguin, N., Madeo, G., & Cardullo, S. (2022) · Brain Sciences · doi:10.3390/brainsci12060745 · Cited by 26
“Dysregulation of the dopaminergic system is also related to chronic use of drugs such as stimulants [11].”
BackgroundAcute alcohol administration dampens central extended amygdala reactivity
Hur, J., Kaplan, C. M., Smith, J. F., Bradford, D. E., Fox, A. S., Curtin, J. J., & Shackman, A. J. (2018) · Scientific Reports · doi:10.1038/s41598-018-34987-3 · Cited by 26
Fuchshuber, J., & Unterrainer, H. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.00531 · Cited by 32
“While contradicting evidence from neuroscientific research (83, 90, 127), this finding might be the result of conceptual differences between functional aspects of the ML-DA or SEEKING system and the trait like disposition towards SEEKING assessed by the ANPS.”
ResultChen, H., Zhao, B., Li, X., Xie, R., & Li, W. (2020) · Substance Use & Misuse · doi:10.1080/10826084.2020.1846195 · Cited by 28
“Traditionally, pharmacological perspectives on smoking have regarded the nicotine present in cigarettes to be a highly addictive substance that makes it difficult for heavy smokers to quit smoking (Volkow et al., 2016).”
BackgroundMaldonado, R. J., Calvé, P., García‐Blanco, A., Domingo‐Rodriguez, L., Senabre, E., & Martín‐García, E. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108466 · Cited by 33
“In the DSM-5, the term addiction is now synonymous with the concept of severe substance-use disorder (Volkow et al., 2016).”
InfluentialZhu, T., Tao, W., Peng, B., Su, R., Wang, D., Hu, C. Y., & Chang, Y. (2021) · International Journal of Mental Health and Addiction · doi:10.1007/s11469-021-00518-x · Cited by 28
“The brain disease model of addiction suggests that the mental craving and impulsivity associated with relapse risk are caused by cognitive impairment (Koob & Volkow, 2016; Volkow et al., 2016).”
BackgroundNeuroadaptations and TGF-β signaling: emerging role in models of neuropsychiatric disorders
Mitra, S., Werner, C. T., & Dietz, D. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01186-y · Cited by 29
Updated Perspectives on the Neurobiology of Substance Use Disorders Using Neuroimaging
Murnane, K. S., Edinoff, A. N., Cornett, E. M., & Kaye, A. D. (2023) · Substance Abuse and Rehabilitation · doi:10.2147/sar.s362861 · Cited by 29
“The disease model of substance addiction 14,15 is a widely accepted theory that views substance misuse as a chronic brain disorder characterized by significant alterations in brain structure and function.”
Extended treatment for cigarette smoking cessation: a randomized control trial
Laude, J. R., Bailey, S. R., Crew, E., Varady, A. N., Lembke, A., McFall, D., Jeon, A., Killen, D. T., Killen, J. D., & David, S. P. (2017) · Addiction · doi:10.1111/add.13806 · Cited by 26
Mellis, A. M., Snider, S. E., & Bickel, W. K. (2018) · Experimental and Clinical Psychopharmacology · doi:10.1037/pha0000168 · Cited by 26
Animal models in addiction research: A dimensional approach
Lamontagne, S. J., & Olmstead, M. C. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.06.005 · Cited by 25
Predictors of cocaine use disorder treatment outcomes: a systematic review
Palazón-Llecha, A., Caparrós, B., Trujols, J., Duran‐Sindreu, S., Batlle, F., Madre, M., & Mallorquí‐Bagué, N. (2024) · Systematic Reviews · doi:10.1186/s13643-024-02550-z · Cited by 25
“Consequently, impulsivity increases, placing youths at greater risk of engaging in drug and other risky behaviors [43, 44].”
BackgroundCrane, N. A., Funkhouser, C. J., Burkhouse, K. L., Klumpp, H., Phan, K. L., & Shankman, S. A. (2020) · Addictive Behaviors · doi:10.1016/j.addbeh.2020.106669 · Cited by 26
“During the transition to SUD, brain reward circuitry becomes hypoactive, or less sensitive, to rewards (Volkow et al., 2016).”
BackgroundAschbacher, K., Hendershot, C. S., Tison, G. H., Hahn, J. A., Avram, R., Olgin, J. E., & Marcus, G. M. (2021) · npj Digital Medicine · doi:10.1038/s41746-021-00441-4 · Cited by 25
“This study engineered autoregressive features representing within-user behavior trends, which provided one means to quantitatively represent alcohol use as a habitual behavior 24 .”
BackgroundCalarco, C. A., Fox, M. E., Terheyden, S. V., Turner, M. D., Alipio, J. B., Chandra, R., & Lobo, M. K. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.737389 · Cited by 27
Kang, T., Ding, X., Zhao, J., Li, X., Xie, R., Jiang, H., He, L., Hu, Y., Liang, J., Zhou, G., et al. (2022) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2022.06.010 · Cited by 25
Guan, Y., Shangguan, R., Ke, Y., & Wang, S. (2022) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph19158983 · Cited by 29
Allain, F., Delignat‐Lavaud, B., Beaudoin, M.-P., Jacquemet, V., Robinson, T. E., Trudeau, L., & Samaha, A. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-020-0773-1 · Cited by 25
A Narrative Review of Current and Emerging Trends in the Treatment of Alcohol Use Disorder
Celik, M., Gold, M. S., & Fuehrlein, B. (2024) · Brain Sciences · doi:10.3390/brainsci14030294 · Cited by 25
“Animal models have shown that both ethanol intake and anticipation prompt dopamine release in the NAc, impacting the mesocorticolimbic system associated with craving, reward, and behavioral control [111].”
BackgroundApplication of the DREADD technique in biomedical brain research
Dobrzański, G., & Kossut, M. M. (2016) · Pharmacological Reports · doi:10.1016/j.pharep.2016.10.015 · Cited by 24
Global susceptibility and response to noncommunicable diseases
Hatefi, A., Allen, L. N., Bollyky, T. J., Roache, S. A., & Nugent, R. A. (2018) · Bulletin of the World Health Organization · doi:10.2471/blt.17.206763 · Cited by 24
Perski, O., Herd, N. L., West, R., & Brown, J. (2018) · Addictive Behaviors · doi:10.1016/j.addbeh.2018.11.030 · Cited by 28
Current Understanding of the Neurobiology of Opioid Use Disorder: an Overview
Moningka, H., Lichenstein, S. D., & Yip, S. W. (2019) · Current Behavioral Neuroscience Reports · doi:10.1007/s40473-019-0170-4 · Cited by 24
Markert, C., Klein, S., Strahler, J., Kruse, O., & Stark, R. M. (2021) · Journal of Behavioral Addictions · doi:10.1556/2006.2021.00018 · Cited by 27
“…behavioral, physiological and cognitive response to addiction-related stimuli (Berridge & Robinson, 2016; Tiffany & Wray, 2012) is an important concept to explain the transition from occasional use of a drug to addictive use (Brand et al., 2019; Koob & Volkow, 2010; Volkow, Koob, & McLellan, 2016).”
Biochemical Mechanisms Associating Alcohol Use Disorders with Cancers
Rodriguez, F. D., & Coveñas, R. (2021) · Cancers · doi:10.3390/cancers13143548 · Cited by 27
“The brain uses its neurochemical circuitry to adapt and tackle the presence of alcohol [3-6].”
BackgroundInternet-use disorders: A theoretical framework for their conceptualization and diagnosis
Wegmann, E., Billieux, J., & Brand, M. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-822201-0.00022-8 · Cited by 26
Metadata
- Authors
- Volkow, N. D., Koob, G. F., & McLellan, A. T.
- Affiliations
- National Institute on Drug Abuse (US)
- National Institute on Alcohol Abuse and Alcoholism (US)
- Treatment Research Institute (US)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2016-01-28
- Volume
- 374
- Issue
- 4
- Pages
- 363-371
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC6135257
- OpenAlex
- W2283026346
- Cited by
- 2,008
- References
- 52
- Citations by year
- 2026: 264 · 2025: 198 · 2024: 172 · 2023: 193 · 2022: 179 · 2021: 208 · 2020: 245 · 2019: 160 · 2018: 154 · 2017: 178 · 2016: 54
- FWCI
- 19.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99‐AA999999)
- National Institute on Drug Abuse
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Social Sciences › Psychology › Clinical Psychology › Gambling Behavior and Treatments
- Keywords
- brain disease model of addiction, neurobiology of addiction, substance use disorders, conditioned response, stress reactivity, drug craving, executive function, relapse, behavioral addiction, addiction genetics, social environment, addiction prevention, addiction treatment, public health policy, Mental Health Parity and Addiction Equity Act
- MeSH terms
- Brain Diseases, Humans, Models, Neurological, Substance Withdrawal Syndrome, Substance-Related Disorders
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