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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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“We can interpret these results in the light of the model of addiction presented by Volkow et al. (2016).”
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“Impaired daily reinforcement learning is an important aspect of addiction pathology, and also has practical and theoretical meaningfulness (Volkow et al., 2016).”
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“However, there is a dominant biomedical explanatory model in which drug addiction is often characterized by loss of control and a compulsive relationship with the drug (Volkow & Li, 2004; Volkow et al., 2016).”
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Bio-Behavioral Indices of Emotion Regulation: Potential Targets for Treatment in Addiction
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Aqeel, K. I., & Misra, S. K. (2020) · International Journal of Community Medicine and Public Health · doi:10.18203/2394-6040.ijcmph20204764 · Cited by 4
Prevention and Treatment of Sex Addiction
Reid, R. C., Grubbs, J. B., & Kraus, S. W. (2020) · Cambridge University Press eBooks · doi:10.1017/9781108632591.025 · Cited by 4
Protocol Design and Implementation for Monitoring Parental Substance Use in Child Custody Litigation
Weiss, C. J. (2021) · Family Court Review · doi:10.1111/fcre.12544 · Cited by 2
Tavares, V. D. D. O., Schuch, F. B., Vancampfort, D., Jenkins, M., Rêgo, M. L. D. M., Coelho, N. L. G., & Cabral, D. A. R. (2021) · Physiology & Behavior · doi:10.1016/j.physbeh.2021.113587 · Cited by 4
Luongo, N. M. (2021) · International Journal of Drug Policy · doi:10.1016/j.drugpo.2021.103450 · Cited by 7
Zhai, T., Gu, H., & Yang, Y. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.768602 · Cited by 3
“…example, in exploring neurobiological mechanisms of substance use disorder, a highly relapsing chronic brain disease (Dutra et al., 2008; Koob and Volkow, 2016; Volkow et al., 2016) currently without effective Frontiers in Neuroscience | www.frontiersin.org 1 November 2021 | Volume 15 | Article…”
BackgroundShaari, A. A. H. (2021) · Pertanika Journal of Social Sciences and Humanities · doi:10.47836/pjssh.29.4.12 · Cited by 3
Нейроиммуноэндокринные нарушения при психических расстройствах и болезнях зависимости
(2018) · Сибирский вестник психиатрии и наркологии · doi:10.26617/1810-3111-2018-2(99)-45-55 · Cited by 4
Food addiction and metabolic diseases
Meléndez-Diego, K. S., Mendiola-Pastrana, I. R., López‐Ortiz, E., Henríquez, L. F. R., Guízar-Sánchez, D., Zentella, A. G. C., & López-Ortiz, G. (2022) · Alad · doi:10.24875/alad.21000027 · Cited by 7
Ochterbeck, D., Frense, J., & Forberger, S. (2023) · Addiction Research & Theory · doi:10.1080/16066359.2023.2189244 · Cited by 4
“After a considerable period of promoting and funding research on brain-based explanations of addiction, the majority of the participants do not consider the hopes and expectations placed in this approach fully met (Leshner 1997; Volkow et al. 2016; Volkow and Boyle 2018).”
BackgroundInfluentialKoenig, H. G., VanderWeele, T. J., & Peteet, J. R. (2023) · Oxford University Press eBooks · doi:10.1093/oso/9780190088859.003.0002 · Cited by 5
Ethics at the Intersection of Chronic Pain and Substance Use
Kofi, L. S., Sud, A., & Buchman, D. Z. (2018) · Developments in neuroethics and bioethics · doi:10.1016/bs.dnb.2018.08.007 · Cited by 4
Blanco, A. P., López, M. L., Machado, I. C., González, M. V., Costa, X. C., Pérez, V. B., Spuch, C., & Otero-Lamas, F. (2019) · African journal of rhetoric · doi:10.21134/haaj.v19i1.412 · Cited by 4
Bogren, A. (2019) · Addiction Research & Theory · doi:10.1080/16066359.2018.1524880 · Cited by 4
Billieux, J., & Maurage, P. (2021) · Addictive Behaviors · doi:10.1016/j.addbeh.2021.106842 · Cited by 5
Insights in Public Health: Methamphetamine Use during COVID-19 in Hawai'i.
Kiyokawa, M., Cape, M. C., & Streltzer, J. (2021) · PubMed Central · Cited by 4
Arenas, M. C., Castro‐Zavala, A., Martín‐Sánchez, A., Blanco-Gandía, M. C., Miñarro, J., Valverde, O., & Manzanedo, C. (2021) · Behavioural Brain Research · doi:10.1016/j.bbr.2021.113545 · Cited by 4
“Cocaine addiction is characterized by a high and persistent susceptibility to relapse [3], and its compulsive use is a serious public health problem with an important social and economic impact [4–6].”
Machine Learning Classification Model for Identifying Pornography Addiction Among Children
Kang, X., Handayani, D. O. D., & Kit, M. H. (2021) · IEEE International Conference on Computing, Engineering and Design (ICCED) · doi:10.1109/icced53389.2021.9664849 · Cited by 4
Shaffer, S. K., & Stockdale, C. K. (2017) · Cambridge University Press eBooks · doi:10.1017/9781316662571.033 · Cited by 4
Carruthers, S., & Sutton-Inocencio, E. (2023) · Critical Care Nursing Quarterly · doi:10.1097/cnq.0000000000000463 · Cited by 4
Second Trimester Pregnancy Loss
Casey, F. E. (2017) · Cambridge University Press eBooks · doi:10.1017/9781316662571.026 · Cited by 5
Drug analyses in human plasma by chromatography
Ali, I., Suhail, M., ALOthman, Z. A., Abdulrahman, A., & Aboul-Enein, H. Y. (2019) · Handbook of analytical separations · doi:10.1016/b978-0-444-64066-6.00002-2 · Cited by 5
Reward Circuitry and Drug Addiction
Steele, V. R., Pariyadath, V., Goldstein, R. Z., & Stein, E. A. (2017) · Oxford University Press eBooks · doi:10.1093/med/9780190681425.003.0044 · Cited by 4
The Substance-Use Prevention Workforce: An International Perspective
Sumnall, H. R. (2019) · Advances in prevention science · doi:10.1007/978-3-030-00627-3_25 · Cited by 4
Causal Explanation in Psychiatry
Pernu, T. K. (2019) · Bloomsbury Publishing Plc eBooks · doi:10.5040/9781350024090.ch-011 · Cited by 4
Burke, M. A., Sullivan, R., Carman, K. G., Wen, H., Wharam, J. F., & Yu, H. (2021) · Working paper series · doi:10.29412/res.wp.2021.03 · Cited by 4
“The condition is also characterized as a chronic brain disease rooted in neurobiology (Volkow et al. 2016).”
BackgroundHyman, S. M., Richardson, G. B., Andrés-Hyman, R. C., & Fox, H. C. (2020) · Springer eBooks · doi:10.1007/978-3-319-16999-6_3855-1 · Cited by 4
Dopamine “Ups and Downs” in Addiction RevisitedPreprint
Samaha, A., Khoo, S. Y., Ferrario, C. R., & Robinson, T. E. (2020) · PsyArXiv (OSF Preprints) · doi:10.31234/osf.io/8vch5 · Cited by 4
Standardising early liver transplantation for severe alcohol-related hepatitis
Im, G. Y. (2022) · The Lancet. Gastroenterology & hepatology · doi:10.1016/s2468-1253(22)00171-6 · Cited by 4
Wang, K., Li, Y., Zhang, T., Liu, H., & Luo, J. (2025) · General Hospital Psychiatry · doi:10.1016/j.genhosppsych.2025.01.001 · Cited by 4
Sonkaya, Z. İ., & Yazgan, B. (2025) · BMC Psychology · doi:10.1186/s40359-025-03247-1 · Cited by 6
“Acute substance use lowers the reward threshold, while chronic use raises this threshold, creating a need for progressively higher amounts to achieve the same effect [9, 10].”
Zhang, H., Kader, G., Zhang, H., Zhao, H. V., Pan, W., & Lei, P. (2025) · BMC Psychiatry · doi:10.1186/s12888-025-07200-9 · Cited by 4
“According to Volkow et al. [74], chronic substance use leads to downregulation of dopamine D2 receptors and reduced baseline dopaminergic tone, resulting in diminished sensitivity to natural rewards.”
Raketić, D., Lalović, N., Barišić, J., Celic, I., & Milovanović, S. (2025) · Scientific Reports · doi:10.1038/s41598-025-25967-5 · Cited by 4
“Although acute withdrawal symptoms are typically resolved within 1–2 weeks, post-acute withdrawal syndrome (PAWS)—characterized by persistent emotional and cognitive disturbances—can last for several months 63–65 .”
Chen, J., Zhang, Z., Fu, S., Wen, B., Chen, Z., & Wang, X. C. (2025) · BMC Psychiatry · doi:10.1186/s12888-025-07663-w · Cited by 5
“These findings underscore the importance of guiding individuals toward healthier emotional values, providing potential intervention targets for those with IGD and comorbid anxiety.”
The rising burden of drug use disorders in the Americas, 2000–2021
Martínez, R., Zapata, M. A., Tausch, A., Lange, S., Russell, C., Hennis, A. J. M., & Souza, R. O. E. (2025) · Revista Panamericana de Salud Pública · doi:10.26633/rpsp.2025.132 · Cited by 3
Goto, Y., Krieger, J., Won, M., & Lee, Y.-A. (2026) · Frontiers in Psychology · doi:10.3389/fpsyg.2026.1753662 · Cited by 5
“Volkow et al. (2016) have argued that “ … as is the case for any other medical condition, there is a severity dimension … and that only a small percentage of those with a substance use disorder fall in the most severe category… this severity dimension and the mechanisms underlying the transition…”
InfluentialAzahar, Q., & Mansor, S. (2026) · Brain Imaging and Behavior · doi:10.1007/s11682-026-01132-y · Cited by 3
“…drug craving or acute exposure, while hypometabolism is often observed in the prefrontal cortex, anterior cingulate cortex, and other executive control regions, which are responsible for inhibitory control, decision-making, and behavioural regulation (Bosch et al., 2013; Volkow et al., 2016).”
Samulenaite, S., Parkitna, J. M. R., Baltriukienė, D., Martín‐García, E., Maldonado, R. J., & Burokas, A. (2026) · Gut Microbes · doi:10.1080/19490976.2026.2647535 · Cited by 3
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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