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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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Neural Variability and Cognitive Control in Individuals With Opioid Use Disorder
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Sleep alterations in substance use disorders: a systematic review and meta-analysis
Oliva, H. N. P., Prudente, T. P., Naveda, A. M. P., Monteiro-Júnior, R. S., Potenza, M. N., MORGAN, P. T., & Angarita, G. A. (2026) · EClinicalMedicine · doi:10.1016/j.eclinm.2025.103723 · Cited by 9
Eskandari, K., Fattahi, M., Yazdanian, H., & Haghparast, A. (2022) · Neurochemical Research · doi:10.1007/s11064-022-03818-3 · Cited by 7
Methylphenidate as a treatment option for substance use disorder: a transdiagnostic perspective
van Ruitenbeek, P., Franzen, L., Mason, N. L., Stiers, P. L. J., & Ramaekers, J. G. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1208120 · Cited by 8
“In support, transcranial direct current stimulation of the DLPFC can improve inhibitory control and reduces impulsivity in ADHD patients (140).”
BackgroundInfluentialPointing Fingers: Who US Adults Blame for the Opioid Overdose Epidemic
Kim, Y., Kresovich, A., MacLean, K., Lamuda, P. A., Ngobo-Ekamby, M., McQueen, C., Schneider, J. A., Pollack, H. A., & Taylor, B. G. (2024) · Substance Use & Addiction Journal · doi:10.1177/29767342241262556 · Cited by 8
“29 Regarding OUD as a medical condition is associated with lower levels of stigma, not endorsing OUD as a crime, and agreeing with policies to help people access OUD treat-ment.”
Role of serotonin neurons in the dorsal raphe nucleus in heroin self-administration and punishment
Li, C., McCloskey, N. S., Inan, S., & Kirby, L. G. (2024) · Neuropsychopharmacology · doi:10.1038/s41386-024-01993-1 · Cited by 10
“Our study, to the best of our knowledge, is the fi rst to show that in the presence of mild contingent footshock, rats self-administering heroin can be separated into punishment-resistant or punishment-sensitive phenotypes.”
The overlapping neurobiology of addiction and ADHD
Eme, R. F. (2017) · Mental Health and Addiction Research · doi:10.15761/mhar.1000129 · Cited by 8
Opioid Overdose Protocols in the Emergency Department: Are We Asking the Right Questions?
Doran, K. M., Raja, A. S., & Samuels, E. A. (2018) · Annals of Emergency Medicine · doi:10.1016/j.annemergmed.2018.05.024 · Cited by 8
Alsebaaly, J., Dugast, E., Favot, L., Khabbaz, L. R., Solinas, M., & Thiriet, N. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00457 · Cited by 8
Systemic Issues in the Opioid Epidemic: Supporting the Individual, Family, and Community
Vincenzes, K. A., McMahon, B., Lange, J., & Forziat‐Pytel, K. (2018) · International Journal of Mental Health and Addiction · doi:10.1007/s11469-018-0041-3 · Cited by 8
Gladwin, T. E. (2019) · Alcoholism and Drug Addiction · doi:10.5114/ain.2019.85769 · Cited by 8
The grey future: Overgenerality of emotional future thinking in alcohol-use disorders
Nandrino, J., & Haj, M. E. (2019) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2019.107659 · Cited by 11
Guillou-Landréat, M., Beauvais, C., Grall‐Bronnec, M., Goff, D. L., Reste, J. Y. L., Lever, D., Dany, A., & Gallopel‐Morvan, K. (2020) · Substance Abuse Treatment Prevention and Policy · doi:10.1186/s13011-020-00329-8 · Cited by 8
Padovano, H. T., & Miranda, R. (2021) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2021.108642 · Cited by 8
Lanzillotta‐Rangeley, J., Zeller, T. A., Beachler, T., Litwin, A. H., Clark, A. K., & Stem, J. (2021) · Pain Management Nursing · doi:10.1016/j.pmn.2021.03.004 · Cited by 8
Linking drug and food addiction via compulsive appetite
Laque, A., Wagner, G. E., Matzeu, A., Ness, G. L. D., Kerr, T. M., Carroll, A. M., de Guglielmo, G., Nedelescu, H., Buczynski, M. W., Gregus, A. M., et al. (2022) · British Journal of Pharmacology · doi:10.1111/bph.15797 · Cited by 8
“Extensive cocaine histories cause aberrant neuroadaptations in the reward circuits, thereby dysregulating motivation for this non-caloric reward and ultimately manifesting as compulsive drug craving and use (Volkow et al., 2016).”
BackgroundWeinberg, D. (2022) · International Journal of Drug Policy · doi:10.1016/j.drugpo.2022.103609 · Cited by 8
Decesare, J. Z. (2017) · Cambridge University Press eBooks · doi:10.1017/9781316662571.029 · Cited by 8
Huang, C.-Y., Hung, C., Ho, Y.-J., & Fang, S. (2022) · International Journal of Mental Health and Addiction · doi:10.1007/s11469-022-00872-4 · Cited by 8
“From view of early prevention, only a fraction of people who used illicit drugs eventually became addicted due to their difference in susceptibility (Volkow et al., 2016); hence, we need practical susceptibility markers that can be used in real-world contexts to tailor interventions for those at…”
Person, A. K., Armstrong, W. S., Evans, T. S., Fangman, J. J. W., Goldstein, R. H., Haddad, M. S., Jain, M. K., Keeshin, S. W., Tookes, H. E., Weddle, A., et al. (2022) · Clinical Infectious Diseases · doi:10.1093/cid/ciac626 · Cited by 8
The Executive Functioning Paradox in Substance Use Disorders
Jakubiec, L., Chirokoff, V., Abdallah, M., Sanz‐Arigita, E., Dupuy, M., Swendsen, J. D., Berthoz, S., Gierski, F., Guionnet, S., Misdrahi, D., et al. (2022) · Biomedicines · doi:10.3390/biomedicines10112728 · Cited by 8
“EF deficits have also been associated with decreases in frontal cortex activity and other markers of brain function [11,12].”
BackgroundFeatures of Addiction in Binge-Eating Disorder: Considerations for Screening and Treatment
Paul, A. M., Ghanta, A., & Chao, A. M. (2023) · Substance Abuse and Rehabilitation · doi:10.2147/sar.s391636 · Cited by 10
“Chronic Status Addictions are frequently viewed as chronic and relapsing brain disorders because neurobiological changes take place which can never be completely cured, even in remission.(26) To be in remission, the patient must meet 2 of the DSM-5 criteria for SUD over a 12-month period while being abstinent from the…”
Pepe, M., Nicola, M. D., Cocciolillo, F., Chiappini, S., Martinotti, G., Calcagni, M. L., & Sani, G. (2024) · Pharmaceuticals · doi:10.3390/ph17040452 · Cited by 8
“According to the disease model of addiction, SUD relies on the interplay of biological, psychological, and social factors, which can lead to long-lasting neuroadaptations in brain structure and functioning (e.g., in neurotransmission and blood flow) [70].”
BackgroundManaging Opioid Use in Orthopaedic Patients Through Harm Reduction Strategies
Worley, J. (2019) · Orthopaedic Nursing · doi:10.1097/nor.0000000000000524 · Cited by 9
Factorial validity of a substance-use stigma scale in methamphetamine-using adults in China
Chen, S., Ma, Y., Cai, W., Moretta, T., Wang, X., Liu, T., & Potenza, M. N. (2019) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2019.107677 · Cited by 8
Toward isolating reward changes in diet-induced obesity: A demand analysis
Batten, S. R., Hicks, K., Dwoskin, L. P., & Beckmann, J. S. (2019) · Physiology & Behavior · doi:10.1016/j.physbeh.2019.112729 · Cited by 8
Transcranial magnetic stimulation and addiction: Toward uncovering known unknowns
Steele, V. R. (2020) · EBioMedicine · doi:10.1016/j.ebiom.2020.102839 · Cited by 8
Stress-related endogenous neuropeptides induce neuronal excitation in the Laterodorsal Tegmentum
Leguizamón, C. R. R., & Kohlmeier, K. A. (2020) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2020.07.008 · Cited by 8
Rationally Risking Addiction: A Two-Stage Approach
Kühn, M., & Wrzaczek, S. (2020) · Dynamic modeling and econometrics in economics and finance · doi:10.1007/978-3-030-54576-5_4 · Cited by 8
Wscieklica, T., Sueur, L. D. P. L., Prearo, L. C., Conte, R., Viana, M. D. B., & Céspedes, I. C. (2019) · The American Journal of Drug and Alcohol Abuse · doi:10.1080/00952990.2019.1569667 · Cited by 10
Asking How Our Patients Understand Addiction
Jack, H. E., Oller, D. A., Kelly, J. F., Magidson, J. F., & Wakeman, S. E. (2018) · The American Journal of Medicine · doi:10.1016/j.amjmed.2018.09.007 · Cited by 8
Li, G., Zhang, Z., Zhang, Y., Tang, X., & Li, C.-S. R. (2023) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2023.111734 · Cited by 7
Davies, J. N., Harty, S. C., & Boden, J. M. (2024) · Personality and Mental Health · doi:10.1002/pmh.1611 · Cited by 7
“Cannabis use in adolescence is associated with declines in cognitive processing, memory impairment, an increased likelihood of risky behaviours and an increased risk among those with a genetic predisposition to developing a psychotic disorder (Volkow et al., 2016).”
Pickard, H. (2024) · Mind & Language · doi:10.1111/mila.12502 · Cited by 7
“2 https://nida.nih.gov; see also Volkow et al. (2016); Leshner (1997) is the classic statement.”
BackgroundProblematic Gaming and Gambling: A Systematic Review of Task-Specific EEG Protocols
Šimkutė, D., Dores, A. R., Barbosa, F., & Griškova-Bulanova, I. (2024) · Journal of Gambling Studies · doi:10.1007/s10899-024-10332-4 · Cited by 7
“Addiction emerges as an imbalance in the information processing and integration among various brain circuits and functions (Campanella et al., 2014; Volkow et al., 2016).”
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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