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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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“Processes in the central nervous system are considered to play a major role in the etiology of addiction, and the transition from chronic alcohol consumption to AUD [5].”
BackgroundBach, P., Zaiser, J., Zimmermann, S., Geßner, T., Hoffmann, S., Gerhardt, S., Berhe, O., Bekier, N. K., Abel, M., Radler, P., et al. (2023) · Alcohol · doi:10.1016/j.alcohol.2026.01.035 · Cited by 39
McNeill, A. M., Monk, R. L., Qureshi, A., Makris, S., & Heim, D. (2018) · Cognitive Affective & Behavioral Neuroscience · doi:10.3758/s13415-018-0631-3 · Cited by 39
Neuroepigenetics and addictive behaviors: Where do we stand?
Nogueira, D. D. S., Mérienne, K., & Befort, K. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.08.018 · Cited by 41
Wang, D., Zhu, T., Chen, J., Lu, Y., Zhou, C., & Chang, Y. (2020) · Frontiers in Psychology · doi:10.3389/fpsyg.2020.561590 · Cited by 39
Stubbs, J. L., Taylor, J. J., Siddiqi, S., Schaper, F. L. W. V. J., Cohen, A. L., Drew, W., Hanlon, C. A., Abdolahi, A., Wang, H. Z., Honer, W. G., et al. (2023) · Nature Mental Health · doi:10.1038/s44220-023-00128-7 · Cited by 35
“In the United States alone, more than 20 million individuals have substance use disorders, which is associated with annual costs of more than US$700 billion, related to lost productivity, healthcare and crime 3,4 .”
BackgroundEffects of Marijuana Use on Brain Structure and Function
Brumback, T., Castro, N., Jacobus, J., & Tapert, S. F. (2016) · International review of neurobiology · doi:10.1016/bs.irn.2016.06.004 · Cited by 38
Transcranial magnetic stimulation for the treatment of cocaine addiction: evidence to date
Bolloni, C., Badas, P., Corona, G., & Diana, M. (2018) · Substance Abuse and Rehabilitation · doi:10.2147/sar.s161206 · Cited by 40
Onaolapo, O. J., & Onaolapo, A. Y. (2018) · World Journal of Psychiatry · doi:10.5498/wjp.v8.i2.64 · Cited by 39
The Relational Essence of Natural Recovery: Natural Recovery as Relational Practice
Mudry, T., Nepustil, P., & Ness, O. (2018) · International Journal of Mental Health and Addiction · doi:10.1007/s11469-018-0010-x · Cited by 37
Harun, N., Johari, I. S., Mansor, S. M., & Shoaib, M. C. (2019) · Psychopharmacology · doi:10.1007/s00213-019-05418-6 · Cited by 37
Scheyer, A. F., Yasmin, F., Naskar, S., & Patel, S. (2022) · Neuropsychopharmacology · doi:10.1038/s41386-022-01438-7 · Cited by 37
“Repeated administration of these substances induces adaptive changes in DA reward circuitry leading to attenuated release in both rodent and human models [227, 228], and simultaneously induces adaptive changes in the amygdala, leading to enhanced stress-reactivity and negative affect which promote negative reinforceme…”
BackgroundNeurobiological mechanisms and related clinical treatment of addiction: a review
Fang, Y., Sun, Y., Liu, Y., Liu, T., Hao, W., & Liao, Y. (2022) · Psychoradiology · doi:10.1093/psyrad/kkac021 · Cited by 39
“…intervention based on the core characteristics of the different stages of addiction is expected to achieve therapeutic breakthroughs,and the analysis of the neuro-biological mechanisms related to therapeutic effects is conducive to finding better treatment methods (Volkow et al. , 2016).”
MethodGarland, E. L., Hanley, A. W., Bedford, C. E., Zubieta, J., Howard, M. O., Nakamura, Y., Donaldson, G. W., & Froeliger, B. (2018) · Journal of Addictive Diseases · doi:10.1080/10550887.2018.1459148 · Cited by 37
Pyeon, A., Choi, J., Cho, H., Kim, J.-Y., Choi, I. Y., Ahn, K. J., Choi, J., Chun, J., & Kim, D. (2021) · Journal of Behavioral Addictions · doi:10.1556/2006.2021.00085 · Cited by 36
Modelos animales de adicción a las drogas
García-Pardo, M. P., Sánchez, C. R., Ortí, J. E. D. L. R., & Calpe, M. A. A. (2017) · Adicciones · doi:10.20882/adicciones.862 · Cited by 35
Nelson, M. B., O’Neil, S., Wisnowski, J. L., Hart, D., Sawardekar, S., Rauh, V., Perera, F. P., Andrews, H., Hoepner, L., Garcia, W. E., et al. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.2422-18.2019 · Cited by 41
Yedinak, J. L., Goedel, W. C., Paull, K., Lebeau, R., Krieger, M. S., Thompson, C., Buchanan, A. L., Coderre, T., Boss, R., Rich, J. D., et al. (2019) · PLoS Medicine · doi:10.1371/journal.pmed.1002963 · Cited by 35
Luján, M. Á., & Valverde, O. (2020) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2020.00109 · Cited by 35
“Additionally, the circuitry involved in the regulation of mood and stress overlaps with the brain circuitry affected by motivation disorders (Koob, 2015; Volkow et al., 2016).”
da Silva, M. C. M., Gomes, G. F., Fernandes, H. D. B., Silva, A. M., Teixeira, A. L., Moreira, F. A., de Miranda, A. S., & de Oliveira, A. C. P. (2021) · Scientific Reports · doi:10.1038/s41598-021-95059-7 · Cited by 37
PTSD symptoms and alcohol-related problems among veterans: Temporal associations and vulnerability.
Simons, J. S., Simons, R. M., Keith, J. A., Grimm, K. J., Stoltenberg, S. F., O’Brien, C., & Andal, K. (2018) · Journal of Abnormal Psychology · doi:10.1037/abn0000376 · Cited by 34
Exaggerating Harmful Drug Effects on the Brain Is Killing Black People
Hart, C. L. (2020) · Neuron · doi:10.1016/j.neuron.2020.06.019 · Cited by 34
Disparities in Addiction Treatment
Jackson, D. S., Tiako, M. J. N., & Jordan, A. (2021) · Medical Clinics of North America · doi:10.1016/j.mcna.2021.08.008 · Cited by 41
Precision Psychiatry and Dual Disorders
Szerman, N., & Peris, L. (2018) · Journal of Dual Diagnosis · doi:10.1080/15504263.2018.1512727 · Cited by 34
Do Primary Emotions Predict Psychopathological Symptoms? A Multigroup Path Analysis
Fuchshuber, J., Hiebler‐Ragger, M., Kresse, A. E., Kapfhammer, H., & Unterrainer, . (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00610 · Cited by 34
Coronavirus Disease 2019 and the Impact on Substance Use Disorder Treatments
Melamed, O. C., deRuiter, W. K., Buckley, L., & Selby, P. L. (2021) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2021.11.006 · Cited by 34
“Stress can induce cravings and preoccupation with substance use that eventually culminates in substance consumption.(16) For example, those who are working toward stabilization of excess substance consumption or those in early remission usually require intensive in-person support, characterized by high”
Dong, H., Zheng, H., Wang, M., Ye, S., & Dong, G. (2022) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2022.110582 · Cited by 31
The CADM2 Gene and Behavior: A Phenome-Wide Scan in UK-Biobank
Pasman, J. A., Chen, Z., Smit, D. J. A., Vink, J. M., van den Oever, M. C., Pattij, T., Vries, T. J. D., Abdellaoui, A., & Verweij, K. J. H. (2022) · Behavior Genetics · doi:10.1007/s10519-022-10109-8 · Cited by 30
“Speculatively, CADM2 could then contribute to reward-learning and associative learning, giving rise to risky behavior, substance use, and other kinds of behaviors that involve such processes (Volkow et al. 2016).”
BackgroundSeeking legitimacy for broad understandings of substance use
Kiepek, N. C., van de Ven, K., Dunn, M., & Forlini, C. (2019) · International Journal of Drug Policy · doi:10.1016/j.drugpo.2019.07.014 · Cited by 32
Methamphetamine Consumption during Pregnancy – Effects on Child Health
Dinger, J., Hinner, P., Reichert, J., & Rüdiger, M. (2017) · Pharmacopsychiatry · doi:10.1055/s-0042-122711 · Cited by 32
“Narcan Encounters:” Overdose and Naloxone Rescue Experiences among People who use Opioids
Kahn, L. S., Wozniak, M., Vest, B. M., & Moore, C. (2020) · Substance Abuse · doi:10.1080/08897077.2020.1748165 · Cited by 32
“Among the hallmarks of substance use disorder are changes in brain neurocircuitry resulting in increased tolerance and drug dependence.(69,70) Some study participants spoke about needing larger amounts of opioids to attain the same level of euphoria that they previously experienced—and then suddenly “falling out” and…”
BackgroundMaurage, P., Bollen, Z., Masson, N., & D’Hondt, F. (2020) · Neuropsychology Review · doi:10.1007/s11065-020-09458-0 · Cited by 34
“Beyond the dual-process model, the most influential models of addictive disorders (e.g., Everitt et al., 2008; Lewis, 2018; Volkow et al., 2016) jointly underline the existence of an increased salience of addiction-related cues (related to an over-reactivity of the reward system), as well as the…”
BackgroundFairbairn, C. E., Kang, D., & Federmeier, K. D. (2020) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.11.024 · Cited by 34
Mahoney, J. J., Haut, M. W., Hodder, S., Zheng, W., Lander, L. R., Berry, J. H., Farmer, D. L., Marton, J. L., Ranjan, M., Brandmeir, N. J., et al. (2021) · Experimental and Clinical Psychopharmacology · doi:10.1037/pha0000453 · Cited by 32
“The NAc maintains direct and indirect involvement with several brain regions associated with addictive behaviors including the dorsal striatum, amygdala, hippocampus, and prefrontal cortex (Volkow et al., 2016).”
Background
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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