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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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“This paucity of treatments persists despite a medical consensus that opioid and stimulant addictions are brain disorders and, as such, should be amenable to pharmacological interventions (4).”
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Sigma Receptors and Substance Use Disorders
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Neural systems mediating the inhibition of cocaine-seeking behaviors
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GABAA receptor polymorphisms in alcohol use disorder in the GWAS era
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Shifts in the functional topography of frontal cortex‐striatum connectivity in alcohol use disorder
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“This negative affect is mediated by pathological neuroadaptations in the extended amygdala which cause the individual to return to drinking in order to escape the dysphoria (7).”
BackgroundInfluentialBarnett, A., O’Brien, K., Hall, W., & Carter, A. (2020) · Journal of Substance Abuse Treatment · doi:10.1016/j.jsat.2020.108033 · Cited by 19
Self-Injury as an Addictive Disorder.
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“However, the role of dopamine transmission is unquestionable [20].”
BackgroundCross-reinstatement of mitragynine and morphine place preference in rats
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Self-citationWorries About Discontinuing Buprenorphine Treatment: Scale Development and Clinical Correlates
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“Classical theory of addiction suggests that the molecular mechanisms of reward produced by drugs of abuse produce elevated signaling of the mesolimbic dopamine reward pathway and present as a rewarding and reinforcing drive (Volkow et al., 2016).”
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“Decades of research into the neurobiological effects of addictive substances have identi fi ed three distinct behavioral stages of addiction: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation resulting in relapse to drug use [29].”
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Individuals with substance use disorders have a distinct oral microbiome pattern
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“Over the course of addiction, substance users switch from using drugs to feel “good” to using drugs to avoid feeling “bad”, and this transition from positive to negative reinforcement parallels important changes in brain function that drive chronic use and impair adaptive decision-making (Koob and Le Moal, 2001; Koob,…”
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“However, with the continued drug use, blunted phasic dopamine release and lower BOLD response within the VS to both drug-related and non-drug-related rewards has been shown in individuals with substance use disorder (59, 61, 62).”
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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