The new england journal of medicine

Review Article

Dan L. Longo, M.D., Editor Neurobiologic Advances from the Brain Disease Model of

Nora D. Volkow, M.D., George F. Koob, Ph.D., and A. Thomas McLellan, Ph.D.​​

his article reviews scientific advances in the prevention and From the National Institute on Drug treatment of substance-use disorder and related developments in public Abuse (N.D.V.) and the National Institute of Abuse and (G.F.K.) policy. In the past two decades, research has increasingly supported the — both in Bethesda, MD; and the Treat- T ment Research Institute, Philadelphia view that addiction is a disease of the brain. Although the brain disease model of addiction has yielded effective preventive measures, treatment interventions, and (A.T.M.). Address reprint requests to Dr. Volkow at the National Institute on Drug public health policies to address substance-use disorders, the underlying concept Abuse, 6001 Executive Bld., Rm. 5274, of substance abuse as a brain disease continues to be questioned, perhaps because Bethesda, MD 20892, or at ­nvolkow@​ the aberrant, impulsive, and compulsive behaviors that are characteristic of addic- ­nida​.­nih​.­gov. tion have not been clearly tied to neurobiology. Here we review recent advances in N Engl J Med 2016;374:363-71. the neurobiology of addiction to clarify the link between addiction and brain func- DOI: 10.1056/NEJMra1511480 Copyright © 2016 Massachusetts Medical Society. tion 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 func- tions such as decision making, , and self-regulation that leads to repeated relapse. We also review the ways in which social environments, develop- mental stages, and genetics are intimately linked to and influence vulnerability and recovery. We conclude that neuroscience continues to support the brain dis- ease model of addiction. Neuroscience research in this area not only offers new opportunities for the prevention and treatment of substance 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 behav- ioral 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, alco- hol, 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 ad- diction). 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 pro- vide 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

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Box 1. Definitions. Advances in neurobiology have begun to clarify the mechanisms underlying the profound In this article, the terms apply to the use of alcohol, tobacco and , pre- disruptions in decision-making ability and emo- scription drugs, and illegal drugs. Substance-use disorder: A diagnostic term in the fifth edition of the Diag- tional balance displayed by persons with drug nostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent addiction. These advances also provide insight use of alcohol or other drugs that causes clinically and functionally significant into the ways in which fundamental biologic impairment, such as health problems, disability, and failure to meet major re- sponsibilities at work, school, or home. Depending on the level of severity, processes, when disrupted, can alter voluntary this disorder is classified as mild, moderate, or severe. behavioral control, not just in drug addiction but Addiction: A term used to indicate the most severe, chronic stage of sub- also in other, related disorders of self-regula- stance-use disorder, in which there is a substantial loss of self-control, as indi- cated by compulsive drug taking despite the desire to stop taking the drug. In tion, such as obesity and pathologic gambling the DSM-5, the term addiction is synonymous with the classification of severe and video-gaming — the so-called behavioral substance-use disorder. addictions. Although these disorders also mani- fest as compulsive behaviors, with impaired self- would reduce prison sentences for some nonvio- regulation, the concept of behavioral addiction lent drug offenders,6 which is a substantial shift is still controversial, particularly as it relates to in policy fueled in part by the growing realiza- obesity. (Behavioral addictions are described in tion among law-enforcement leaders that “reduc- Box S2 in the Supplementary Appendix.9) This ing incarceration will improve public safety be- research has also begun to show how and why cause people who need treatment for drug and early, voluntary drug use can interact with envi- alcohol problems or mental health issues will be ronmental and genetic factors to result in addic- more likely to improve and reintegrate into soci- tion in some persons but not in others. ety if they receive consistent care.”7 Nonetheless, despite the scientific evidence Stages of Addiction and the resulting advances in treatment and changes in policy, the concept of addiction as a For heuristic purposes, we have divided addic- disease of the brain is still being questioned. tion into three recurring stages: binge and in- The concept of addiction as a disease of the toxication, withdrawal and negative affect, and brain challenges deeply ingrained values about preoccupation and anticipation (or craving).10 self-determination and personal responsibility Each stage is associated with the activation of that frame drug use as a voluntary, hedonistic specific neurobiologic circuits and the conse- act. In this view, addiction results from the rep- quential clinical and behavioral characteristics etition of voluntary behaviors. How, then, can it (Fig. 1). be the result of a disease process? The concept of addiction as a brain disease has even more Binge and Intoxication disconcerting implications for public attitudes All known addictive drugs activate reward re- and policies toward the addict. This concept of gions in the brain by causing sharp increases in addiction appears to some to excuse personal the release of .11-13 At the receptor level, irresponsibility and criminal acts instead of pun- these increases elicit a reward signal that trig- ishing harmful and often illegal behaviors. Ad- gers associative learning or conditioning. In this ditional criticisms of the concept of addiction as type of Pavlovian learning, repeated experiences a brain disease include the failure of this model of reward become associated with the environ- to identify genetic aberrations or brain abnor- mental stimuli that precede them. With repeated malities that consistently apply to persons with exposure to the same reward, dopamine cells addiction and the failure to explain the many in- stop firing in response to the reward itself and stances in which recovery occurs without treat- instead fire in an anticipatory response to the ment. (Arguments against the disease model of conditioned stimuli (referred to as “cues”) that addiction and counterarguments in favor of it8 in a sense predict the delivery of the reward.14 are presented in Box S1 in the Supplementary This process involves the same molecular mech- Appendix, available with the full text of this ar- anisms that strengthen synaptic connections ticle at NEJM.org.) during learning and memory formation (Box 2).

364 n engl j med 374;4 nejm.org January 28, 2016 The New England Journal of Medicine Downloaded from nejm.org on July 6, 2016. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved. Advances from the Brain Disease Model of Addiction

Binge and intoxication BRAIN Thalamus

Withdrawal and Anterior negative affect cingulate cortex Globus pallidus Dorsal striatum

Hippocampus Basal nucleus of the stria terminalis Orbitofrontal cortex Ventral striatum

Response Stress and to drug reward

Preoccupation and anticipation

Neuroadaptations

Neurocircuits Synaptic Molecules Epigenetics systems

Stage of Addiction Shifting Drivers Resulting from Neuroadaptations

Binge and intoxication Feeling euphoric Feeling good Escaping dysphoria

Withdrawal and negative affect Feeling reduced energy Feeling reduced excitement Feeling depressed, anxious, restless

Preoccupation and anticipation Looking forward Desiring drug Obsessing and planning to get drug

Behavioral Changes Voluntary action Sometimes taking when not intending Impulsive action Abstinence Sometimes having trouble stopping Relapse Constrained drug taking Sometimes taking more than intended Compulsive consumption

Figure 1. Stages of the Addiction Cycle. During intoxication, drug-induced activation of the brain’s reward regions (in blue) is enhanced by conditioned cues in areas of increased (in green). During withdrawal, the activation of brain regions involved in emotions (in pink) results in negative mood and enhanced sensitivity to stress. During preoccupation, the decreased function of the prefrontal cortex leads to an inability to balance the strong desire for the drug with the will to abstain, which triggers relapse and reinitiates the cycle of addiction. The compromised neuro- circuitry reflects the disruption of the dopamine and glutamate systems and the stress-control systems of the brain, which are affected by corticotropin-releasing factor and dynorphin. The behaviors during the three stages of addiction change as a person transitions from drug experimentation to addiction as a function of the progressive neuroadaptations that occur in the brain.

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Box 2. Drug-Induced . natural satiation and continue to directly increase dopamine levels,11,26 a factor that helps to ex- The drug-induced release of dopamine triggers neuroplasticity (systematic plain why compulsive behaviors are more likely changes in the synaptic signaling, or communication, between neurons in ­various reward regions of the brain).15,16 These neuroplastic changes are fun- to emerge when people use drugs than when damental to learning and memory. Experience-dependent learning (such as they pursue a natural reward (Box 2). that which occurs in repeated episodes of drug use) may invoke both long- term potentiation, in which the transmission of signals between neurons in- Withdrawal and Negative Affect creases, and long-term depression, in which signal transmission decreases. Synaptic strength is controlled by the insertion or removal of receptors An important result of the conditioned physio- that are stimulated by the excitatory neurotransmitter glutamate (which acts logic processes involved in drug addiction is that largely through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] and N-methyl-d-aspartate [NMDA] receptors) and by changes in the composi- ordinary, healthful rewards lose their former tion of the subunits of these receptors. Specifically, the insertion of a subunit motivational power. In a person with addiction, of the AMPA receptor that is highly permeable to calcium, glutamate receptor 2 the reward and motivational systems become (GluR2), enhances the efficiency of transmission and has been shown to con- tribute to long-term potentiation in animal studies of addiction.17 Changes in reoriented through conditioning to focus on the long-term potentiation and long-term depression are in turn associated with more potent release of dopamine produced by larger or smaller synapses, respectively, and with differences in the shapes of the drug and its cues. The landscape of the per- the dendritic spines in the receptive site of the receiving neuron.18 The up-regulation of AMPA receptors that are highly permeable to calcium son with addiction becomes restricted to one of increases the responsiveness of the to glutamate, which is cues and triggers for drug use. However, this is released by cortical and limbic terminals when exposed to drugs or drug cues.17 only one of the ways in which addiction changes Neuroplastic changes triggered by drugs have been uncovered not only in the nucleus accumbens (a crucial brain-reward region) but also in the dorsal stria- motivation and behavior. tum (a region implicated in the encoding of habits and routines), the amygdala For many years it was believed that over time (a region involved in emotions, stress, and desires), the hippocampus (a re- persons with addiction would become more sen- gion involved in memory), and the prefrontal cortex (a region involved in self- regulation and the attribution of salience [the assignment of relative value]). sitive to the rewarding effects of drugs and that All these regions of the brain participate in the various stages of addiction, in- this increased sensitivity would be reflected in cluding conditioning and craving (see Fig. 1). These regions also regulate the higher levels of dopamine in the circuits of their firing of dopamine cells and the release of dopamine.19 brains that process reward (including the nu- cleus accumbens and the dorsal striatum) than In this way, environmental stimuli that are re- the levels in persons who never had a drug ad- peatedly paired with drug use — including envi- diction. Although this theory seemed to make ronments in which a drug has been taken, per- sense, research has shown that it is incorrect. In sons with whom it has been taken, and the fact, clinical and preclinical studies have shown mental state of a person before it was taken — that drug consumption triggers much smaller may all come to elicit conditioned, fast surges of increases in dopamine levels in the presence of dopamine release that trigger craving for the addiction (in both animals and humans) than in drug20 (see Box 2 for the mechanisms involved), its absence (i.e., in persons who have never used motivate drug-seeking behaviors, and lead to drugs).22,23,27,28 This attenuated release of dopa- heavy “binge” use of the drug.21-23 These condi- mine renders the brain’s much tioned responses become deeply ingrained and less sensitive to stimulation by both drug-related can trigger strong cravings for a drug long after and non–drug-related rewards.29-31 As a result, use has stopped (e.g., owing to incarceration or persons with addiction no longer experience the treatment) and even in the face of sanctions same degree of from a drug as they did against its use. when they first started using it. It is for this As is true with other types of motivational same reason that persons with addiction often learning, the greater the motivational attribute become less motivated by everyday stimuli (e.g., associated with a reward (e.g., a drug), the relationships and activities) that they had previ- greater the effort a person is willing to exert and ously found to be motivating and rewarding. the greater the negative consequences he or she Again, it is important to note that these changes will be willing to endure in order to obtain it.24,25 become deeply ingrained and cannot be imme- However, whereas dopamine cells stop firing diately reversed through the simple termination after repeated consumption of a “natural re- of drug use (e.g., detoxification). ward” (e.g., food or sex) satiating the drive to In addition to resetting the brain’s reward sys- further pursue it, addictive drugs circumvent tem, repeated exposure to the dopamine-enhanc-

366 n engl j med 374;4 nejm.org January 28, 2016 The New England Journal of Medicine Downloaded from nejm.org on July 6, 2016. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved. Advances from the Brain Disease Model of Addiction ing effects of most drugs leads to adaptations and emotional circuits of prefrontal regions is in the circuitry of the extended amygdala in the further disrupted by neuroplastic changes in basal forebrain; these adaptations result in in- glutamatergic signaling.37 In persons with addic- creases in a person’s reactivity to stress and lead tion, the impaired signaling of dopamine and to the emergence of negative emotions.32,33 This glutamate in the prefrontal regions of the brain “antireward” system is fueled by the neurotrans- weakens their ability to resist strong urges or to mitters involved in the stress response, such as follow through on decisions to stop taking the corticotropin-releasing factor and dynorphin, drug. These effects explain why persons with which ordinarily help to maintain homeostasis. addiction can be sincere in their desire and in- However, in the addicted brain, the antireward tention to stop using a drug and yet simultane- system becomes overactive, giving rise to the ously impulsive and unable to follow through on highly dysphoric phase of drug addiction that their resolve. Thus, altered signaling in prefron- ensues when the direct effects of the drug wear tal regulatory circuits, paired with changes in off or the drug is withdrawn34 and to the de- the circuitry involved in reward and emotional creased reactivity of dopamine cells in the brain’s response, creates an imbalance that is crucial to reward circuitry.35 Thus, in addition to the direct both the gradual development of compulsive and conditioned pull toward the “rewards” of behavior in the addicted disease state and the drug use, there is a correspondingly intense mo- associated inability to voluntarily reduce drug- tivational push to escape the discomfort associ- taking behavior, despite the potentially cata- ated with the aftereffects of use. As a result of strophic consequences. these changes, the person with addiction transi- tions from taking drugs simply to feel pleasure, Biologic and Social Factors or to “get high,” to taking them to obtain tran- Involved in Addiction sient relief from dysphoria (Fig. 1). Persons with addiction frequently cannot Only a minority of people who use drugs ulti- understand why they continue to take the drug mately become addicted — just as not everyone when it no longer seems pleasurable. Many state is equally at risk for the development of other that they continue to take the drug to escape the chronic diseases. Susceptibility differs because distress they feel when they are not intoxicated. people differ in their vulnerability to various Unfortunately, although the short-acting effects genetic, environmental, and developmental fac- of increased dopamine levels triggered by drug tors. Many genetic, environmental, and social administration temporarily relieve this distress, factors contribute to the determination of a the result of repeated bingeing is to deepen the person’s unique susceptibility to using drugs dysphoria during withdrawal, thus producing a initially, sustaining drug use, and undergoing vicious cycle. the progressive changes in the brain that charac- terize addiction.38,39 Factors that increase vulner- Preoccupation and Anticipation ability to addiction include family history (pre- The changes that occur in the reward and emo- sumably through heritability and child-rearing tional circuits of the brain are accompanied by practices), early exposure to drug use (adoles- changes in the function of the prefrontal corti- cence is among the periods of greatest vulnera- cal regions, which are involved in executive bility to addiction), exposure to high-risk environ- processes. Specifically, the down-regulation of ments (typically, socially stressful environments dopamine signaling that dulls the reward cir- with poor familial and social supports and re- cuits’ sensitivity to pleasure also occurs in pre- stricted behavioral alternatives and environments frontal brain regions and their associated cir- in which there is easy access to drugs and per- cuits, seriously impairing executive processes, missive normative attitudes toward drug taking), among which are the capacities for self-regula- and certain mental illnesses (e.g., mood disor- tion, decision making, flexibility in the selection ders, attention deficit–hyperactivity disorder, and initiation of action, attribution of salience psychoses, and anxiety disorders).40,41 (the assignment of relative value), and the moni- It is estimated that the most severe pheno- toring of error.36 The modulation of the reward typic characteristics of addiction will develop in

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approximately 10% of persons exposed to addic- terventions should be designed to enhance so- tive drugs.42 Thus, although long-term exposure cial skills and improve self-regulation. Also im- to drugs is a necessary condition for the devel- portant are early screening and intervention for opment of addiction, it is by no means suffi- the prodromal presentation of mental illness cient. Yet for those in whom there is progress to and the provision of social opportunities for per- addiction, the neurobiologic changes are distinct sonal educational and emotional development.46-49 and profound. When prevention has failed and there is need for treatment, research based on the brain dis- Implications of the Brain ease model of addiction has shown that medical Disease Model of Addiction treatment can help to restore healthy function in for Prevention and Treatment the affected brain circuitry and lead to improve- ments in behavior. The health care system al- As is the case in other medical conditions in ready has at its disposal several evidence-based which voluntary, unhealthful behaviors contrib- treatment interventions that could improve clin- ute to disease progression (e.g., heart disease, ical outcomes in patients with substance-use diabetes, chronic pain, and lung cancer), evi- disorders if properly and comprehensively imple- dence-based interventions aimed at prevention, mented. During treatment, medication can as- along with appropriate public health policies, sist in preventing relapse while the brain is are the most effective ways of changing out- healing and normal emotional and decision- comes. A more comprehensive understanding of making capacities are being restored. For pa- the brain disease model of addiction may help to tients with opioid-use disorder, maintenance moderate some of the moral judgment attached therapy with agonists or partial agonists such as to addictive behaviors and foster more scientific methadone or buprenorphine can be essential in and public health–oriented approaches to pre- helping to control symptoms of withdrawal and vention and treatment. cravings.50 Opioid antagonists such as extended- release naltrexone may be used to prevent opioid Behavioral and Medical Interventions intoxication.51 Naltrexone and acamprosate have The findings from neurobiologic research show been efficacious in the treatment of alcohol-use that addiction is a disease that emerges gradu- disorders, and other medications can help in the ally and that has its onset predominantly during recovery from nicotine addiction.27 a particular risk period: adolescence. Adoles- The brain disease model of addiction has also cence is a time when the still-developing brain is fostered the development of behavioral interven- particularly sensitive to the effects of drugs, a tions to help restore balance in brain circuitry factor that contributes to adolescents’ greater that has been affected by drugs.52 For example, vulnerability to drug experimentation and addic- strategies to enhance the salience of natural, tion. Adolescence is also a period of enhanced healthy rewards such as social contact or exer- neuroplasticity during which the underdeveloped cise could enable those rewards to compete with neural networks necessary for adult-level judg- the direct and acquired motivating properties of ment (the prefrontal cortical regions) cannot yet drugs. Strategies to mitigate a person’s stress properly regulate emotion. Studies have also reactivity and negative emotional states could shown that children and adolescents with evi- help to manage the strong urges they engender, dence of structural or functional changes in and strategies to improve executive function and frontal cortical regions or with traits of novelty self-regulation could help recovering patients seeking or are at greater risk for plan ahead in order to avoid situations in which substance-use disorders.43-45 Awareness of indi- they are particularly vulnerable to taking drugs. vidual and social risk factors and the identifica- Finally, strategies to help patients recovering tion of early signs of substance-use problems from addiction to change their circle of friends make it possible to tailor prevention strategies to and to avoid drug-associated environmental cues the patient. According to research related to the can reduce the likelihood that conditioned crav- brain disease model of addiction, preventive in- ing will lead to relapse.

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Public Health Policy tions for alleged discrimination against patients A compelling argument for the translational who were wrongly denied benefits related to value of the brain disease model of addiction is addiction and mental health after patients with the knowledge that the prefrontal and other diabetes were used as the comparators. The ac- cortical networks that are so critical for judg- tion was taken on the basis of the amount and ment and self-regulation do not fully mature extent of preauthorization required for the treat- until people reach 21 to 25 years of age.53 As a ment of patients with substance-use disorder result, the adolescent brain is much less able to versus those with diabetes, the arbitrary and cognitively modulate strong desires and emo- capricious manner in which the insurers stopped tions. This observation is particularly relevant to treatment, and the lack of treatment alternatives the establishment of 21 years of age as the legal offered or even suggested to patients.56 The settle- drinking age in the United States, a ruling that ment has not been contested, and the organiza- is often questioned even though a dramatic re- tions stopped their discriminatory preauthoriza- duction in highway deaths followed its institu- tion procedures. A similar suit has been filed in tion.54 One could legitimately argue that the California. study of the neurobiology of addiction provides Similarly, there are early indications that the a compelling argument for leaving the drinking integration of primary care and specialty behav- age at 21 years and for increasing the legal ioral health care can substantially improve the smoking age to 21 years, by which time the management of substance-use disorders and the brain networks that underlie the capacity for treatment of many addiction-related medical con- self-regulation are more fully formed. ditions, including the human immunodeficiency The brain disease model of addiction has also virus, hepatitis C virus, cancer, cirrhosis, and informed policies that take advantage of the in- trauma.57,58 frastructure of primary health care to address Despite such reports of benefits to the public substance-use disorders and to provide a model from practices and policies generated by re- for paying for it through the Mental Health Par- search based on the brain disease model of ad- ity and Addiction Equity Act (MHPAEA) and the diction, mobilizing support for further research Affordable Care Act. Although it is still too early will require the public to become better educat- to evaluate the effects of these policies on the ed about the genetic, age-related, and environ- nation, an initial examination of the MHPAEA in mental susceptibilities to addiction as they relate three states showed increased enrollment and to structural and functional changes in the brain. care delivery among patients with substance-use If early voluntary drug use goes undetected and disorders and an overall reduction in spending unchecked, the resulting changes in the brain on emergency department visits and hospital can ultimately erode a person’s ability to control stays.55 the impulse to take addictive drugs. The social and financial effects of these laws Dr. McLellan reports receiving fees for serving on the board are also illustrated in the recent legal action of directors of Indivior Pharmaceuticals. No other potential conflict of interest relevant to this article was reported. taken by the State of New York against Value Disclosure forms are available with the full text of this article Options and two other managed-care organiza- at NEJM.org.

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