PERSPECTIVES

The aberrant behavioural manifestationsthat occur during addiction have beenviewed by many as ‘choices’ of the addictedindividual, but recent imaging studies haverevealed an underlying disruption to brainregions that are important for the normalprocesses of motivation, reward and inhib-itory control in addicted individuals1. Thisprovides the basis for a different view: thatdrug addiction is a disease of the brain, andthe associated abnormal behaviour is theresult of dysfunction of brain tissue, just ascardiac insufficiency is a disease of the heartand abnormal blood circulation is the resultof dysfunction of myocardial tissue2 (FIG. 1).Therefore, although initial drug experimen-tation and recreational use might be volitio-nal, once addiction develops this control ismarkedly disrupted. Although imaging stud-ies consistently show specific abnormalitiesin the brain function of addicted individu-als, not all addicted individuals show theseabnormalities. This highlights the need forfurther research to delineate other neuro-biological processes that are involved inaddiction.

Chronic exposure to drugs of abuse isrequired for drug addiction, and its expres-sion involves complex interactions betweenbiological and environmental factors. Thismight explain why some individuals becomeaddicted and others do not, and why attemptsto understand addiction as a purely biologicalor a purely environmental disease have beenlargely unsuccessful. Recently, important dis-coveries have increased our knowledge ofhow drugs affect gene expression, protein

products and neuronal circuits3, and howthese biological factors might affect humanbehaviour. This sets the stage for a betterunderstanding of how different environmen-tal factors interact with biological factors andcontribute to patterns of behaviour that leadto addiction.

Here, we summarize how new methodolo-gies that allow us to study genes, molecularbiology and the human brain are providing uswith a greater understanding of drug addic-tion, and the implications of these findings forthe prevention and treatment of addiction.

Addiction: a developmental disorderNormal developmental processes mightresult in a higher risk of drug use at certaintimes in life than others. Experimentationoften starts in adolescence, as does the processof addiction4 (FIG. 2). Normal adolescent-specific behaviours (such as risk-taking,novelty-seeking and response to peer pres-sure) increase the propensity to experimentwith legal and illegal drugs5, which mightreflect incomplete development of brainregions (for example, myelination of frontallobe regions)6 that are involved in the pro-cesses of executive control and motivation. Inaddition, studies indicate that drug exposureduring adolescence might result in differentneuroadaptations from those that occurduring adulthood. For example, in rodents,exposure to nicotine during the period thatcorresponds to adolescence, but not duringadulthood, led to significant changes innicotine receptors and an increased rein-forcement value for nicotine later in life7.Future research might allow us to clarifywhether this is the reason that adolescentsseem to become addicted to nicotine afterless nicotine exposure than adults8. Similarly,further studies might enable us to determinewhether the increased neuroadaptations toalcohol that occur during adolescence, com-pared with those that occur during adult-hood9 explain the greater vulnerability toalcoholism in individuals who start usingalcohol early in life10.

Abstract | Drug addiction manifests as acompulsive drive to take a drug despiteserious adverse consequences. Thisaberrant behaviour has traditionally beenviewed as bad ‘choices’ that are madevoluntarily by the addict. However, recentstudies have shown that repeated drug useleads to long-lasting changes in the brain thatundermine voluntary control. This, combinedwith new knowledge of how environmental,genetic and developmental factors contributeto addiction, should bring about changes inour approach to the prevention andtreatment of addiction.

Drugs, both legal (for example, alcohol andnicotine) and illegal (such as cocaine, meth-amphetamine, heroin and marijuana) aremisused for various reasons, including forpleasurable effects, the alteration of mentalstate, to improve performance and, in certaininstances, for self-medication of a mental disorder. Repeated drug use can result inaddiction, which is manifested as an intensedesire for the drug with an impaired ability tocontrol the urges to take that drug, even at theexpense of serious adverse consequences. Toavoid confusion with physical dependence, theterm ‘drug addiction’ is used here instead of‘drug dependence’, which is the clinical termfavoured by the Diagnostic and StatisticalManual of Mental Disorders (fourth edition;DSM-IV). Physical dependence results in with-drawal symptoms when drugs, such as alcoholand heroin, are discontinued, but the adapta-tions that are responsible for these effects aredifferent from those that underlie addiction.

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Drug addiction: the neurobiology ofbehaviour gone awry

Nora D. Volkow and Ting-Kai Li

S C I E N C E A N D S O C I E T Y

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with the drug become salient. These previouslyneutral stimuli then increase dopamine bythemselves and elicit the desire for the drug21.This explains why the addicted person isat risk of relapsing when exposed to an envi-ronment where he/she has previously takenthe drug.

If natural reinforcers increase dopamine,why do they not lead to addiction? The differ-ence might be due to qualitative and quantita-tive differences in the increases in dopamineinduced by drugs, which are greater in magni-tude (at least five- to tenfold) and durationthan those induced by natural reinforcers13. Inaddition, whereas the dopamine increasesproduced by natural reinforcers in the NAcundergo habituation, those induced by drugsof abuse do not12. Non-decremental dopa-mine stimulation of the NAc from repeateddrug use strengthens the motivational proper-ties of the drug, which does not occur fornatural reinforcers.

Neurobiology of drug addictionAddiction probably results from neuro-biological changes that are associated withchronic and intermittent supraphysiologicalperturbations in the dopamine system, whichoccur in the same circuits that affect bio-logically important functions1. We and othershave postulated that adaptations in thesedopaminergic circuits make the addictedindividual more responsive to the supra-physiological increases in dopamine that areproduced by drugs of abuse and less sensitiveto the physiological increases in dopamineproduced by natural reinforcers22. Recentadvances in both molecular biology andimaging have increased our insight into howthese neural adaptations occur.

At a cellular level, drugs have beenreported to alter the expression of certaintranscription factors (nuclear proteins thatbind to regulatory regions of genes, therebyregulating their transcription into mRNA), aswell as a wide variety of proteins involved inneurotransmission in brain regions that areregulated by dopamine17. The long-lastingchanges that occur in the transcription fac-tors δFosB and cAMP responsive element binding protein (CREB) after chronic drugadministration are of particular interestbecause they modulate the synthesis of pro-teins that are involved in synaptic plasticity3.Indeed, chronic drug exposure alters the mor-phology of neurons in dopamine-regulatedcircuits. For example, in rodents, chroniccocaine or amphetamine administrationincreases neuronal dendritic branching andspine density in the NAc and prefrontal cortex— an adaptation that is thought to participate

firing through their effects on nicotine, GABA,mu opiate or cannabinoid CB1 receptors,respectively15.

It seems that increases in dopamine arenot directly related to reward per se, as waspreviously believed, but rather to the predic-tion of reward16 and for salience17. Saliencerefers to stimuli or environmental changesthat are arousing or that elicit an attentional–behavioural switch18. Salience, which, inaddition to reward, applies to aversive, newand unexpected stimuli, affects the motiva-tion to seek the anticipated reward and facili-tates conditioned learning19,20. This provides adifferent perspective about drugs, as it impliesthat drug-induced increases in dopamine willinherently motivate further procurement ofmore drug (regardless of whether or not theeffects of the drug are consciously perceivedto be pleasurable). Indeed, some addictedindividuals report that they seek the drugeven though its effects are no longer pleasur-able. Drug-induced increases in dopaminewill also facilitate conditioned learning, sopreviously neutral stimuli that are associated

Neurobiology of drugs of abuseMany neurotransmitters, including GABA(γ-aminobutyric acid), glutamate, acetyl-choline, dopamine, serotonin and endogenousopioid peptides, have been implicated in theeffects of the various types of drugs of abuse.Of these, dopamine has been consistentlyassociated with the reinforcing effects of mostdrugs of abuse. Drugs of abuse increase extra-cellular dopamine concentrations in limbicregions, including the nucleus accumbens(NAc)11,12. Specifically, it seems that the rein-forcing effects of drugs of abuse are due totheir ability to surpass the magnitude andduration of the fast dopamine increases thatoccur in the NAc when triggered by naturalreinforcers such as food and sex13. Drugs suchas cocaine, amphetamine, methamphetamineand ecstasy increase dopamine by inhibitingdopamine reuptake or promoting dopaminerelease through their effects on dopaminetransporters14. Other drugs, such as nicotine,alcohol, opiates and marijuana, work indirectlyby stimulating neurons (GABA-mediated orglutamatergic) that modulate dopamine cell

a Brain

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Figure 1 | Drug addiction as a disease of the brain. Images of the brain (a) in a healthy control and in anindividual addicted to a drug, and parallel images of the heart (b) in a healthy control and in an individual witha myocardial infarction. The images were obtained with positron emission tomography (PET) and [18F]fluoro-2-deoxyglucose (FDG–PET) to measure glucose metabolism, which is a sensitive indicator of damage tothe tissue in the brain and the heart. Note the decreased glucose metabolism in the OFC (orbitofrontalcortex; arrow) of the addicted person and the decreased metabolism in the myocardial tissue (arrow) in theperson with a myocardial infarct. Damage to the OFC will result in improper inhibitory control andcompulsive behaviour, and damage to the myocardium will result in improper blood circulation. Althoughabnormalities in the OFC are some of the most consistent findings in imaging studies of addicted individuals(including alcoholics), they are not detected in all addicted individuals. This implies that disruption of thisfrontal region is not the only mechanism that underlies the addictive process. Heart images courtesy of H. Schelbert, University of California at Los Angeles.

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Environmental factors. Environmental factorsthat have been consistently associated withthe propensity to self-administer drugsinclude low socio-economic class, poorparental support and drug availability. Stressmight be a common feature in a wide varietyof environmental factors that increase the riskfor drug abuse. The mechanisms responsiblefor stress-induced increases in vulnerability todrug use and to relapse in people who areaddicted are not yet well understood, butthere is evidence that the stress-responsiveneuropeptide corticotropin-releasing factor isinvolved through its effects in the amygdalaand the pituitary–adrenal axis35.

Imaging techniques now allow us toinvestigate how environmental factors affectthe brain and how these, in turn, affect thebehavioural responses to drugs of abuse. Forexample, in non-human primates, socialstatus affects D2-receptor expression in thebrain, which in turn affects the propensity forcocaine self-administration36. Animals thatachieve a dominant status in the group showincreased numbers of D2 receptors and arereluctant to administer cocaine, whereasanimals that are subordinate have lowerD2-receptor numbers and readily administercocaine. As animal studies have shown thatincreasing D2 receptors in NAc markedlydecreases drug consumption (which has beenshown for alcohol37), this could provide amechanism by which a social stressor couldmodify the propensity to self-administerdrugs.

Co-morbidity with mental illness. The riskfor substance abuse and addiction in individ-uals with mental illness is significantly higherthan for the general population. The highco-morbidity probably reflects, in part, over-lapping environmental, genetic and neuro-biological factors that influence drug abuseand mental illness38.

It is likely that different neurobiologicalfactors are involved in co-morbidity depend-ing on the temporal course of its develop-ment (that is, mental illness followed by drugabuse or vice versa). In some instances, themental illness and addiction seem to co-occur independently39, but in others theremight be a sequential dependency. It hasbeen proposed that co-morbidity might bedue to the use of the abused drugs to self-medicate the mental illness in cases in whichthe onset of mental illness is followed byabuse of some types of drug. But, whendrug abuse is followed by mental illness, thechronic exposure could lead to neurobiologi-cal changes, which might explain the increasedrisk of mental illness38. For example, the high

in the enhanced incentive motivational valueof the drug (a process that results in increased‘wanting’ in contrast to just ‘liking’ the drug)in the addicted person23.

At the neurotransmitter level, addiction-related adaptations have been documentednot only for dopamine, but also for glutamate,GABA, opiates, serotonin and various neuro-peptides. These changes contribute to theabnormal function of brain circuits. Forexample, in individuals who are addicted tococaine, imaging studies have documentedthat disrupted dopamine activity in the brain(shown by reductions in dopamine D2 re-ceptors) is associated with abnormal activityin the orbitofrontal cortex (OFC) and in theanterior cingulate gyrus (CG) — brain regionsthat are involved in salience attribution andinhibitory control24 (FIG. 3).Abnormal functionof these cortical regions has been particularlyrevealing in furthering our understanding ofaddiction , as their disruption is linked tocompulsive behaviour (OFC) and disinhibi-tion24 (CG). Therefore, the abnormalities inthese frontal regions could underlie the com-pulsive nature of drug administration inaddicted individuals and their inability to con-trol their urges to take the drug when they areexposed to it. In addition, animal studies haveshown that drug-related adaptations in thesefrontal regions result in enhanced activity in the glutamatergic pathway that regulates

dopamine release in the NAc25. The adapta-tions in this pathway seem to be involved in therelapse that occurs after drug withdrawal inanimals previously trained to self-administer adrug when they are again exposed to the drug,a drug stimulus or stress25.

At the circuit level, there is clear evidencethat adaptations in the mesocortical circuit(including the OFC and CG) cause compulsivedrug administration and poor inhibitorycontrol, and they probably participate inrelapse. However, adaptations also seem tooccur in the mesolimbic circuit (including theNAc, amygdala and hippocampus), whichprobably cause the enhanced saliency value ofthe drug and drug stimuli, and the decreasedsensitivity to natural reinforcers26. Further-more, adaptations have also been reported inthe nigrostriatal circuit (including the dorsalstriatum), which might underlie habits thatare linked to the rituals of drug consumption27.

Vulnerability to addictionGenetic factors. It is estimated that 40–60% ofthe vulnerability to addiction is attributable togenetic factors28. In animal studies, severalgenes have been identified that are involvedin drug responses, and their experimentalmodifications markedly affect drug self-administration29. In humans, several chromo-somal regions have been linked to drug abuse,but only a few specific genes have been identi-fied with polymorphisms (alleles) that eitherpredispose to or protect from drug addiction28.Some of these polymorphisms interfere withdrug metabolism. For example, specific allelesfor the genes that encode alcohol dehydroge-nases ADH1B and ALDH2 (enzymes involvedin the metabolism of alcohol) are reportedlyprotective against alcoholism30. Similarly,polymorphisms in the gene that encodescytochrome P-450 2A6 (an enzyme that isinvolved in nicotine metabolism) are report-edly protective against nicotine addiction31.Furthermore, genetic polymorphisms in thecytochrome P-450 2D6 gene (an enzyme thatis involved in conversion of codeine to mor-phine) seem to provide a degree of protectionagainst codeine abuse32.

Some polymorphisms in receptor genesthat mediate drug effects have also beenassociated with a higher risk of addiction. Forexample, there is an association betweenalcoholism and the genes for the GABA type A(GABA

A) receptors GABRG3 (REF. 33) and

GABRA2 (REF. 34). D2-receptor polymorphismshave been linked to a higher vulnerability todrug addiction, although some studies havefailed to replicate this finding28. Replication ofmany of the genetic findings in substanceabuse and addiction is still pending.

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lives when they are more likely to take risks,interventions that educate them about theharmful effects of drugs with age-appropriatemessages can decrease the rate of drug use44,45.However, not all media campaigns andschool-based educational programmes havebeen successful46. Tailored interventions thattake into account socio-economic, cultural,age and gender characteristics of children andadolescents are more likely to improve theeffectiveness of the interventions.

At present, prevention strategies includenot only educational interventions based oncomprehensive school-based programmes andeffective media campaigns and strategies thatdecrease access to drugs and alcohol, but alsostrategies that provide supportive communityactivities that engage adolescents in productiveand creative ways. However, as we begin tounderstand the neurobiological consequencesthat underlie the adverse environmental fac-tors that increase the risks for drug use and foraddiction, we will be able to develop interven-tions to counteract these changes. Similarly, inthe future, as we gain knowledge of the genesand the proteins that they encode that make aperson more or less vulnerable to taking drugsand to addiction, more targets will be availableto tailor interventions for those at higher risk.

Treating addiction. The adaptations in thebrain that result from chronic drug exposureare long lasting; therefore, addiction must beviewed as a chronic disease. Long-term treat-ment will be required for most cases, just asfor other chronic diseases (such as hyperten-sion, diabetes and asthma)47. This perspectivemodifies our expectations of treatment andprovides a new understanding of relapse.First, discontinuation of treatment, as forother chronic diseases, is likely to result inrelapse. Also, as for other chronic medicalconditions, relapse should not be interpretedas a failure of treatment (as is the view inmost cases of addiction), but instead as atemporary setback due to lack of complianceor tolerance to an effective treatment47. Indeed,the rates of relapse and recovery in the treat-ment of drug addiction are equivalent to thoseof other medical diseases47.

The involvement of multiple brain circuits(reward, motivation, learning, inhibitorycontrol and executive function) and theirassociated disruption of behaviour indicatethe need for a multimodal approach in thetreatment of the addicted individual. There-fore, interventions should not be limited toinhibiting the rewarding effects of a drug, butshould also include strategies to enhance thesaliency value of natural reinforcers (includingsocial support), strengthen inhibitory control,

Preventing addiction. The greater vulnerabil-ity of adolescents to experimentation withdrugs of abuse and to subsequent addictionunderscores why prevention of early exposureis such an important strategy to combat drugaddiction. Epidemiological studies show thatthe prevalence of drug use in adolescents haschanged significantly over the past 30 years,and some of the decreases seem to be relatedto education about the risks of drugs. Forexample, for marijuana, the prevalence ratesof use in the United States in 1979 were ashigh as 50%, whereas in 1992 they were as lowas 20% (REF. 42) (FIG. 4). This changing patternof marijuana use seems to be related in part tothe perception of the risks associated with thedrug; when adolescents perceived the drug tobe risky, the rate of use was low, whereas whenthey did not, the rate of use was high (FIG. 4).Similarly, the significant decreases in ecstasyuse as well as cigarette smoking in adolescentsseem to partly reflect effective educationalcampaigns43. These results show that, despitethe fact that adolescents are at a stage in their

prevalence of smoking that is initiated afterindividuals experience depression couldreflect, in part, the antidepressant effects ofnicotine as well as the antidepressant effectsof monoamine oxidase A and B (MAO-Aand -B) inhibition by cigarette smoke40. Onthe other hand, the reported risk for depres-sion with early drug abuse41 could reflectneuroadaptations in dopamine systems thatmight make individuals more vulnerable todepression.

The higher risk of drug abuse in individ-uals with mental illnesses highlights the rele-vance of the early evaluation and treatmentof mental diseases as an effective strategy to prevent drug addiction that starts asself-medication.

Strategies to combat addictionThe knowledge of the neurobiology of drugsand the adaptive changes that occur withaddiction is guiding new strategies for pre-vention and treatment, and identifying areasin which further research is required.

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Figure 3 | Dopamine D2 receptors and glucose metabolism in addiction. a,b | Positron emissiontomography (PET) images showing dopamine D2 receptors and brain glucose metabolism in the OFC(orbitofrontal cortex) in controls and in individuals who abuse cocaine. Note that the individuals abusingcocaine have reductions in D2 receptors and in OFC metabolism. c | Correlation between measures of D2receptors and brain glucose metabolism in the OFC and anterior cingulate gyrus (CG). The lower the D2-receptor expression, the lower the metabolism in the OFC and CG. Decreased activity in the OFC, a brainregion that is implicated in salience attribution and whose disruption results in compulsive behaviour, couldunderlie the compulsive drug administration that occurs in addiction. Decreased activity in the CG, a brainregion that is involved in inhibitory control, could underlie the inability to restrain from taking the drug whenthe addicted person is exposed to them58.

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(such as 12-step programmes (self-help sup-port groups whose members attempt recoveryfrom addiction, in part, by ‘admitting’ that theyhave a problem and by sharing experiences))would be more effective if complemented withmedications that could help the patient remaindrug free.

Pharmacological intervention. Pharmaco-logical interventions can be grouped into twoclasses. First, there are those that interfere withthe reinforcing effects of drugs of abuse (that is,medications that interfere with the binding ofthe drug, drug-induced dopamine increase,postsynaptic responses or with the drug’sdelivery to the brain, or medications thattrigger aversive responses). Second, there arethose that compensate for the adaptations thateither pre-dated or developed after long-termuse (that is, medications that decrease theprioritized motivational value of the drug,enhance the saliency value of natural rein-forcers, interfere with conditioned responses,interfere with stress-induced relapse or inter-fere with physical withdrawal). The usefulness

decrease conditioned responses and improvemood if disrupted. The most obvious multi-modal approach is the combination of phar-macological and behavioural interventions,

which might target different underlying fac-tors and therefore have synergistic effects. Forexample, it might be predicted that addictiontreatments that use behavioural interventions

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Table 1 | Medications for Treating Drug and Alcohol Addiction*

Clinical target Medication Biological target

Alcoholism

FDA approved60 Disulfiram (Antabuse; Wyeth-Ayerst) Aldehyde dehydrogenase (triggers aversive response)Naltrexone Mu opioid receptor (antagonist; interferes with reinforcement)Acamprosate Glutamate related‡Topiramate61 (Topamax; Ortho-McNeil) GABA/glutamate

Under investigation ‡Valproate62 GABA/glutamateOndansetron63 5-HT3 receptorNalmefene64 Mu opioid receptor (antagonist)Baclofen65 (Lioresal; Novartis) GABAB receptor (agonist)Pyrrolopyrimidine compound66 (Antalarmin; CRF1 receptor (inhibits stress-triggered responses)George Chrousos et al.)Rimonabant (Acomplia; Sanofi-Synthelabo)67 CB1 receptor (antagonist)

Nicotine addiction

FDA approved68 Nicotine replacement Nicotinic receptor (substitution with different pharmacokinetics)Bupropion DA transporter blocker (amplifies DA signals)

Under investigation Deprenyl69 MAO-B inhibitor (inhibits metabolism of DA)Rimonabant (Acomplia; Sanofi-Synthelabo)67 CB1-receptor (antagonist)Methoxsalen70 CYP2A6 (inhibits nicotine metabolism)Nicotine conjugate vaccine71 (NicVax; Blocks entry into brainNabi Biopharmaceuticals)

Heroin/opiate addiction

FDA approved72 Naltrexone Mu opioid receptor (antagonist)Methadone Mu opioid receptor (substitution with different

pharmacokinetics)Buprenorphine Mu opioid receptor (substitution)

Cocaine addiction

Under investigation ‡Topiramate73 (Topamax; Ortho-McNeil) GABA (agonist)‡γ-vinyl GABA (GVG)74 (Sabril; Hoechst Marion Roussel) GABA transaminase (inhibits GABA metabolism)‡Gabapentin75 (Neurontin; Parke-Davis) GABA/glutamate (synthesis)‡Tiagabine76 (Gabitril; Abbott) GABA transporter (inhibitor)Baclofen77 (Lioresal; Novartis) GABAB receptor (agonist)Modafinil78 Glutamate (?)Disulfiram79 (Antabuse; Wyeth-Ayerst) Unknown for cocaineCocaine vaccine71 (TA-CD; Xenova) Blocks entry into brain

*Medications used for physical withdrawal are not included. ‡Antiepileptic drugs that have been shown to decrease both drug-induced dopamine(DA) increases and conditioned responses. FDA, Food and Drug Administration; GABA, γ-aminobutyric acid; GABAB, GABA type B; 5-HT3, 5-hydroxytryptamine (serotonin) receptor subtype 3; MAO-B, monoamine oxidase B.

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Challenges for societyIn most cases, drug abuse and addictionalienates the individual from both familyand community, increasing isolation andinterfering with treatment and recovery. Asboth the family and the community provideintegral aspects of effective treatment andrecovery, this identifies an important chal-lenge: to reduce the stigma of addiction thatinterferes with intervention and proper rehabilitation.

Effective treatment of drug addiction inmany individuals requires consideration ofsocial policy, such as the treatment of drugaddiction in the criminal justice system, therole of unemployment in vulnerability tothe use of drugs and family dysfunctionsthat contribute to stress and that mightblock the efficacy of otherwise effectiveinterventions. For example, studies haveshown that providing drug treatment toprisoners who were substance abusers andcontinuing the treatment after they left theprison dramatically reduced not only theirrate of relapse to drugs, but also their rate ofre-incarceration53,54. Similarly, drug courtsin the United States, which incorporate drugtreatment into the judicial system, haveproved to be beneficial in decreasing druguse and arrests of offenders who areinvolved in drug-taking55. However, despitethese preliminary positive results, there arestill many unanswered questions that futureresearch should address. For example, whatare the active ingredients in the treatment ofthe drug offender? How does the systemdeal with the fact that few offenders stay in treatment long enough to receive theminimally required services? What are theimplications of these findings for pre-trialdiversion laws, post-prison re-entry initiativesand so on?

The recognition of addiction as a diseasethat affects the brain might be essential forlarge-scale prevention and treatment pro-grammes that require the participation of themedical community. Engagement of paedia-tricians and family physicians (including theteaching of addiction medicine as part ofmedical students’ training) might facilitateearly detection of drug abuse in childhoodand adolescence. Moreover, screening fordrug use could help clinicians better managemedical diseases that are likely to be adverselyaffected by the concomitant use of drugs,such as cardiac and pulmonary diseases.Unfortunately, physicians, nurses, psycho-logists and social workers receive little train-ing in the management of addiction, despiteit being one of the most common chronicdisorders.

and memory rehabilitation after braininjury50, but has not yet been applied to theremediation of brain circuits altered by drugabuse. Dual approaches that pair cognitive–behavioural strategies with medications tocompensate or counteract the neurobiologicalchanges induced by chronic drug exposuremight, in the future, provide more robustand longer lasting treatments for addictionthan either given in isolation.

Treating co-morbidities. Abuse of multiplesubstances, such as alcohol and nicotine oralcohol and cocaine, should be considered in the proper management of the addictedindividual. Similarly, co-morbidities withmental illness will require treatment for the mental illness concurrent with treatmentfor drug abuse.

As drugs of abuse adversely affect manyorgans in the body (FIG. 5), uncontrolled con-sumption contributes to the burden of manymedical diseases, including cancer, cardiovas-cular and pulmonary diseases, HIV/AIDS andhepatitis C, as well as to accidents and vio-lence. Therefore, substance-abuse treatmentwill help to prevent or improve the outcomefor medical diseases. For example, drug abuseis a leading contributor to the spread of HIV/AIDS, and treatment of addiction in someinstances prevents its dissemination51,52.

of some of the medications for drug addic-tion has been clearly validated; for others thedata are still preliminary, and for most theresults are limited to promising preclinicalfindings. TABLE 1 summarizes proven medica-tions as well as medications for which thereare preliminary clinical data. Many of thesepromising new medications target differentneurotransmitters (such as GABA, cannabi-noids or glutamate) from the older drugs,offering a wider range of therapeutic options.

Cognitive–behavioural intervention. In asimilar fashion, behavioural interventionscan be classified by their intended remedialfunction, such as to strengthen inhibitorycontrol circuits, to provide alternative rein-forcers and to strengthen executive function.Traditionally, behavioural therapy has focusedon symptom-based targets rather thanunderlying causes of addiction. However, forother brain disorders, new views of brainplasticity, which recognize the capacity ofneurons in the adult brain to increase synap-tic connections and in certain instances toregenerate48, have resulted in more focusedcognitive–behavioural interventions designedto increase the efficiency of dysfunctionalbrain circuits. This has been applied inattempts to improve reading in children withlearning disabilities49 and to facilitate motor

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Figure 5 | Monoamine oxidase B concentration and cigarette smoking. Positron emissiontomography (PET) images of the concentration of the enzyme MAO-B (monoamine oxidase B) in thebody of a healthy control and of a cigarette smoker. There are significant decreases in the concentrationof the enzyme throughout the body of the smoker. Reproduced, with permission, from REF. 59 © (2003)National Academy of Sciences, USA.

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The participation of the medical com-munity in many countries, including theUnited States, is further curtailed by the lackof reimbursement by most private medicalinsurance policies for the evaluation ortreatment of drug abuse and addiction. Thislack of reimbursement limits the treatmentinfrastructure and the choices that theaddicted person has with respect to theirtreatment. It also sends a negative messageto medical students who are interested inclinical practice, discouraging them fromchoosing a speciality for which the reim-bursement of their services is limited by thelack of parity.

Another considerable obstacle in thetreatment of addiction is the limited involve-ment of the pharmaceutical industry in thedevelopment of new medications. Issuessuch as stigma, lack of reimbursement fordrug-abuse treatment and the lack of a largemarket all contribute to the limited involve-ment of the pharmaceutical industry in thedevelopment of medications to treat drugaddiction. The importance of this issue was identified by the Institute of Medicine ofthe United States, which recommended aprogramme to provide incentives to thepharmaceutical industry as a way of helpingto address this problem56.

The translation of scientific findings indrug abuse into prevention and treatmentinitiatives clearly requires partnership withfederal agencies such as the Substance Abuseand Mental Health Services Administration(SAMHSA, which is responsible for U.S. pro-grammes to prevent and treat drug abuse)and the Office of National Drug ControlPolicy (ONDCP, which is responsible forU.S. programmes to control availability andreduce demand for drugs of abuse). Further-more, improved prevention and treatmentprogrammes could result from collabora-tions with other agencies and groups, suchas the Department of Education (which canbring prevention interventions into the schoolenvironment), the Department of Justice(which can implement treatment strategiesthat will minimize the chances of recidivismand re-incarceration of inmates withdrug-abuse problems) and state and localagencies (which can bring evidence-basedand science-based treatments into thecommunities).

As we learn more about the neurobiologyof normal and pathological human behav-iour, a challenge for society will be to use thisknowledge to effectively guide public policy.For example, as we understand the neuro-biological substrates that underlie voluntaryactions, how will society define the boundaries

of personal responsibility in those individualswho have impairments in these brain circuits?This will have implications not only for themanagement of drug offenders, but also ofother offenders with diagnoses such as antiso-cial personality disorder or conduct disorder.At present, critics of the medical model ofaddiction argue that this model removes theresponsibility of the addicted individual fromhis/her behaviour. However, the value of themedical model of addiction as a public policyguide is not to excuse the behaviour of theaddicted individual, but to provide a frame-work to understand it and to treat it moreeffectively.

SummaryRemarkable scientific advances have beenmade in genetics, molecular biology, behav-ioural neuropharmacology and brain imag-ing that offer new insights into how thehuman brain works and moulds behaviour.In the case of addiction, we can now investi-gate questions that were previously inaccessi-ble, such as how environmental factors andgenes affect the responses of the brain todrugs and produce neural adaptations thatlead to the aberrant behavioural manifesta-tions of addiction. This new knowledge ishelping us to understand why drug addictsrelapse even in the face of threats such asdivorce, loss of child custody and incarcera-tion, even when, in some cases, the drug is nolonger perceived as pleasurable, and is chang-ing how we should approach prevention andtreatment of addiction.

The field is at a crossroads where majoradvances in understanding the neuro-biology of addiction have helped identifypromising new medications, but where thetranslation of these findings into clinicalpractice is limited by several factors, includ-ing the limited involvement of the medicalcommunity in the treatment of addiction,the restricted involvement of the pharma-ceutical industry, the lack of reimbursementby private insurance policies and thestigma associated with drug addiction. One ofthe main challenges for agencies like theNational Institute on Drug Abuse (NIDA)and the National Institute on Alcohol Abuseand Alcoholism (NIAAA) is to developknowledge that will help to overcome theseobstacles.

Nora Volkow is at the National Institute on DrugAbuse, Bethesda, Maryland 20892, USA.

Ting-Kai Li is at the National Institute on AlcoholAbuse and Alcoholism, Bethesda, Maryland

20892, USA.

e-mail: nvolkow@nida.nih.gov

doi:1038/nrn1539

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Competing interests statementThe authors declare no competing financial interests.

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