DOI: 10.1126/science.278.5335.45, 45 (1997);278 Science

Alan I. LeshnerAddiction Is a Brain Disease, and It Matters

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Addiction Is a Brain Disease, and It MattersAlan I. Leshner

Scientific advances over the past 20 years have shown that drug addiction is a chronic,relapsing disease that results from the prolonged effects of drugs on the brain. As withmany other brain diseases, addiction has embedded behavioral and social-contextaspects that are important parts of the disorder itself. Therefore, the most effectivetreatment approaches will include biological, behavioral, and social-context compo-nents. Recognizing addiction as a chronic, relapsing brain disorder characterized bycompulsive drug seeking and use can impact society’s overall health and social policystrategies and help diminish the health and social costs associated with drug abuse andaddiction.

Dramatic advances over the past two dec-ades in both the neurosciences and thebehavioral sciences have revolutionized ourunderstanding of drug abuse and addiction.Scientists have identified neural circuitsthat subsume the actions of every knowndrug of abuse, and they have specified com-mon pathways that are affected by almostall such drugs. Researchers have also iden-tified and cloned the major receptors forvirtually every abusable drug, as well as thenatural ligands for most of those receptors.In addition, they have elaborated many ofthe biochemical cascades within the cellthat follow receptor activation by drugs.Research has also begun to reveal majordifferences between the brains of addictedand nonaddicted individuals and to indi-cate some common elements of addiction,regardless of the substance.

That is the good news. The bad news is thedramatic lag between these advances in sci-ence and their appreciation by the generalpublic or their application in either practiceor public policy settings. There is a wide gapbetween the scientific facts and public percep-tions about drug abuse and addiction. Forexample, many, perhaps most, people see drugabuse and addiction as social problems, to behandled only with social solutions, particular-ly through the criminal justice system. On theother hand, science has taught that drug abuseand addiction are as much health problems asthey are social problems. The consequence ofthis gap is a significant delay in gaining con-trol over the drug abuse problem.

Part of the lag and resultant disconnectioncomes from the normal delay in transferringany scientific knowledge into practice andpolicy. However, there are other factorsunique to the drug abuse arena that com-pound the problem. One major barrier isthe tremendous stigma attached to being a

drug user or, worse, an addict. The mostbeneficent public view of drug addicts is asvictims of their societal situation. However,the more common view is that drug addictsare weak or bad people, unwilling to leadmoral lives and to control their behaviorand gratifications. To the contrary, addic-tion is actually a chronic, relapsing illness,characterized by compulsive drug seekingand use (1). The gulf in implications be-tween the “bad person” view and the“chronic illness sufferer” view is tremen-dous. As just one example, there are manypeople who believe that addicted individu-als do not even deserve treatment. Thisstigma, and the underlying moralistic tone,is a significant overlay on all decisions thatrelate to drug use and drug users.

Another barrier is that some of the peo-ple who work in the fields of drug abuseprevention and addiction treatment alsohold ingrained ideologies that, althoughusually different in origin and form from theideologies of the general public, can be justas problematic. For example, many drugabuse workers are themselves former drugusers who have had successful treatmentexperiences with a particular treatmentmethod. They therefore may zealously de-fend a single approach, even in the face ofcontradictory scientific evidence. In fact,there are many drug abuse treatments thathave been shown to be effective throughclinical trials (1, 2).

These difficulties notwithstanding, I be-lieve that we can and must bridge thisinformational disconnection if we are goingto make any real progress in controllingdrug abuse and addiction. It is time to re-place ideology with science.

Drug Abuse and Addiction asPublic Health Problems

At the most general level, research hasshown that drug abuse is a dual-edgedhealth issue, as well as a social issue. It

affects both the health of the individual andthe health of the public. The use of drugshas well-known and severe negative conse-quences for health, both mental and phys-ical. But drug abuse and addiction also havetremendous implications for the health ofthe public, because drug use, directly orindirectly, is now a major vector for thetransmission of many serious infectious dis-eases—particularly acquired immunodefi-ciency syndrome (AIDS), hepatitis, and tu-berculosis—as well as violence. Because ad-diction is such a complex and pervasivehealth issue, we must include in our overallstrategies a committed public health ap-proach, including extensive education andprevention efforts, treatment, and research.

Science is providing the basis for suchpublic health approaches. For example, twolarge sets of multisite studies (3) have dem-onstrated the effectiveness of well-delineat-ed outreach strategies in modifying the be-haviors of addicted individuals that putthem at risk for acquiring the human im-munodeficiency virus (HIV), even if theycontinue to use drugs and do not want toenter treatment. This approach runscounter to the broadly held view that ad-dicts are so incapacitated by drugs that theyare unable to modify any of their behaviors.It also suggests a base for improved strate-gies for reducing the negative health con-sequences of injection drug use for the in-dividual and for society.

What Matters in Addiction

Scientific research and clinical experiencehave taught us much about what reallymatters in addiction and where we need toconcentrate our clinical and policy efforts.However, too often the focus is on thewrong aspects of addiction, and efforts todeal with this difficult issue can be badlymisguided.

Any discussion about psychoactive drugsinevitably turns to the question of whethera particular drug is physically or psycholog-ically addicting. In essence, this issue re-volves around whether or not dramaticphysical withdrawal symptoms occur whenan individual stops taking a drug, what istypically called physical dependence by pro-fessionals in the field. The assumption thatoften follows is that the more dramatic thephysical withdrawal symptoms, the moreserious or dangerous the drug must be.

This thinking is outdated. From bothclinical and policy perspectives, it does not

The author is with the National Institute on Drug Abuse,National Institutes of Health, 5600 Fishers Lane, Room10-05, Rockville, MD 20857, USA. E-mail: leshner@nih.gov

FRONTIERS IN NEUROSCIENCE: THE SCIENCE OF SUBSTANCE ABUSE

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matter much what physical withdrawalsymptoms, if any, occur. First, even theflorid withdrawal symptoms of heroin ad-diction can now be easily managed withappropriate medication. Second, and moreimportant, many of the most addicting anddangerous drugs do not produce severephysical symptoms upon withdrawal. Crackcocaine and methamphetamine are clearexamples: Both are highly addicting, butcessation of their use produces few physicalwithdrawal symptoms, certainly nothinglike the physical symptoms accompanyingalcohol or heroin withdrawal.

What does matter tremendously iswhether or not a drug causes what we nowknow to be the essence of addiction: com-pulsive drug seeking and use, even in theface of negative health and social conse-quences (4). These are the characteristicsthat ultimately matter most to the patientand are where treatment efforts should bedirected. These behaviors are also the ele-ments responsible for the massive healthand social problems that drug addictionbrings in its wake.

Addiction Is a Brain Disease

Although each drug that has been studiedhas some idiosyncratic mechanisms of ac-tion, virtually all drugs of abuse have com-mon effects, either directly or indirectly, ona single pathway deep within the brain.This pathway, the mesolimbic reward sys-tem, extends from the ventral tegmentumto the nucleus accumbens, with projectionsto areas such as the limbic system and theorbitofrontal cortex. Activation of this sys-tem appears to be a common element inwhat keeps drug users taking drugs. Thisactivity is not unique to any one drug; alladdictive substances affect this circuit (5).

Not only does acute drug use modifybrain function in critical ways, but pro-longed drug use causes pervasive changes inbrain function that persist long after theindividual stops taking the drug. Significanteffects of chronic use have been identifiedfor many drugs at all levels: molecular, cel-lular, structural, and functional (6, 7). Theaddicted brain is distinctly different fromthe nonaddicted brain, as manifested bychanges in brain metabolic activity, recep-tor availability, gene expression, and re-sponsiveness to environmental cues. Someof these long-lasting brain changes are idio-syncratic to specific drugs, whereas othersare common to many different drugs (6–9).The common brain effects of addicting sub-stances suggest common brain mechanismsunderlying all addictions (5, 7, 9, 10).

That addiction is tied to changes inbrain structure and function is what makesit, fundamentally, a brain disease. A meta-

phorical switch in the brain seems to bethrown as a result of prolonged drug use.Initially, drug use is a voluntary behavior,but when that switch is thrown, the indi-vidual moves into the state of addiction,characterized by compulsive drug seekingand use (11).

Understanding that addiction is, at itscore, a consequence of fundamentalchanges in brain function means that amajor goal of treatment must be either toreverse or to compensate for those brainchanges. These goals can be accomplishedthrough either medications or behavioraltreatments [behavioral treatments havebeen successful in altering brain functionin other psychobiological disorders (12)].Elucidation of the biology underlying themetaphorical switch is key to the develop-ment of more effective treatments, partic-ularly antiaddiction medications.

But Not Just a Brain Disease

Of course, addiction is not that simple.Addiction is not just a brain disease. It is abrain disease for which the social contextsin which it has both developed and is ex-pressed are critically important. The case ofthe many thousands of returning Vietnamwar veterans who were addicted to heroinillustrates this point. In contrast to addictson the streets of the United States, it wasrelatively easy to treat the returning veter-ans’ addictions. This success was possiblebecause they had become addicted while ina setting almost totally different from theone to which they had returned. At homein the United States, they were exposed tofew of the conditioned environmental cuesthat had initially been associated with theirdrug use in Vietnam. Exposure to condi-tioned cues can be a major factor in causingpersistent or recurrent drug cravings anddrug use relapses even after successful treat-ment (13).

The implications are obvious. If we un-derstand addiction as a prototypical psycho-biological illness, with critical biological,behavioral, and social-context components,our treatment strategies must include bio-logical, behavioral, and social-context ele-ments. Not only must the underlying braindisease be treated, but the behavioral andsocial cue components must also be ad-dressed, just as they are with many otherbrain diseases, including stroke, schizophre-nia, and Alzheimer’s disease.

A Chronic, Relapsing Disorder

Addiction is rarely an acute illness. Formost people, it is a chronic, relapsing dis-order. Total abstinence for the rest of one’slife is a relatively rare outcome from a single

treatment episode. Relapses are more thenorm. Thus, addiction must be approachedmore like other chronic illnesses—such asdiabetes and chronic hypertension—thanlike an acute illness, such as a bacterialinfection or a broken bone (1). This re-quirement has tremendous implications forhow we evaluate treatment effectivenessand treatment outcomes. Viewing addictionas a chronic, relapsing disorder means that agood treatment outcome, and the most rea-sonable expectation, is a significant de-crease in drug use and long periods of ab-stinence, with only occasional relapses.That makes a reasonable standard for treat-ment success—as is the case for otherchronic illnesses—the management of theillness, not a cure (1, 2).

Conclusion

Addiction as a chronic, relapsing disease ofthe brain is a totally new concept for muchof the general public, for many policymak-ers, and, sadly, for many health care profes-sionals. Many of the implications have beendiscussed above, but there are others.

At the policy level, understanding theimportance of drug use and addiction forboth the health of individuals and thehealth of the public affects many of ouroverall public health strategies. An accurateunderstanding of the nature of drug abuseand addiction should also affect our crimi-nal justice strategies. For example, if weknow that criminals are drug addicted, it isno longer reasonable to simply incarceratethem. If they have a brain disease, impris-oning them without treatment is futile. Ifthey are left untreated, their recidivismrates to both crime and drug use are fright-eningly high; however, if addicted criminalsare treated while in prison, both types ofrecidivism can be reduced dramatically(14). It is therefore counterproductive tonot treat addicts while they are in prison.

At an even more general level, under-standing addiction as a brain disease alsoaffects how society approaches and dealswith addicted individuals. We need to facethe fact that even if the condition initiallycomes about because of a voluntary behavior(drug use), an addict’s brain is different froma nonaddict’s brain, and the addicted indi-vidual must be dealt with as if he or she is ina different brain state. We have learned todeal with people in different brain states forschizophrenia and Alzheimer’s disease. Re-call that as recently as the beginning of thiscentury we were still putting individuals withschizophrenia in prisonlike asylums, whereasnow we know they require medical treat-ments. We now need to see the addict assomeone whose mind (read: brain) has beenaltered fundamentally by drugs. Treatment is

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required to deal with the altered brain func-tion and the concomitant behavioral andsocial functioning components of the illness.

Understanding addiction as a brain dis-ease explains in part why historic policystrategies focusing solely on the social orcriminal justice aspects of drug use andaddiction have been unsuccessful. They aremissing at least half of the issue. If the brainis the core of the problem, attending to thebrain needs to be a core part of the solution.

REFERENCES AND NOTES___________________________

1. C. P. O’Brien and A. T. McLellan, Lancet 347, 237(1996).

2. A. T. McLellan et al., in Treating Drug Abusers Effec-tively, J. A. Egertson et al., Eds. (Blackwell, Malden,MA, 1997), pp. 7–40.

3. R. Booth et al., Drug Alcohol Depend. 42, 11 (1996);H. M. Colon et al., AIDS Educ. Prev. 7, 195 (1995);R. C. Stephens et al., in Handbook on Risk of AIDS,B. S. Brown and G. M. Beschner, Eds. (Greenwood,Westport, CT 1993), pp. 519–556; W. W. Wiebel etal., J. Acquired Immune Defic. Syndr. 12, 282 (1996).

4. American Psychiatric Association, Diagnostic andStatistical Manual of Mental Disorders, (AmericanPsychiatric Association Press, Washington, DC, ed. 4,1994); Institute of Medicine, Pathways of Addiction(National Academy Press, Washington, DC, 1996).

5. G. F. Koob, Trends Pharmacol. Sci. 13, 177 (1992);G. F. Koob et al., Semin. Neurosci. 6, 221 (1994).

6. S. E. Hyman, Neuron 16, 901 (1996); E. J. Nestler,ibid., p. 897; W. P. Melega et al., Behav. Brain Res.84, 259 (1997); J. Ortiz et al., Synapse 21, 289(1995); N. D. Volkow et al., Am. J. Psychiatry 147,719 (1990).

7. E. J. Nestler et al., Mol. Psychiatry 1, 190 (1996);D. W. Self and E. J. Nestler, Annu. Rev. Neurosci.18, 463 (1995).

8. E. J. Nestler, J. Neurosci. 12, 2439 (1992); T. E.Robinson and K. C. Berridge, Brain Res. Rev. 18,247 (1993); R. Z. Terwilliger et al., Brain Res. 548,100 (1991).

9. G. F. Koob, Neuron 16, 893 (1996).10. A. I. Leshner, Hospital Practice: A Special Report

(McGraw-Hill, Minneapolis, MN, 1997).11. The state of addiction—both the clinical condition

and the brain state—is qualitatively different fromthe effects of large amounts of drugs. The individ-ual, once addicted, has moved from a state wheredrug use is voluntary and controlled to one wheredrug craving, seeking, and use are no longer underthe same kind of voluntary control, and thesechanges reflect changes in brain function. The ex-act mechanisms involved are not known. For ex-ample, it is not clear whether that change in statereflects a relatively precipitous change in a singemechanism or multiple mechanisms acting in con-cert, or whether the shift to addiction representsthe sum of more gradual neuroadaptations. More-over, there are individual differences in the vulner-ability to becoming addicted and the speed of be-coming addicted. For some individuals, the meta-phorical switch moves quickly, whereas for othersthe changes occur quite gradually (6–10).

12. L. B. Baxter et al., Semin. Clin. Neuropsychiatry 1, 32(1996).

13. A. R. Childress et al., Natl. Inst. Drug Abuse Res.Monogr. 84, 25 (1988); D. C. Daley and G. A.Marlatt, in Substance Abuse: A ComprehensiveTextbook, J. H. Lowinson et al., Eds. ( Williams &Wilkins, Baltimore, ed. 3, 1997), pp. 458–467;C. P. O’Brien, Pharmacol. Rev. 27, 535 (1975);C. P. O’Brien et al., Addict. Behav. 15, 355 (1990);S. Grant et al., Proc. Natl. Acad. Sci. U.S.A. 93,12040 (1996).

14. J. A. Inciardi et al., J. Drug Issues 27, 261 (1997);H. K. Wexler and D. S. Lipton, in Drug Treatment andCriminal Justice, J. A. Inciardi, Ed. (Sage, NewburyPark, CA, 1993), pp. 261–278.

Interpreting Dutch CannabisPolicy: Reasoning by Analogy in

the Legalization DebateRobert MacCoun and Peter Reuter

The Dutch depenalization and subsequent de facto legalization of cannabis since 1976is used here to highlight the strengths and limitations of reasoning by analogy as a guidefor projecting the effects of relaxing drug prohibitions. While the Dutch case and otheranalogies have flaws, they appear to converge in suggesting that reductions in criminalpenalties have limited effects on drug use—at least for marijuana—but that commercialaccess is associated with growth in the drug-using population.

Illicit drugs continue to be a major sourceof health and social problems in the Unit-ed States, accounting for 35% of new casesof acquired immunodeficiency syndrome(1) and about $50 billion in criminal in-come (2). Large declines in prevalencehave occurred since the mid-1980s—10.7% of the household population report-ed use of an illicit drug in the previousyear in 1995, compared with 16.3% in1985 (3)— but most measures of adverseconsequences have risen or stabilized.Heroin-related deaths recorded by Medi-cal Examiners in 25 metropolitan areasrose from 1300 in 1985 to 3500 in 1994(4).

U.S. drug policy is heavily committedto a punishment-based approach. This isreflected in budgets; two-thirds of the fed-eral government’s $16 billion expendi-tures go to supply-reduction programs (5),whereas state and local governments, esti-mated to spend $18 billion, probably de-vote 75 to 80% to policing, prosecution,and corrections (6). About 400,000 indi-viduals are currently incarcerated in jailsor prisons for violation of drug laws (7).Moreover, treatment and prevention pro-grams are frequently required to show thatthey are cost-effective, a standard neverimposed on drug enforcement (8). Penal-ties have increased whenever a drug be-comes more prominent, as for example inthe new federal methamphetamine statute(9). The probability of a cocaine or heroinseller being incarcerated has risen sharplysince about 1985 (10), but that has ledneither to increased price (11) nor re-duced availability (12).

The Legalization Debate

Given the persistence of a major drug prob-lem despite expensive, intrusive, and harshpolicies, it is not surprising that there hasbeen a continuing debate in the UnitedStates about the desirability of majorchanges in that policy, indeed a shift inthe basic regime (13). Some press for de-penalization (often misleadingly termeddecriminalization), the removal of crimi-nal penalties for the simple possession ofdrugs; a smaller number press for the moreradical step of legalizing the distribution ofany psychoactive substance, subject to civ-il regulation (14). Few commentators dis-tinguish among drugs in debating theserecommendations.

The debate about legalization invokesconflicts in values, with legalizers empha-sizing the threat that prohibition poses tocivil liberties (15) and opponents the hedo-nism and self-centeredness of drug taking(16). However, the debate also exposesgross discrepancies in predictions of the ef-fects of legalization on levels of drug use.Legalizers point to the failure of increasingenforcement to raise prices or decreaseavailability as evidence that legalizationwould not much increase use or dependence(17), while their opponents emphasize theimportance of symbolic and real barriers toinitiation associated with prohibition tosuggest that legalization would producemassive increases in these rates (18).

There are three general strategies forprojecting the likely consequences of achange in the legal regime for drugs. First,one can draw upon existing theory andresearch. But for a variety of reasons (19),research on variations in drug law enforce-ment within a prohibition regime cannot beextrapolated outside that regime, and exist-ing theories provide an uncertain guide tothe net consequences of such interventions.Legal change is far more fundamental than

R. MacCoun is at the Richard and Rhoda Goldman Schoolof Public Policy, University of California, Berkeley, CA94720–7320, USA. E-mail: maccoun@socrates.berkeley.eduP. Reuter is at the School of Public Affairs and Depart-ment of Criminology, University of Maryland, MD 20742,USA.

ARTICLES

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