PERSPECTIVES
products and neuronal circuits3, and how
SCIENCE AND SOCIETY
Drug addiction: the neurobiology of
behaviour gone awry
Nora D. Volkow and Ting-Kai Li
Abstract | Drug addiction manifests as a
compulsive drive to take a drug despite
serious adverse consequences. This
aberrant behaviour has traditionally been
viewed as bad ‘choices’ that are made
voluntarily by the addict. However, recent
studies have shown that repeated drug use
leads to long-lasting changes in the brain that
undermine voluntary control. This, combined
with new knowledge of how environmental,
genetic and developmental factors contribute
to addiction, should bring about changes in
our approach to the prevention and
treatment of addiction.
Drugs, both legal (for example, alcohol and
nicotine) and illegal (such as cocaine, meth-
amphetamine, heroin and marijuana) are
misused for various reasons, including for
pleasurable effects, the alteration of mental
state, to improve performance and, in certain
instances, for self-medication of a mental
disorder. Repeated drug use can result in
addiction, which is manifested as an intense
desire for the drug with an impaired ability to
control the urges to take that drug, even at the
expense of serious adverse consequences. To
avoid confusion with physical dependence, the
term ‘drug addiction’ is used here instead of
‘drug dependence’, which is the clinical term
favoured by the Diagnostic and Statistical
Manual of Mental Disorders (fourth edition;
DSM-IV). Physical dependence results in with-
drawal symptoms when drugs, such as alcohol
and heroin, are discontinued, but the adapta-
tions that are responsible for these effects are
different from those that underlie addiction.
NATURE REVIEWS | NEUROSCIENCE
The aberrant behavioural manifestations
that occur during addiction have been
viewed by many as ‘choices’ of the addicted
individual, but recent imaging studies have
revealed an underlying disruption to brain
regions that are important for the normal
processes of motivation, reward and inhib-
itory control in addicted individuals1. This
provides the basis for a different view: that
drug addiction is a disease of the brain, and
the associated abnormal behaviour is the
result of dysfunction of brain tissue, just as
cardiac insufficiency is a disease of the heart
and abnormal blood circulation is the result
of dysfunction of myocardial tissue2 (FIG. 1).
Therefore, although initial drug experimen-
tation and recreational use might be volitio-
nal, once addiction develops this control is
markedly disrupted. Although imaging stud-
ies consistently show specific abnormalities
in the brain function of addicted individu-
als, not all addicted individuals show these
abnormalities. This highlights the need for
further research to delineate other neuro-
biological processes that are involved in
addiction.
Chronic exposure to drugs of abuse is
required for drug addiction, and its expres-
sion involves complex interactions between
biological and environmental factors. This
might explain why some individuals become
addicted and others do not, and why attempts
to understand addiction as a purely biological
or a purely environmental disease have been
largely unsuccessful. Recently, important dis-
coveries have increased our knowledge of
how drugs affect gene expression, protein
these biological factors might affect human
behaviour. This sets the stage for a better
understanding of how different environmen-
tal factors interact with biological factors and
contribute to patterns of behaviour that lead
to addiction.
Here, we summarize how new methodolo-
gies that allow us to study genes, molecular
biology and the human brain are providing us
with a greater understanding of drug addic-
tion, and the implications of these findings for
the prevention and treatment of addiction.
Addiction: a developmental disorder
Normal developmental processes might
result in a higher risk of drug use at certain
times in life than others. Experimentation
often starts in adolescence, as does the process
of addiction4 (FIG. 2). Normal adolescent-
specific behaviours (such as risk-taking,
novelty-seeking and response to peer pres-
sure) increase the propensity to experiment
with legal and illegal drugs5, which might
reflect incomplete development of brain
regions (for example, myelination of frontal
lobe regions)6 that are involved in the pro-
cesses of executive control and motivation. In
addition, studies indicate that drug exposure
during adolescence might result in different
neuroadaptations from those that occur
during adulthood. For example, in rodents,
exposure to nicotine during the period that
corresponds to adolescence, but not during
adulthood, led to significant changes in
nicotine receptors and an increased rein-
forcement value for nicotine later in life7.
Future research might allow us to clarify
whether this is the reason that adolescents
seem to become addicted to nicotine after
less nicotine exposure than adults8. Similarly,
further studies might enable us to determine
whether the increased neuroadaptations to
alcohol that occur during adolescence, com-
pared with those that occur during adult-
hood9 explain the greater vulnerability to
alcoholism in individuals who start using
alcohol early in life10.
VOLUME 5 | DECEMBER 2004 | 9 6 3
PERSPECTIVES

with the drug become salient. These previously

a Brain neutral stimuli then increase dopamine by
themselves and elicit the desire for the drug 21.
High This explains why the addicted person is
at risk of relapsing when exposed to an envi-
ronment where he/she has previously taken
the 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 dopamine
induced by drugs, which are greater in magni-
Healthy brain Addicted brain
tude (at least five- to tenfold) and duration
than those induced by natural reinforcers13. In
addition, whereas the dopamine increases
b Heart
produced by natural reinforcers in the NAc
undergo habituation, those induced by drugs
of abuse do not12. Non-decremental dopa-
mine stimulation of the NAc from repeated
drug use strengthens the motivational proper-
Low ties of the drug, which does not occur for
natural reinforcers.
Healthy heart Myocardial infarction
Neurobiology of drug addiction
Figure 1 | Drug addiction as a disease of the brain. Images of the brain (a) in a healthy control and in an
Addiction probably results from neuro-
individual addicted to a drug, and parallel images of the heart (b) in a healthy control and in an individual with
a myocardial infarction. The images were obtained with positron emission tomography (PET) and [18F]fluoro- biological changes that are associated with
2-deoxyglucose (FDG–PET) to measure glucose metabolism, which is a sensitive indicator of damage to chronic and intermittent supraphysiological
the tissue in the brain and the heart. Note the decreased glucose metabolism in the OFC (orbitofrontal perturbations in the dopamine system, which
cortex; arrow) of the addicted person and the decreased metabolism in the myocardial tissue (arrow) in the occur in the same circuits that affect bio-
person with a myocardial infarct. Damage to the OFC will result in improper inhibitory control and logically important functions1. We and others
compulsive behaviour, and damage to the myocardium will result in improper blood circulation. Although
have postulated that adaptations in these
abnormalities 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 this
dopaminergic circuits make the addicted
frontal region is not the only mechanism that underlies the addictive process. Heart images courtesy of individual more responsive to the supra-
H. Schelbert, University of California at Los Angeles. physiological increases in dopamine that are
produced by drugs of abuse and less sensitive
to the physiological increases in dopamine
Neurobiology of drugs of abuse firing through their effects on nicotine, GABA, produced by natural reinforcers22. Recent
Many neurotransmitters, including GABA mu opiate or cannabinoid CB1 receptors, advances in both molecular biology and
(γ-aminobutyric acid), glutamate, acetyl- respectively15. imaging have increased our insight into how
choline, dopamine, serotonin and endogenous It seems that increases in dopamine are these neural adaptations occur.
opioid peptides, have been implicated in the not directly related to reward per se, as was At a cellular level, drugs have been
effects of the various types of drugs of abuse. previously believed, but rather to the predic- reported to alter the expression of certain
Of these, dopamine has been consistently tion of reward16 and for salience17. Salience transcription factors (nuclear proteins that
associated with the reinforcing effects of most refers to stimuli or environmental changes bind to regulatory regions of genes, thereby
drugs of abuse. Drugs of abuse increase extra- that are arousing or that elicit an attentional– regulating their transcription into mRNA), as
cellular dopamine concentrations in limbic behavioural switch18. Salience, which, in well as a wide variety of proteins involved in
regions, including the nucleus accumbens addition to reward, applies to aversive, new neurotransmission in brain regions that are
(NAc)11,12. Specifically, it seems that the rein- and unexpected stimuli, affects the motiva- regulated by dopamine17. The long-lasting
forcing effects of drugs of abuse are due to tion to seek the anticipated reward and facili- changes that occur in the transcription fac-
their ability to surpass the magnitude and tates conditioned learning19,20. This provides a tors δFosB and cAMP responsive element
duration of the fast dopamine increases that different perspective about drugs, as it implies binding protein (CREB) after chronic drug
occur in the NAc when triggered by natural that drug-induced increases in dopamine will administration are of particular interest
reinforcers such as food and sex13. Drugs such inherently motivate further procurement of because they modulate the synthesis of pro-
as cocaine, amphetamine, methamphetamine more drug (regardless of whether or not the teins that are involved in synaptic plasticity3.
and ecstasy increase dopamine by inhibiting effects of the drug are consciously perceived Indeed, chronic drug exposure alters the mor-
dopamine reuptake or promoting dopamine to be pleasurable). Indeed, some addicted phology of neurons in dopamine-regulated
release through their effects on dopamine individuals report that they seek the drug circuits. For example, in rodents, chronic
transporters14. Other drugs, such as nicotine, even though its effects are no longer pleasur- cocaine or amphetamine administration
alcohol, opiates and marijuana, work indirectly able. Drug-induced increases in dopamine increases neuronal dendritic branching and
by stimulating neurons (GABA-mediated or will also facilitate conditioned learning, so spine density in the NAc and prefrontal cortex
glutamatergic) that modulate dopamine cell previously neutral stimuli that are associated — an adaptation that is thought to participate

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80
70
60
50
Percent of initiates
40
30
20
10
0
Child Teen Young
<12 12–17 adult
18–25
Figure 2 | Age at which marijuana use is first
initiated. Data from the National Survey of Drug
Use and Health57.
in the enhanced incentive motivational value
of 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 documented
not only for dopamine, but also for glutamate,
GABA, opiates, serotonin and various neuro-
peptides. These changes contribute to the
abnormal function of brain circuits. For
example, in individuals who are addicted to
cocaine, imaging studies have documented
that disrupted dopamine activity in the brain
(shown by reductions in dopamine D2 re-
ceptors) is associated with abnormal activity
in the orbitofrontal cortex (OFC) and in the
anterior cingulate gyrus (CG) — brain regions
that are involved in salience attribution and
inhibitory control24 (FIG. 3). Abnormal function
of these cortical regions has been particularly
revealing in furthering our understanding of
addiction , as their disruption is linked to
compulsive behaviour (OFC) and disinhibi-
tion24 (CG). Therefore, the abnormalities in
these frontal regions could underlie the com-
pulsive nature of drug administration in
addicted individuals and their inability to con-
trol their urges to take the drug when they are
exposed to it. In addition, animal studies have
shown that drug-related adaptations in these
frontal regions result in enhanced activity
in the glutamatergic pathway that regulates
NATURE REVIEWS | NEUROSCIENCE
dopamine release in the NAc25. The adapta-
tions in this pathway seem to be involved in the
relapse that occurs after drug withdrawal in
animals previously trained to self-administer a
drug when they are again exposed to the drug,
a drug stimulus or stress25.
At the circuit level, there is clear evidence
that adaptations in the mesocortical circuit
(including the OFC and CG) cause compulsive
drug administration and poor inhibitory
control, and they probably participate in
relapse. However, adaptations also seem to
occur in the mesolimbic circuit (including the
NAc, amygdala and hippocampus), which
probably cause the enhanced saliency value of
the drug and drug stimuli, and the decreased
sensitivity to natural reinforcers26. Further-
more, adaptations have also been reported in
the nigrostriatal circuit (including the dorsal
striatum), which might underlie habits that
are linked to the rituals of drug consumption27.
Adult
>25 Vulnerability to addiction
Genetic factors. It is estimated that 40–60% of
the vulnerability to addiction is attributable to
genetic factors28. In animal studies, several
genes have been identified that are involved
in drug responses, and their experimental
modifications 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 either
predispose to or protect from drug addiction28.
Some of these polymorphisms interfere with
drug metabolism. For example, specific alleles
for the genes that encode alcohol dehydroge-
nases ADH1B and ALDH2 (enzymes involved
in the metabolism of alcohol) are reportedly
protective against alcoholism30. Similarly,
polymorphisms in the gene that encodes
cytochrome P-450 2A6 (an enzyme that is
involved in nicotine metabolism) are report-
edly protective against nicotine addiction31.
Furthermore, genetic polymorphisms in the
cytochrome P-450 2D6 gene (an enzyme that
is involved in conversion of codeine to mor-
phine) seem to provide a degree of protection
against codeine abuse 32.
Some polymorphisms in receptor genes
that mediate drug effects have also been
associated with a higher risk of addiction. For
example, there is an association between
alcoholism and the genes for the GABA type A
(GABAA) receptors GABRG3 (REF. 33) and
GABRA2 (REF. 34). D2-receptor polymorphisms
have been linked to a higher vulnerability to
drug addiction, although some studies have
failed to replicate this finding28. Replication of
many of the genetic findings in substance
abuse and addiction is still pending.
PERSPECTIVES
Environmental factors. Environmental factors
that have been consistently associated with
the propensity to self-administer drugs
include low socio-economic class, poor
parental support and drug availability. Stress
might be a common feature in a wide variety
of environmental factors that increase the risk
for drug abuse. The mechanisms responsible
for stress-induced increases in vulnerability to
drug use and to relapse in people who are
addicted are not yet well understood, but
there is evidence that the stress-responsive
neuropeptide corticotropin-releasing factor is
involved through its effects in the amygdala
and the pituitary–adrenal axis35.
Imaging techniques now allow us to
investigate how environmental factors affect
the brain and how these, in turn, affect the
behavioural responses to drugs of abuse. For
example, in non-human primates, social
status affects D2-receptor expression in the
brain, which in turn affects the propensity for
cocaine self-administration36. Animals that
achieve a dominant status in the group show
increased numbers of D2 receptors and are
reluctant to administer cocaine, whereas
animals that are subordinate have lower
D2-receptor numbers and readily administer
cocaine. As animal studies have shown that
increasing D2 receptors in NAc markedly
decreases drug consumption (which has been
shown for alcohol37), this could provide a
mechanism by which a social stressor could
modify the propensity to self-administer
drugs.
Co-morbidity with mental illness. The risk
for substance abuse and addiction in individ-
uals with mental illness is significantly higher
than for the general population. The high
co-morbidity probably reflects, in part, over-
lapping environmental, genetic and neuro-
biological factors that influence drug abuse
and mental illness38.
It is likely that different neurobiological
factors are involved in co-morbidity depend-
ing on the temporal course of its develop-
ment (that is, mental illness followed by drug
abuse or vice versa). In some instances, the
mental illness and addiction seem to co-
occur independently39, but in others there
might be a sequential dependency. It has
been proposed that co-morbidity might be
due to the use of the abused drugs to self-
medicate the mental illness in cases in which
the onset of mental illness is followed by
abuse of some types of drug. But, when
drug abuse is followed by mental illness, the
chronic exposure could lead to neurobiologi-
cal changes, which might explain the increased
risk of mental illness38. For example, the high
VOLUME 5 | DECEMBER 2004 | 9 6 5
PERSPECTIVES

a Dopamine D2 receptors c lives when they are more likely to take risks,
70
Orbitofrontal cortex (OFC) interventions that educate them about the
65 harmful effects of drugs with age-appropriate
messages can decrease the rate of drug use44,45.

(micromol/100g/min)
60
However, not all media campaigns and

Metabolism
55
school-based educational programmes have
50
been successful46. Tailored interventions that
45
take into account socio-economic, cultural,
40 age and gender characteristics of children and
35 adolescents are more likely to improve the
30
effectiveness of the interventions.
Control Cocaine abuser 1.5 2 2.5 3 3.5 4 4.5 At present, prevention strategies include
D2-receptor availability not only educational interventions based on
b Brain glucose metabolism
70 comprehensive school-based programmes and
Cingulate gyrus (CG) effective media campaigns and strategies that
65
decrease access to drugs and alcohol, but also
(micromol/100g/min) 60 strategies that provide supportive community
OFC
Metabolism

55
activities that engage adolescents in productive
and creative ways. However, as we begin to
50
understand the neurobiological consequences
45 that underlie the adverse environmental fac-
tors that increase the risks for drug use and for
40
addiction, we will be able to develop interven-
35 tions to counteract these changes. Similarly, in
Control Cocaine abuser 1.5 2 2.5 3 3.5 4 4.5
the future, as we gain knowledge of the genes
D2-receptor availability
and the proteins that they encode that make a
Figure 3 | Dopamine D2 receptors and glucose metabolism in addiction. a,b | Positron emission
tomography (PET) images showing dopamine D2 receptors and brain glucose metabolism in the OFC
person more or less vulnerable to taking drugs
(orbitofrontal cortex) in controls and in individuals who abuse cocaine. Note that the individuals abusing and to addiction, more targets will be available
cocaine have reductions in D2 receptors and in OFC metabolism. c | Correlation between measures of D2 to tailor interventions for those at higher risk.
receptors 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 brain Treating addiction. The adaptations in the
region that is implicated in salience attribution and whose disruption results in compulsive behaviour, could brain that result from chronic drug exposure
underlie the compulsive drug administration that occurs in addiction. Decreased activity in the CG, a brain
are long lasting; therefore, addiction must be
region that is involved in inhibitory control, could underlie the inability to restrain from taking the drug when
the addicted person is exposed to them58. viewed as a chronic disease. Long-term treat-
ment will be required for most cases, just as
for other chronic diseases (such as hyperten-
sion, diabetes and asthma)47. This perspective
prevalence of smoking that is initiated after Preventing addiction. The greater vulnerabil- modifies our expectations of treatment and
individuals experience depression could ity of adolescents to experimentation with provides a new understanding of relapse.
reflect, in part, the antidepressant effects of drugs of abuse and to subsequent addiction First, discontinuation of treatment, as for
nicotine as well as the antidepressant effects underscores why prevention of early exposure other chronic diseases, is likely to result in
of monoamine oxidase A and B (MAO-A is such an important strategy to combat drug relapse. Also, as for other chronic medical
and -B) inhibition by cigarette smoke40. On addiction. Epidemiological studies show that conditions, relapse should not be interpreted
the other hand, the reported risk for depres- the prevalence of drug use in adolescents has as a failure of treatment (as is the view in
sion with early drug abuse41 could reflect changed significantly over the past 30 years, most cases of addiction), but instead as a
neuroadaptations in dopamine systems that and some of the decreases seem to be related temporary setback due to lack of compliance
might make individuals more vulnerable to to education about the risks of drugs. For or tolerance to an effective treatment47. Indeed,
depression. example, for marijuana, the prevalence rates the rates of relapse and recovery in the treat-
The higher risk of drug abuse in individ- of use in the United States in 1979 were as ment of drug addiction are equivalent to those
uals with mental illnesses highlights the rele- high as 50%, whereas in 1992 they were as low of other medical diseases47.
vance of the early evaluation and treatment as 20% (REF. 42) (FIG. 4). This changing pattern The involvement of multiple brain circuits
of mental diseases as an effective strategy of marijuana use seems to be related in part to (reward, motivation, learning, inhibitory
to prevent drug addiction that starts as the perception of the risks associated with the control and executive function) and their
self-medication. drug; when adolescents perceived the drug to associated disruption of behaviour indicate
be risky, the rate of use was low, whereas when the need for a multimodal approach in the
Strategies to combat addiction they did not, the rate of use was high (FIG. 4). treatment of the addicted individual. There-
The knowledge of the neurobiology of drugs Similarly, the significant decreases in ecstasy fore, interventions should not be limited to
and the adaptive changes that occur with use as well as cigarette smoking in adolescents inhibiting the rewarding effects of a drug, but
addiction is guiding new strategies for pre- seem to partly reflect effective educational should also include strategies to enhance the
vention and treatment, and identifying areas campaigns43. These results show that, despite saliency value of natural reinforcers (including
in which further research is required. the fact that adolescents are at a stage in their social support), strengthen inhibitory control,

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 PERSPECTIVES

(such as 12-step programmes (self-help sup-

Past year use
50
Perceived risk
port groups whose members attempt recovery
from addiction, in part, by ‘admitting’ that they
have a problem and by sharing experiences))
Percentage of 18–19 year olds

40
would be more effective if complemented with
medications that could help the patient remain
30 drug free.

Pharmacological intervention. Pharmaco-

20
logical interventions can be grouped into two
classes. First, there are those that interfere with
10 the reinforcing effects of drugs of abuse (that is,
medications that interfere with the binding of
1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 the drug, drug-induced dopamine increase,
Year postsynaptic responses or with the drug’s
Figure 4 | Use and risk perception of marijuana. The prevalence rate for marijuana use in the past delivery to the brain, or medications that
12 months and the perception of marijuana as a dangerous drug in 12th graders (18–19 years old) from trigger aversive responses). Second, there are
1979 to 2003 (REF. 42). When teenagers perceived marijuana as dangerous, the prevalence of drug use
those that compensate for the adaptations that
was low and vice versa.
either pre-dated or developed after long-term
use (that is, medications that decrease the
prioritized motivational value of the drug,
decrease conditioned responses and improve which might target different underlying fac- enhance the saliency value of natural rein-
mood if disrupted. The most obvious multi- tors and therefore have synergistic effects. For forcers, interfere with conditioned responses,
modal approach is the combination of phar- example, it might be predicted that addiction interfere with stress-induced relapse or inter-
macological and behavioural interventions, treatments that use behavioural interventions fere with physical withdrawal). The usefulness

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/glutamate
Ondansetron63 5-HT3 receptor
Nalmefene64 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 brain
Nabi 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 cocaine
Cocaine 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.

NATURE REVIEWS | NEUROSCIENCE VOLUME 5 | DECEMBER 2004 | 9 6 7

PERSPECTIVES
Brain
Lungs
Heart
Liver
Kidneys
Non-smoker
Figure 5 | Monoamine oxidase B concentration and cigarette smoking. Positron emission
tomography (PET) images of the concentration of the enzyme MAO-B (monoamine oxidase B) in the
body of a healthy control and of a cigarette smoker. There are significant decreases in the concentration
of the enzyme throughout the body of the smoker. Reproduced, with permission, from REF. 59 © (2003)
National Academy of Sciences, USA.
of some of the medications for drug addic-
tion has been clearly validated; for others the
data are still preliminary, and for most the
results are limited to promising preclinical
findings. TABLE 1 summarizes proven medica-
tions as well as medications for which there
are preliminary clinical data. Many of these
promising new medications target different
neurotransmitters (such as GABA, cannabi-
noids or glutamate) from the older drugs,
offering a wider range of therapeutic options.
Cognitive–behavioural intervention. In a
similar fashion, behavioural interventions
can be classified by their intended remedial
function, such as to strengthen inhibitory
control circuits, to provide alternative rein-
forcers and to strengthen executive function.
Traditionally, behavioural therapy has focused
on symptom-based targets rather than
underlying causes of addiction. However, for
other brain disorders, new views of brain
plasticity, which recognize the capacity of
neurons in the adult brain to increase synap-
tic connections and in certain instances to
regenerate48, have resulted in more focused
cognitive–behavioural interventions designed
to increase the efficiency of dysfunctional
brain circuits. This has been applied in
attempts to improve reading in children with
learning disabilities49 and to facilitate motor
968 | DECEMBER 2004 | VOLUME 5
Smoker
and memory rehabilitation after brain
injury50, but has not yet been applied to the
remediation of brain circuits altered by drug
abuse. Dual approaches that pair cognitive–
behavioural strategies with medications to
compensate or counteract the neurobiological
changes induced by chronic drug exposure
might, in the future, provide more robust
and longer lasting treatments for addiction
than either given in isolation.
Treating co-morbidities. Abuse of multiple
substances, such as alcohol and nicotine or
alcohol and cocaine, should be considered
in the proper management of the addicted
individual. Similarly, co-morbidities with
mental illness will require treatment for
the mental illness concurrent with treatment
for drug abuse.
As drugs of abuse adversely affect many
organs in the body (FIG. 5), uncontrolled con-
sumption contributes to the burden of many
medical diseases, including cancer, cardiovas-
cular and pulmonary diseases, HIV/AIDS and
hepatitis C, as well as to accidents and vio-
lence. Therefore, substance-abuse treatment
will help to prevent or improve the outcome
for medical diseases. For example, drug abuse
is a leading contributor to the spread of HIV/
AIDS, and treatment of addiction in some
instances prevents its dissemination51,52.
Challenges for society
In most cases, drug abuse and addiction
alienates the individual from both family
and community, increasing isolation and
interfering with treatment and recovery. As
both the family and the community provide
integral aspects of effective treatment and
recovery, this identifies an important chal-
lenge: to reduce the stigma of addiction that
interferes with intervention and proper
rehabilitation.
Effective treatment of drug addiction in
many individuals requires consideration of
social policy, such as the treatment of drug
addiction in the criminal justice system, the
role of unemployment in vulnerability to
the use of drugs and family dysfunctions
that contribute to stress and that might
block the efficacy of otherwise effective
interventions. For example, studies have
shown that providing drug treatment to
prisoners who were substance abusers and
continuing the treatment after they left the
prison dramatically reduced not only their
rate of relapse to drugs, but also their rate of
re-incarceration53,54. Similarly, drug courts
in the United States, which incorporate drug
treatment into the judicial system, have
proved to be beneficial in decreasing drug
use and arrests of offenders who are
involved in drug-taking55. However, despite
these preliminary positive results, there are
still many unanswered questions that future
research should address. For example, what
are the active ingredients in the treatment of
the drug offender? How does the system
deal with the fact that few offenders stay
in treatment long enough to receive the
minimally required services? What are the
implications of these findings for pre-trial
diversion laws, post-prison re-entry initiatives
and so on?
The recognition of addiction as a disease
that affects the brain might be essential for
large-scale prevention and treatment pro-
grammes that require the participation of the
medical community. Engagement of paedia-
tricians and family physicians (including the
teaching of addiction medicine as part of
medical students’ training) might facilitate
early detection of drug abuse in childhood
and adolescence. Moreover, screening for
drug use could help clinicians better manage
medical diseases that are likely to be adversely
affected 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, despite
it being one of the most common chronic
disorders.
www.nature.com/reviews/neuro

The participation of the medical com-
munity in many countries, including the
United States, is further curtailed by the lack
of reimbursement by most private medical
insurance policies for the evaluation or
treatment of drug abuse and addiction. This
lack of reimbursement limits the treatment
infrastructure and the choices that the
addicted person has with respect to their
treatment. It also sends a negative message
to medical students who are interested in
clinical practice, discouraging them from
choosing a speciality for which the reim-
bursement of their services is limited by the
lack of parity.
Another considerable obstacle in the
treatment of addiction is the limited involve-
ment of the pharmaceutical industry in the
development of new medications. Issues
such as stigma, lack of reimbursement for
drug-abuse treatment and the lack of a large
market all contribute to the limited involve-
ment of the pharmaceutical industry in the
development of medications to treat drug
addiction. The importance of this issue
was identified by the Institute of Medicine of
the United States, which recommended a
programme to provide incentives to the
pharmaceutical industry as a way of helping
to address this problem56.
The translation of scientific findings in
drug abuse into prevention and treatment
initiatives clearly requires partnership with
federal agencies such as the Substance Abuse
and 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 Control
Policy (ONDCP, which is responsible for
U.S. programmes to control availability and
reduce demand for drugs of abuse). Further-
more, improved prevention and treatment
programmes could result from collabora-
tions with other agencies and groups, such
as the Department of Education (which can
bring prevention interventions into the school
environment), the Department of Justice
(which can implement treatment strategies
that will minimize the chances of recidivism
and re-incarceration of inmates with
drug-abuse problems) and state and local
agencies (which can bring evidence-based
and science-based treatments into the
communities).
As we learn more about the neurobiology
of normal and pathological human behav-
iour, a challenge for society will be to use this
knowledge to effectively guide public policy.
For example, as we understand the neuro-
biological substrates that underlie voluntary
actions, how will society define the boundaries
NATURE REVIEWS | NEUROSCIENCE
of personal responsibility in those individuals
who have impairments in these brain circuits?
This will have implications not only for the
management of drug offenders, but also of
other offenders with diagnoses such as antiso-
cial personality disorder or conduct disorder.
At present, critics of the medical model of
addiction argue that this model removes the
responsibility of the addicted individual from
his/her behaviour. However, the value of the
medical model of addiction as a public policy
guide is not to excuse the behaviour of the
addicted individual, but to provide a frame-
work to understand it and to treat it more
effectively.
Summary
Remarkable scientific advances have been
made in genetics, molecular biology, behav-
ioural neuropharmacology and brain imag-
ing that offer new insights into how the
human 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 and
genes affect the responses of the brain to
drugs and produce neural adaptations that
lead to the aberrant behavioural manifesta-
tions of addiction. This new knowledge is
helping us to understand why drug addicts
relapse even in the face of threats such as
divorce, loss of child custody and incarcera-
tion, even when, in some cases, the drug is no
longer perceived as pleasurable, and is chang-
ing how we should approach prevention and
treatment of addiction.
The field is at a crossroads where major
advances in understanding the neuro-
biology of addiction have helped identify
promising new medications, but where the
translation of these findings into clinical
practice is limited by several factors, includ-
ing the limited involvement of the medical
community in the treatment of addiction,
the restricted involvement of the pharma-
ceutical industry, the lack of reimbursement
by private insurance policies and the
stigma associated with drug addiction. One of
the main challenges for agencies like the
National Institute on Drug Abuse (NIDA)
and the National Institute on Alcohol Abuse
and Alcoholism (NIAAA) is to develop
knowledge that will help to overcome these
obstacles.
Nora Volkow is at the National Institute on Drug
Abuse, Bethesda, Maryland 20892, USA.
Ting-Kai Li is at the National Institute on Alcohol
Abuse and Alcoholism, Bethesda, Maryland
20892, USA.
e-mail: nvolkow@nida.nih.gov
doi:1038/nrn1539
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Acknowledgments
The authors thank T. Condon, M. Egli, J. Fowler, C. Kassed,
R. Litten, A. Noronha and J. Swanson for thoughtful comments
and editorial assistance.
Competing interests statement
The authors declare no competing financial interests.
Online links
FURTHER INFORMATION
Encyclopedia of Life Sciences: http://www.els.net/
Addiction | Adaptations: meanings | Alcoholism | Cocaine and
amphetamines | Opiates
National Institute on Drug Abuse:
http://www.drugabuse.gov/NIDAHome.html
Office of National Drug Control Policy:
http://www.whitehousedrugpolicy.gov/
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Administration: http://www.samhsa.gov/index.aspx
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