Opinion TRENDS in Molecular Medicine
12
Drug addiction: the neurobiology of
disrupted self-control
Ruben D. Baler and Nora D. Volkow
National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD 20892, USA
The nature of addiction is often debated along moral
versus biological lines. However, recent advances in
neuroscience offer insights that might help bridge the
gap between these opposing views. Current evidence
shows that most drugs of abuse exert their initial rein-
forcing effects by inducing dopamine surges in limbic
regions, affecting other neurotransmitter systems and
leading to characteristic plastic adaptations. Impor-
tantly, there seem to be intimate relationships between
the circuits disrupted by abused drugs and those that
underlie self-control. Significant changes can be
detected in circuits implicated in reward, motivation
and/or drive, salience attribution, inhibitory control
and memory consolidation. Therefore, addiction treat-
ments should attempt to reduce the rewarding proper-
ties of drugs while enhancing those of alternative
reinforcers, inhibit conditioned memories and
strengthen cognitive control. We posit that the time
has come to recognize that the process of addiction
erodes the same neural scaffolds that enable self-control
and appropriate decision making.
What is addiction?
Addiction (see Glossary) is the quintessential complex
disorder. Indeed, some of the lingering debates in the field
(Box 1) stem from the many interactions across its socio-
cultural, political, behavioral and biological dimensions.
First, addiction itself remains ill-defined, in part because
the term attempts to encompass the deleterious effects of
many classes of psychoactive licit and illicit drugs with
both overlapping and distinct mechanisms of action. Sec-
ond, the understanding of addiction vulnerability is still
rudimentary: the fact that only a largely unpredictable
minority of drug abusers progresses to a bona fide state of
drug addiction hints at the complex interplay between
genetic and environmental risk factors. Third, researchers
are only beginning to understand, catalog and therapeu-
tically exploit the extensive neurochemical changes that
precede and accompany the process of addiction.
Controversies aside, we can agree on several established
principles. First, sustained exposure to drugs of abuse might
be a prerequisite for drug addiction, but its emergence is
ultimately a function of interactions between drug effects,
biological and environmental factors, which are crucially
influenced by the developmental stage of the individual
[1,2]. Indeed, most experimentation with drugs and the
Corresponding author: Volkow, N.D. (nvolkow@nida.nih.gov).
Available online 27 October 2006.
www.sciencedirect.com 1471-4914/$ – see front matter . Published by Elsevier Ltd. doi:10.1016/j.molmed.2006.10.005
Vol.12 No.
development of addiction occur during adolescence and
early adulthood [3,4]. The complexity of such interactions
might help explain why some individuals become addicted,
whereas others do not. Second, addiction usually takes hold
when vulnerable individuals repeatedly seek to replicate an
originally pleasurable experience. However, during the gra-
dual transition from recreational use to addiction, a funda-
mental motivational shift takes place whereby a drug is no
longer taken to derive pleasure from it but to satiate intense
craving and to relieve the distress of not having the drug [5].
Repeated use of the drug changes the brain of the user so
that behaviors become more reflexive and, consequently,
much less amenable to cognitive interference. Third, both
pre-clinical and clinical research produced convincing evi-
dence of the serious consequences that the acute and
repeated administration of drugs can bring upon the brain
at the molecular, cellular and circuit organizational levels
[5]. Inasmuch as drugs affect the physiological processes
that support learning, decision making, and emotional and
behavioral control, we are starting to understand why the
addicted-person ability to exert self-control might become so
disrupted. To the extent that some of these changes are long-
lasting and, in some instances, perhaps even irreversible,
they support the view that addiction can be conceptualized
as a chronic disease [6].
The timing and rationale for this review derive from the
growing understanding of the processes that underlie
addiction. This knowledge is bound to provide important
clues for the development of potentially better strategies to
prevent and treat drug addiction, and is posed to influence
still prevalent attitudes towards addicted individuals. We
describe some of the evidence for the proposed role of
dopamine (DA) dysregulation in the various phases of
addiction, and the contribution of other neurotransmitter
Glossary
Addiction: a process that manifests itself in the uncontrollable, compulsive
drug seeking and use, and that persists even in spite of negative health and
social consequences. These behaviors are much more difficult to control than
the physical dependence that underlies withdrawal symptoms.
Nucleus accumbens: located in the limbic system, it is involved in controlling
motivation and has a central role in the reward circuit. Its operation is heavily
influenced by DA, which some neurons use to evaluate saliency. However,
glutamate, which transmits regulatory signals from the prefrontal cortex, and
serotonin, the effects of which include satiety, inhibition and the modulation of
DA release, also modulate accumbal function.
Reinforcer: a type of stimulus that strengthens (positive reinforcer) or weakens
(negative reinforcer) the behavior that produced it.
Salience: the subjective prominence or quality to stand out of a stimulus or
object in the context of neighboring or competing stimuli or objects.
560 Opinion TRENDS in Molecular Medicine
Box 1. Remaining controversies
 Plastic changes. Drugs of abuse produce a large number of plastic
changes in the brain. One of the remaining challenges is to
determine which of these changes represent fundamental pro-
cesses for the establishment of a particular stage in the
progression from drug self-administration to habitual drug use,
to addiction and relapse, in animals and in humans. Advances in
this area will result in a better definition of addiction and a more-
focused treatment research.
 Vulnerabilities. The definition and characterization of addiction
vulnerabilities remains one the most-challenging issues and its
implications far-reaching. Further progress in genomics and
social sciences are key to optimizing the match between preven-
tion and treatment approaches with the presence of specific risk
factors in various populations.
 Addiction as a chronic disease of the brain. As we present the
evidence and champion the concept of addiction as a chronic and
relapsing disease, some quarters are reluctant to embrace a view
that in their opinion undermines the robust moral boundaries that
the concept of personal responsibility bestows upon individuals.
This is an evolving debate with far-reaching implications, which
involves contributions from widely diverse fields, such as
neuroimaging, genomics, criminal law, ethics and religion.
systems to the long-term establishment of this disordered
state. A discussion of the identifiable brain circuits affected
by abuse and addiction follows: this section represents the
main thrust of our commentary, which ends with a brief
discussion of some of the current approaches for developing
addiction treatments.
The neurobiology of drug addiction
Dopamine: a major node in the addiction network
It is widely accepted that the initial reinforcing effects of
most drugs of abuse rely heavily upon the induction of
large and rapid increases in the level of DA in the nucleus
accumbens. DA, a multifaceted neurotransmitter, is
involved in the fine-tuning of motor and cognitive func-
tion, modulation of salience attribution and attention,
and regulation of reward and motivation. Interestingly,
in contrast to the increases in DA neurotransmission that
are observed during acute drug intake, imaging studies
have shown that in drug-addicted individuals, supra-
physiological levels of DA in the nucleus accumbens
are followed by marked decreases in dopamine function
[7]. For example, positron emission tomography (PET)
studies have consistently shown long-lasting reductions
in the level of striatal DA D2 receptors in drug abusers,
an observation that supports our hypothesis that, as
drug-associated experiences gain in significance, the
threshold required for natural reinforcers to activate
DA might increase [8]. Indeed, drug-addicted individuals
seem to suffer from an overall reduction in the sensitivity
of their reward circuits to natural reinforcers. For exam-
ple, a functional magnetic resonance imaging (MRI)
study showed significantly perturbed patterns of brain
activation in response to sexual cues in cocaine-addicted
individuals [9]. Similarly, a PET study found evidence
suggesting that the brains of smokers react in a different
way to monetary and non-monetary rewards compared
with those of non-smokers – a difference that involves
regions of the dopaminergic reward system [10]. It is
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Vol.12 No.12
important to emphasize, however, that not just natural
rewards but also the entire reward system is compro-
mised in addicted individuals. Drugs of abuse are simply
exceedingly effective at temporarily blocking the negative
reinforcement that addicted individuals experience dur-
ing abstinence [11].
As the drug achieves increasing preeminence over that
of alternative reinforcers, the conditioned learning
towards the drug and previously neutral stimuli asso-
ciated with it (cues) strengthens. The newfound ability
of cues to increase DA by themselves and elicit a strong
desire for the drug [12,13] might explain why an addicted
person is at high risk of relapsing whenever exposed to
them [13,14].
Researchers have amassed vast amounts of data that
reflect the connections between DA and the reinforcing
properties of drugs. However, it is not fully understood the
extent to which DA reinforcing properties, as measured in
various animal models, maps onto the rewarding mechan-
isms elicited by abused drugs in humans. Drug-induced
euphorigenic surges in DA mimic those that occur in
response to salient stimuli that typically signal pleasure
(e.g. food and sex) [15–17], but tend to reach dramatically
higher levels and/or last much longer. From the brain
perspective, however, accumbal DA increases might not
be synonymous with pleasure per se; rather, the firing rate
of DA neurons at that site has been proposed to encode the
saliency of a given event or stimulus [18] as a function of
prevalent expectations [19], and in a way that facilitates
the consolidation of memory traces connected to such
stimulus [20]. If this is the case, then stimuli might be
interpreted as salient not solely on the basis of their
predicting rewarding effects but also of their aversive,
unexpected or novel characteristics.
The understanding of how salient stimuli that are
non-rewarding or aversive modulate DA neurons and
behavior is still incomplete. Aversive stimuli can induce
slow increases in extracellular DA; yet, paradoxically, they
fail to trigger robust firing patterns in DA neurons. A
recently published model [21] has attempted to reconcile
these observations by proposing that aversive stimuli acti-
vate opposing processes: a rapid one that overlaps with the
stimulus and a protracted one that outlasts it. There is
limited amount of data supporting various aspects of this
model [22,23], which offers a potentially better description
of DA role in positive and negative reward.
Taking all this information into account, we and others
have proposed that the computational outcome of synaptic
transmission within DA networks might drive motivation
to modify the behavior in response to a stimulus [24]. If
this view is correct, then drugs of abuse might induce
addiction not just because they are experienced as plea-
surable but also because they are being processed as
salient events that motivate procurement of more drug,
while they help solidify memories linked to the experience.
This might explain why nicotine, which triggers DA
release without being particularly euphorigenic, can
nevertheless be highly addictive, and why in some
instances addicted individuals claim that they take the
drug compulsively even when it is no longer perceived as
pleasurable.
 Opinion TRENDS in Molecular Medicine Vol.12 No.12 561

Other neurotransmitter systems roles in motivation, reward, judgment and the inhibitory
In contrast to the considerable gaps in the understanding control of behavior [34].
of how drugs of abuse affect behaviour, there is a large body For example, chronic adaptations in DA-receptor
of evidence regarding the direct and indirect mechanisms signaling might trigger compensatory glutamate-receptor
that drugs can use to activate the DA system supraphy- responses with the potential to affect synaptic plasticity
siologically. Drugs such as cocaine, amphetamine, [35]. The fact that DA, glutamate, GABA and other neuro-
methamphetamine and ecstasy increase DA level by inhi- transmitters are all highly versatile effectors of synaptic
biting or perturbing the mechanism of DA reuptake and plasticity [35,36] draws a direct path connecting the effects
facilitating DA release [25], whereas other drugs such as of drug abuse with the adaptive alterations not only in the
nicotine, alcohol, opiates and marijuana work indirectly by reward center but also in many other circuits, through the
stimulating neurons (GABAergic or glutamatergic) that strengthening, formation and elimination of synapses
modulate DA-cell firing through their effects on nicotine, g- (Figure 1a).
aminobutyric acid (GABA), m-opiate or cannabinoid (CB)1 It is true that uncertainty still exists regarding the
receptors, respectively [26]. complex relationships between circuit activity at the neu-
Although a drug-induced increase in extracellular DA ronal level and the expression of overt behaviors, but close
during intoxication seems to be necessary for its ability to scrutiny of pre-clinical and clinical data is providing valu-
produce addiction, it is clearly not sufficient because such able insights into the functional disruption and cognitive
increases are observed in both addicted and non-addicted consequences triggered by the continued abuse of addictive
individuals [7]. One of the main complicating factors might drugs.
be that other neurotransmitter and neuropeptide systems
have equally important roles in the modulation of the
reward system, the establishment of addiction-related
adaptations and the manifestation of behavioral conse-
quences. For example: (i) an intact noradrenergic system
seems to be crucial for psychostimulant-dependent
mesoaccumbal DA release [27]; (ii) the neuropeptide
orexin, previously known to regulate feeding, has recently
been shown to support addiction-related plastic changes
[28]; (iii) chronic cocaine induces long-lasting changes in
accumbal glutamate transmission [29]; (iv) mediators of
the stress response have been implicated in the acquisi-
tion, maintenance and reinstatement of drug self-admin-
istration in rats [30]; and (v), although there is lack of
reliable human data, numerous studies show that, when
given in sufficiently high doses, ecstasy can produce long-
term alterations in serotonin function in rats [31] and
monkeys [32].
The science of acute and chronic changes that
psychoactive drugs can bring upon multiple signaling
systems in the brain is rapidly evolving. There is no
comprehensive picture yet, but the outlines of the key
relevant circuits affected by drugs of abuse are coming
into sharper focus. In the next paragraph, we describe
those circuits in further detail in an attempt to shed light
on the structural underpinnings of the behavioral conse-
quences of abuse and addiction.

Plastic changes and short-circuits in the brain

A cogent and useful theory of addiction must account
for how the drug-induced chemical imbalances outlined
above can lead to the consolidation of addictive beha-
viors, such as compulsive drug-taking, despite the
threat of catastrophic consequences, and to the persis-
tent risk of cue-associated relapse. Psychoactive drugs
are known to induce profound adaptations in neuro-
transmitter systems, reminiscent of those associated
with long-term plasticity in the brain [6,33,34] (Box 1).
Indeed, there is mounting evidence that exposure to
stimulants, nicotine or opiates produces persistent
adaptative changes in the structure of dendrites and
dendritic spines on cells in key areas of the brain with
Figure 1. Addiction circuitry. (a) Schematic and oversimplified sagittal view of a
brain depicting four circuits that are postulated to have key interdependent and
overlapping roles in addiction: (1) reward prediction and the core substrates of
pleasure (red) located in the nucleus accumbens (NAcc) and ventral pallidum (VP); (2)
memory and learning, and the main substrate of conditioning (purple), located in the
amygdala (Amyg) and hippocampus (HIP); (3) motivation, drive and salience
evaluation (green) located in the orbitofrontal cortex (OFC); and (4) cognitive
control (blue), in charge of restraining cravings, located in the prefrontal cortex (PFC)
and anterior cingulate gyrus (ACG). (b) Hypothetical model of addiction as the result
of impaired information processing within the reward network. Compared with the
non-addicted state (left), the salience value of a drug (red) and its associated cues
(purple) is enhanced in the addicted state (right), whereas the strength of inhibitory
control is weakened (blue), setting up the stage for an unrestrained motivation
(green) resulting in compulsive drug taking without regard to potentially catastrophic
consequences. Modified, with permission, from [58].

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562 Opinion TRENDS in Molecular Medicine
Imaging studies have shown that the reduced DA
activity observed in drug-addicted subjects is associated
with disrupted metabolism in frontal brain regions, and
most accentuated in the orbitofrontal cortex (OFC), a brain
region involved in motivation, drive and shifting the rela-
tive saliency value of reinforcers (Figure 1a), and in ante-
rior cingulate gyrus (ACG), a brain region involved in
inhibitory control [37]. The activity of the OFC has been
shown to vary as a function of the state of drug withdrawal,
plunging from hyper- to hypo-metabolism as an addicted
individual goes through a four-week-long detoxification
process [38]. Moreover, imaging studies during craving
provocation have associated the increases in OFC and in
ACG activity with the subjective experience of drug craving
in addicted subjects [15]. Interestingly, the fact that the
OFC had been previously implicated in the expression of
obsessive compulsive disorders (OCD) [39], together with
the observation that OFC lesions lead to behavioral com-
pulsion [40], strengthens in our view the evidence in favour
of overlaps between the neurobiology of the compulsive
drug-taking observed in the drug-addicted individual and
the compulsive ritualistic behaviors characteristic of OCD
[41]. The ACG, and in particular the ventral area (Brod-
mann area 25; BA 25), has also been linked with craving
responses and mood elevations experienced by cocaine
abusers when exposed to a stimulant drug [42]. Inasmuch
as BA 25 is disrupted in mood disorders [43], this might
also underlie the dysphoria reported in cocaine abusers.
Naturally, the circuit involved in learning and memory
is also of obvious interest in the face of the vast literature
dealing with the intense craving that drug-associated
cues are able to rekindle in formerly addicted individuals
[14]. The involvement of Pavlovian conditioning mechan-
isms in drug-addiction processes has been demonstrated
repeatedly in animal models in which a single exposure to
drug-related cues can re-instate addiction behaviors, even
after a long period of abstinence [44]. These types of studies
have implicated limbic structures, particularly the hippo-
campus and amygdala (Figure 1a), as major contributors to
the acquisition, consolidation and expression of the drug-
stimulus learning that drives relapse to drug-seeking
behaviors [45,46].
Predictably, there is also a well-documented executive
component to addiction, suggesting that impaired cognitive
functions have an important role in prolonging abuse or
predisposing users towards relapse. The compromised abil-
ity of cocaine users to reign in uncontrollable urges has been
linked to reduced activity in the ACG and in the prefrontal
cortex (PFC) [47] (Figure 1a), which is consistent with the
impaired attention and/or executive functioning found in
both alcohol and cocaine abusers, as assessed with tradi-
tional neuropsychological measures [48]. The role and mod-
ulation of executive function in the process of drug addiction
have been the focus of heightened interest in recent years
because of the research showing that PFC maturation in
humans continues well into the early twenties [49]. In
addition, the neuroanatomical connections between the
amygdala and the PFC, which are indispensable for the
cognitive modulation of emotions, are not fully developed
until adult life [50]. This convergence of data might help
explain in part why adolescents might be at increased risk of
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Vol.12 No.12
experimenting with drugs, which is an indispensable first
step towards the process of addiction.
In addition to these major neural substrates of
drug-induced impairment, there is growing evidence that
other brain regions are implicated in the manifestation of
addictive behaviors as well, suggesting the recruitment of
far more complex networks. Cerebellar activation, for exam-
ple, has been associated with cue-induced alcohol craving
[51] and with cocaine persisting and acute effects [52]. This
is interesting in light of previous findings suggesting that
the dysexecutive component of cocaine addiction might be
due in part to a compensatory imbalance in the cerebellum
[47]. In other areas, recently detoxified methamphetamine
abusers display lower metabolism not only in the striatum
but also in the thalamus (filtering and coordination) and in
the insula (emotions and autonomic responses) [53]. Also,
discrete lesions of the subthalamic nucleus in rats have been
reported to reduce the motivation to self-administer cocaine
but to increase it for food reward, suggesting that this area
might be a promising target for new, more discriminative
treatments for cocaine addiction [54]. Finally, and in the
spirit of acknowledging the difficulties faced for achieving a
full picture of addiction substrates, it will be important to
pay closer attention to the gender differences that might
influence the neural correlates of cue-induced regional brain
activation [55].
While documenting the functional repercussions of drug
addiction, it is difficult not to notice the important overlap
that exists between the key circuits mentioned above and
the neural substrates that contribute to individual differ-
ences in impulsivity [56] and value-based exploitative
decision making [57]. This has further shaped our position
that, when drafting a model of addiction, it is important to
bear in mind the probable profound impact of drug abuse
and addiction on an individual ability to exert self-control.
A growing collection of relevant findings enabled us to
propose an integrated model to explain some of the beha-
vioral signatures of addiction as the corruption of informa-
tion-processing events within this network of brain circuits.
According to this simple model [58], the major neural sub-
strates underlying addiction make up a network of, at a
minimum, four interdependent and overlapping circuits
(Figure 1): (i) reward, located in nucleus accumbens (NAcc),
ventral pallidum (VP) and hypothalamus; (ii) motivation
and/or drive, located in the OFC; (iii) memory and learning,
located in the amygdala and hippocampus; and (iv) cognitive
control, located in the PFC and dorsal ACG. In addition,
brain regions and neurotransmitters that are involved in
the sensitivity to stress, such as the amygdala through
corticotropin releasing factor [59], and regions involved with
mood, such as the ventral cingulate [43], are also likely to
modulate the reactivity of the above circuits.
These four major circuits are modulated by DA both via
direct and indirect neuroanatomical pathways. Because
they connect with each other mostly through glutamatergic
and GABA-ergic projections, plasticity in these neuro-
transmitter systems might ultimately sustain an impor-
tant fraction of the long-term molecular changes that
mediate addictive behaviors. The interactions between
these highly connected circuits are integrated to generate
the behavioral output in response to a reinforcing stimulus.
 Opinion TRENDS in Molecular Medicine Vol.12 No.12 563

The decision to act or not to procure a given stimulus will
weigh its saliency value in the context of alternative sti-
muli and as a function of past experiences and of the
current internal needs and expectations of the individual
[60]. Based on the evidence described herein, we endorse
the hypothesis [61,62] according to which addiction entails
the attribution of distorted weights onto key variables
within the network (Figure 1b). As a result, the saliency
value of a drug and its associated cues is enhanced, that of
natural reinforcers is decreased and the strength of inhi-
bitory control is weakened, setting up the stage for an
unrestrained cycle that results in compulsive drug-taking
without regard to potentially catastrophic consequences.
This schematic view of disrupted value attributions in
addiction is bound to evolve with time, particularly as
we add new potential layers of complexity, such as dys-
functions within the non-dopaminergic aspects of the
‘drive’ domain that might modulate aversive systems.
Integrating science to treat addiction
A better understanding of the signaling systems and neural
circuits that are affected by various drugs of abuse is produ-
cing a more-comprehensive picture of addiction and provid-
ing new opportunities for developing better interventions.
Currently, pharmacotherapeutic approaches that attempt
to modulate glutamate and GABA plasticity, which are
important in the mesocorticolimbic pathways, represent
some of the most-promising treatment approaches.
Given the long-lasting nature of many of the
drug-induced adaptations, addiction might be best
construed as a chronic disease [63], such as heart disease
or diabetes, so that most addicted patients will require
long-term treatment and relapse can be expected to occur
sometimes during treatment [64]. Therefore, the occa-
sional relapse is only a predictable setback, not a failure
of the treatment; medications ought to be developed along
with realistic expectations of what they can achieve.
Another important lesson stemming from the model of
addiction circuitry is that interventions should be multi-
modal and incorporate approaches designed to: (i) decrease
the reward value of the drug of choice; (ii) weaken condi-
tioned memories to the drug and drug-related stimuli: (iii)
increase the saliency value of non-drug reinforcers; and (iv)
strengthen frontal inhibitory and executive control, with
extra efforts made towards developing interventions that
prevent relapse. This knowledge also stresses the impor-
tance of preventing early onset and adolescent drug use [5].
These goals seem to be custom-made for the types of
behavioral treatments that proved so useful for the man-
agement of other forms of psychiatric illness, such as
phobias and obsessive-compulsive disorders. During the
past three decades, there has been remarkable progress in
the optimization and implementation of various modalities
of behavioral therapies that proved effective also for the
treatment of drug abuse and addiction. Combined with
continuous improvements in the understanding of the
molecular and cellular effects of substance abuse on the
brain, a continuous expansion of potential targets for new
medications can be expected (Table 1), in addition to novel,
and perhaps synergistic, combinations of pharmacological

Table 1. Pipeline of medications for the treatment of drug addictiona

Proposed targets Medication Clinical effectiveness for
Interfere with the reinforcing effects of a drug
Substitution Methadone Heroin
Buprenorphine Heroin
Nicotine replacement Nicotine
Trigger aversion Disulfiram Alcoholism (cocaine) b
Inhibit DA increase Topiramate Alcoholism (cocaine)
Antiepileptics (g-Vinyl-GABA) (Cocaine)
(Gabapentin) (Cocaine)
Non-DA targets
m-Opiate receptors Naltrexone Alcoholism and heroin
Cannabinoid receptors (CB1-R antagonists) (Being tested for weight loss, nicotine and
other addictions)
GABA receptors (Baclofen) (Alcoholism and cocaine)
Interfere with drug delivery to the brain Vaccines Nicotine
Cocaine
Interfere with drug metabolism Methoxsalen Nicotine
Compensate for long-term effects of drugs in brain
Interfere with conditioned responses Antiepileptics (same as above) Alcoholism (cocaine)
Glutamate
Acamprosate c Alcoholism (cocaine)
(Modafinil) c
Strengthen saliency of natural reinforcers Enhance DA function
Bupropion Nicotine
(Deprenyl) (Nicotine)
Interfere with stress responses (CRF antagonist) (Not tested)
Interferes with withdrawal Clonidine
Benzodiazepines Heroin
Antiepileptics Alcohol
Propranolol
a
Medications for which there is only preliminary clinical data are identified in brackets to differentiate them from those for which there is proven efficacy.
b
The effects in cocaine addiction are not understood but do not seem to be mediated by triggering aversive responses.
c
Mechanisms of action are not properly understood.

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564 Opinion TRENDS in Molecular Medicine
and behavioral approaches. The promises (and limitations)
of selected medications, either deployed or at various
stages of development, are described below in further
detail.
Replacement therapies
Medications that act on the same molecular targets of
drugs of abuse but with different potencies and pharma-
cokinetics have been useful for the treatment of heroin
[e.g. methadone, levo-a-acetylmethadol (LAAM) and
buprenorphine] and nicotine (i.e. nicotine patches, nico-
tine chewing gum and nicotine breathalyzers) addictions.
For example, buprenorphine, which is the most-recently
developed treatment for heroin addiction, is a partial m-
opioid receptor agonist [65]. This makes it much less
potent than heroin as a reinforcer and also safer because
it is more difficult to overdose with buprenorphine [65].
Buprenorphine is also the first office-based treatment
option for opiate addiction. Current research is evaluat-
ing its potential utility in the treatment of addiction to
opiate analgesics.
Unfortunately, the potential of current D2 selective
agonists as maintenance medications for cocaine addiction
seems low because they all tend to have a high degree of
abuse liability. Preliminary studies with D1 agonists,
however, suggest they might have a more-promising ther-
apeutic outlook.
DA transporter blockers
DA transporter blockers have generated considerable
interest as potential treatments for cocaine addiction,
but the results of clinical trials with compounds such as
methylphenidate or bupropion have been for the most part
disappointing. Bupropion, however, which was initially
developed as an antidepressant, turned out to be an effec-
tive treatment for nicotine addiction. Ongoing clinical
trials are evaluating the utility of bupropion in metham-
phetamine addiction.
Non-DA drugs
Because many of the adaptations that lead to addiction
occur in cortical circuits that involve glutamate and GABA
neurotransmission [66], these neurotransmitters are
attractive targets for pharmacological intervention.
Indeed, some medications that target either or both of
these neurotransmitters could interfere with drug self-
administration in pre-clinical models. There are two
examples of potentially useful antiepileptic drugs in this
category. Topiramate has shown some promise for the
treatment of alcohol [67], opiate [68] and cocaine [69]
addictions. g Vinyl-GABA (GVG) has shown some positive
results in a preliminary open clinical trial in cocaine- and
methamphetamine-addicted subjects [70]. In addition, the
muscle relaxant baclofen, which reduced acquisition of
cocaine self-administration [71] and attenuated the rein-
forcing effects of the psychostimulant d-amphetamine in
rats [72], could block craving in alcoholics [73] and improve
abstinence in drug-abusing patients [74]. Finally, promis-
ing results have been obtained with the compound N-
acetylcysteine (NAC), an activator of cystine–glutamate
exchange that can block cocaine-induced reinstatement
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Vol.12 No.12
in animals [75]. Recent results of a double-blind
placebo-controlled crossover Phase I trial suggest that
NAC is well tolerated in healthy, cocaine-dependent indi-
viduals and might reduce cocaine-related withdrawal
symptoms and craving [76].
Naltrexone is an opioid antagonist that blocks the
subjective effects of opioids. In spite of its demonstrated
effectiveness as a treatment for alcoholism and opiate
addiction [77], the success of naltrexone has been limited
because of poor compliance. The recent development of
depot naltrexone might help improve treatment retention
[78].
Cannabinoid antagonists
Research on the CB-receptor system has demonstrated its
involvement in reward, learning and memory. Rimonabant
is the first CB-receptor antagonist developed by the phar-
maceutical industry. Although it is targeted as a treatment
for obesity and the metabolic syndrome [79], pre-clinical
studies and clinical pilot studies suggest that it might also
be effective for the treatment of addictions [80].
Adenosine-receptor antagonists
Adenosine 2a (A2a) receptors are highly expressed in the
nucleus accumbens and dorsal striatum, where they seem
to modulate the m-opiate plus CB1-receptor post-synaptic
signaling that facilitates heroin reinstatement. An A2a
antagonist has been recently shown to eliminate heroin-
induced reinstatement in rats, a finding that suggests that
A2a antagonists might be helpful to heroin addicts
attempting to manage withdrawal symptoms that are
elicited during periods of abstinence [81].
Corticotropin-releasing factor antagonists
The negative effects of stress upon drug-addicted
individuals are well established. The notion that dampen-
ing the stress response might help preventing relapse [82]
has triggered interest in corticotropin-releasing factor
(CRF)-receptor antagonists that can block the initiation
of the stress response in the brain. These compounds have
shown a remarkable ability to block the initiation of drug-
taking in animals, and the stress-induced reinstatement of
drug-seeking behavior for several drugs of abuse [83].
Memory blockers and enhancers
Because memory circuits are so intimately involved in
conditioned responses, medications that either erase or
replace them with new memories, might hold promise in
addiction. A preliminary study showed that the use of
drugs that interfere with memory formation might inhibit
the establishment of conditioned responses to cocaine [84].
In contrast, medications designed to enhance memory
might be developed to improve the effects of psychother-
apeutic interventions. Encouraging results have been
recently reported in this context when D-cycloserine was
found to enhance desensitization interventions in the
treatment of acrophobia [85].
Future directions
The basic science of drug abuse and addiction continues to
move forward at a rapid pace and on several fronts. The
 Opinion TRENDS in Molecular Medicine
ability to identify underlying vulnerabilities will grow
exponentially as researchers take advantage of powerful
13
new genomic screening tools. To maximize the return on
this genetic investment, however, the ability to codify
intermediate phenotypes of addiction and key environmen- 14
tal variables needs to improve greatly (Box 1). Advances in
15
brain imaging, neurochemistry and molecular biology are
adding crucial depth to the understanding of the complex
pathophysiology involved and revealing, along the way, 16
new targets for pharmaceutical, behavioral and combined
treatments. The medical implications of such develop- 17
ments might be profound. Wide genomic associations for
addiction will enhance the ability to identify vulnerable
populations and enable individually tailored treatments of 18
those afflicted by addiction. Intriguingly, one of the most-
persistent obstacles to the successful translation of this
19
growing knowledge is neither scientific nor economic but
cultural. The stigma that surrounds drug abuse and addic-
tion is still common and a considerable barrier to the 20
paradigm shift needed to addressing this disease as a
21
mental health issue (Box 1).
22
Concluding remarks
Current advances in addiction research have cast a new
light on the extent and nature of the brain changes caused 23
by chronic drug abuse, their impact on the neural sub-
24
strates of self-control, and the biological and environmen-
tal factors that might confer increased vulnerability to
these effects. The growing understanding of the addiction 25
process should help find a more-balanced, humane and
dignified approach to care for those afflicted by this chronic
26
brain disease.
27
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