Understanding drug addiction: a

neuropsychological perspective

Murat Yücel, Dan I. Lubman, Nadia Solowij, Warrick J. Brewer

The purpose of the present review is to describe the neuropsychological correlates of long-
term substance abuse and to discuss the findings within the context of premorbid
vulnerabilities, comorbidity and adolescent neurodevelopment. The authors critically
review key findings from the neuropsychological literature related to the long-term
sequelae of alcohol, cannabis, inhalant, opiates, psychostimulants and ecstasy use.
Leading electronic databases such as PubMed were searched to identify relevant studies
published in the past 20 years. References identified from bibliographies of pertinent
articles and books in the field were also collected and selectively reviewed. Across
substances, individuals with long-term abuse consistently demonstrate neuropsychological
impairments of executive (inhibitory) control, working memory and decision making,
together with neurobiological abnormalities involving frontotemporal and basal ganglia
circuits. In some instances these deficits are dose dependent, implying that they are a
direct consequence of prolonged drug exposure. However, comorbid behavioural,
personality and mental health problems are common among drug-using populations and
are associated with similar neuropsychological deficits. Presented herein is a
neuropsychological model of addictive behaviour that highlights the complex interplay
between cognition, brain maturation, psychopathology and drug exposure.
Key words: brain, cognition, drug, imaging, vulnerability.

Australian and New Zealand Journal of Psychiatry 2007; 41:957 968

‘Addiction’, derived from the Latin verb addicere stances by addicted individuals, despite an apparent
(meaning ‘to enslave’), is characterized by an awareness of associated adverse consequences, sug-
apparent loss of control or autonomy over one’s gests that addictive behaviour may involve deficits in
behaviour. Indeed, the continued abuse of sub- inhibitory control, decision-making and the regula-
tion of affect [1
7]. In line with this, recent
neuroimaging studies across a variety of substance-
Murat Yücel, Senior Lecturer and Senior Research Fellow (Correspon- using populations have implicated impairments in
dence)
frontal cortical networks [6
10]. However, an im-
ORYGEN Research Centre, and Melbourne Neuropsychiatry Centre,
Department of Psychiatry, University of Melbourne, Melbourne, portant question is whether these frontally mediated
Victoria, Australia (ORYGEN Research Centre, 35 Poplar Road executive control deficits relate to the use of specific
(Locked Bag 10), Parkville, Vic. 3052, Australia. Email: murat@unimelb.
edu.au) substances or are common across the major classes
Dan I. Lubman, Senior Lecturer; Warrick J. Brewer, Senior Neuro- of drugs.
psychologist In the present paper we critically review the
ORYGEN Research Centre, Melbourne, Victoria, Australia neuropsychological literature related to the long-
Nadia Solowij, Lecturer and Research Fellow term sequelae of alcohol, cannabis, inhalants, opiates,
School of Psychology and Illawarra Institute for Mental Health, psychostimulants and ecstasy in humans. Leading
University of Wollongong and Schizophrenia Research Institute, Sydney,
NSW, Australia electronic databases such as PubMed were searched
Received 6 July 2007; accepted 7 September 2007. to identify relevant studies written in English and

# 2007 The Royal Australian and New Zealand College of Psychiatrists

958 NEUROPSYCHOLOGY OF DRUG ABUSE

published in the past 20 years. References identified association between heavy drinking and structural
from bibliographies of pertinent articles and books in neuronal injury and volume loss that is more
the field were also collected and reviewed. Studies extensive in the frontal lobe, temporal lobe, and
examining the acute effects of these substances were cerebellum [20,21]. Results of autopsy studies show
not included in this review because the focus is on the that individuals with a history of chronic alcohol
long-term sequelae. It was not our intention to consumption have smaller, lighter and more shrun-
comprehensively review all studies identified in our ken brains than non-alcoholic adults of the same age
searches, but to selectively focus on key exemplary and gender [22,23].
research to highlight methodological issues and Perhaps the strongest evidence for a direct relation-
determine the primary and most consistent findings ship between chronic substance abuse and neuropsy-
across this broad literature. We discuss these findings chological/neurobiological impairments comes from
in the context of premorbid neuropsychological observations of a dose
response relationship and
vulnerabilities and comorbid personality traits and longitudinal studies demonstrating progressive
disorders (e.g. medical, neurological or psychiatric). changes in such measures with ongoing abstinence
We also discuss the neural and functional changes or continued use. To this end, some alcohol-related
that occur in the adolescent brain and their relevance cognitive impairment and structural brain deficits can
to the neuropsychological outcomes observed. be reversed with abstinence over a period of several
months to years [14]. Abstinence-associated improve-
ments have been documented in neuropsychological
Neuropsychological sequelae of specific drugs functions such as working memory, visuospatial
functioning, and attention, accompanied by signifi-
Alcohol cant increases in brain volume, compared with
alcoholics who subsequently relapsed [24
26].
The most consistent findings of neuropsychological
impairment in heavy and long-term drinkers are in Cannabis
the domains of attention, short-term memory, visuos-
patial abilities, postural stability and executive func- Despite inconsistent findings from early studies and
tions (such as problem-solving, mental flexibility, a small meta-analysis [27], recent well-controlled
judgement, working memory, response inhibition neuropsychological studies of chronic cannabis users
and decision-making), with a relative sparing of in the non-intoxicated state have now demonstrated
declarative memory, language skills and primary impaired performance on a variety of attention,
motor and perceptual abilities [11
14]. The link memory, and executive function tasks [28
33]. Defi-
between lifetime exposure and the development of cits have variously been attributed to duration of
cognitive problems is unclear. While some research cannabis use [33], frequency of cannabis use [31] or
findings suggest that cognitive performance worsens cumulative dosage effects [32]. Performance on exe-
in direct proportion to the frequency and duration of cutive tests, such as the Stroop task [34], is not
drinking [15,16], other studies suggest that cognitive consistently impaired in cannabis users, but perfor-
deficits may be detectable only in those who have mance decrements have nevertheless been shown to
been drinking regularly for at least 10 years [17,18]. be related to duration of use [33], or dose interacting
Some researchers even suggest that neuropsychologi- with lower IQ [32]. Few studies have sought to
cal impairments are not related to alcohol at all, but specifically tease out differential impairments asso-
rather are a direct consequence of head trauma ciated with varying patterns of cannabis use (e.g.
associated with drinking [19]. These contrasting heavy daily use for short periods vs light weekly use
findings highlight the need for further research to for long periods). Solowij showed that the ability to
determine how patterns of alcohol use are related to focus attention and filter out irrelevant information
cognitive impairment, especially in light of some was progressively impaired with increasing years of
evidence to suggest that long-term, light-to-moderate cannabis use, while speed of information processing
social drinkers may also have cognitive deficits [15]. was impaired with increasing frequency of use (days
The nature of the neuropsychological deficits ob- per month) [35].
served in long-term drinkers is consistent with Recent neuroimaging studies of cannabis users
disruption to frontotemporal, frontoparietal and demonstrate impaired performance in attention, ver-
cerebellar brain systems. Indeed, structural magnetic bal memory [36], working memory [37], response
resonance imaging (MRI) indicates a consistent inhibition [34,38,39] and decision-making tasks [40],
 M. YÜCEL, D.I. LUBMAN, N. SOLOWIJ, W.J. BREWER 959

with concomitant alterations in blood flow, activa- longer significant when background social disadvan-
tion or brain tissue density primarily in prefrontal tage was taken into account, although it is important
cortical, anterior cingulate, basal ganglia, cerebellar to note that the inhalant group consisted of primarily
and hippocampal regions. For example, Matochik experimental or recreational users. Other studies
et al. found grey and white matter density changes in suggest that solvent-abusing groups tend to perform
28 day abstinent cannabis users in the medial worse on a range of neuropsychological tasks,
temporal regions, and some of the density changes especially those involving memory and executive
were associated with duration of cannabis use [41]. functioning [48]. However, these individuals typically
Our own study used high-resolution MRI to examine lack the motivation to perform well on such tasks and
a well-characterized sample of long-term (
10 years invariably present with complex problems, such as
of regular use) and very heavy cannabis users (5
7 psychosocial disadvantages (e.g. unstable and dys-
joints per day over many years). We found robust functional families, state-based care, school absentee-
reductions of 12.0% in the hippocampus and 7.1% in ism, trauma and abuse, forensic issues), and histories
the amygdala of users relative to well-matched of comorbid drug use and mental health problems

healthy control participants. Additionally, left hippo- issues that play a major role in neuropsychological
campal volume was negatively associated with cumu- outcomes [48].
lative dose of exposure to cannabis. While some From a neurobiological perspective there is more
studies found no structural brain alterations in conclusive evidence that inhalant exposure is asso-
cannabis users [36,42], our findings corroborate the ciated with adverse consequences. A recent study
animal literature in human subjects suggesting that comparing 55 inhalant abusers (mean age 30 years)
long-term heavy cannabis use is associated with and 61 cocaine abusers (mean age 29 years) found
significant and localized medial temporal reductions substantial brain abnormalities (especially in subcor-
that are related to cumulative cannabis dosage [Yucel tical and white matter regions) and cognitive impair-
M, Solowij N, Respondek C et al: unpublished data, ment within both groups [45]. However, the structural
2007]. Moreover, altered frontal cortical activation is brain abnormalities were more common (44% vs
apparent in cannabis users despite normal Stroop 25%) and more extensive in the inhalant-using group.
task performance [34,39], suggesting that there may In addition, the inhalant group performed signifi-
be disturbances in brain physiology that are not as yet cantly worse on tests of working memory and tests
apparent behaviourally. requiring focused attention, planning, and problem
The extent of persistence of effects or recovery of solving. Similar findings have been observed in other
function following abstinence is also uncertain, with neurobiological and neuroimaging studies of chronic
some studies suggesting no recovery after 25
28 days solvent exposure in occupational settings [49,50].
abstinence [32,34,40], while others report full recov- Very few studies have specifically investigated
ery after 28 days abstinence [31] and partial early recovery of function after prolonged exposure to
recovery after 2 years abstinence [35]. inhalants. Cairney et al. found significant improve-
ments in previously identified neurobehavioural im-
Inhalants pairments following 2 years abstinence from petrol
sniffing [51,52]. In fact, in many cases these deficits
While the toxic effects of chronic inhalant abuse are normalized completely. However, although those
well described [43], there is only a small research with the greatest levels of impairment showed the
literature examining the neurobiological and neurop- greatest degree of improvement with abstinence, they
sychological effects of voluntary inhalant exposure were less likely to recover completely. A handful of
[44,45]. One early study demonstrated that inhalant studies in solvent-abusing individuals have also
abusers (mainly those abusing metallic paints) had reassessed their cases with further neuropsychological
deficits in motor coordination, learning, memory, and/or neuroimaging investigations and found either
executive functioning and overall verbal intelligence greater impairments with continued solvent use
[46]. One of the largest investigations examining the [53,54] or significant improvements with long-term
effects of inhalant use on neuropsychological func- abstinence [55]. Other studies have found associations
tioning in adolescents was conducted by Chadwick between the parameters of solvent use (e.g. duration
et al. [47]. Those who had used volatile substances and extent) and MRI abnormalities [56,57]. While
performed significantly worse on tests of vocabulary these studies support the notion that solvent abuse
and impulsivity, and had significantly lower verbal directly leads to adverse outcomes, and that recovery
and full-scale IQ. However, these differences were no of function is possible through abstinence, one study
960 NEUROPSYCHOLOGY OF DRUG ABUSE

failed to find any significant improvement in MRI or et al., which investigated grey matter density in 63
neuropsychological measures following 5 months of opiate-dependent subjects and 46 matched controls
abstinence [58]. Worryingly, another study found no [68]. They found that relative to controls, the opiate-
improvements in MRI measures of brain pathology dependent group exhibited significantly decreased
following an extended period (18 months) of absti- grey-matter in the prefrontal, as well as superior
nence [59]. temporal cortex, insula and fusiform gyrus. Another
study by Kivisaari et al. in long-term opiate users
Opiates found that the sylvan fissures and ventricles were
wider in opiate-dependent subjects than in controls,
Research on the long-term neuropsychological which may be related to brain atrophy within frontal
effects of chronic opiate abuse has been relatively and temporal lobes [69].
limited. Davis et al. reported that 60% of individuals Our own multimodal neuroimaging study of long-
currently abusing opiates had impairments of at least term opiate users also found abnormalities in the
two standard deviations below published norms on neural substrates of inhibitory control [9,10]. Speci-
two or more neuropsychological tests, a significantly fically, opiate addicts (i) exhibited significantly re-
higher incidence than found in matched controls with duced concentrations of the neuronal marker N-
no history of drug abuse [60]. In particular, deficits acetylaspartate (NAA) and glutamate/glutamine
were identified in impulse control in those with a within the dorsal anterior cingulate cortex (d-ACC);
history of ]5 years of heroin use. Similarly, Pau et al. (ii) failed to show the normal association between d-
examined the impact of heroin on frontal executive ACC activity and behavioural performance demon-
functioning in three cognitive domains, namely atten- strated by healthy controls; and (iii) had relatively
tion, impulse control and mental flexibility [61]. They increased task-related activation of frontoparietal
found that heroin abuse has adverse effects on impulse
and cerebellar regions. These findings suggest that
control but not attention or mental flexibility. Other
neuronal abnormalities and a breakdown of normal
studies have reported more diffuse deficits across the
brain
behaviour relationships within the d-ACC of
domains of attention, working memory, memory and
chronic opiate users may result in the recruitment of a
executive function in chronic opiate abusers [61
65].
compensatory and inadequate network of brain
Ornstein et al. found that heroin addicts were
regions when required to exercise inhibitory control.
impaired on performance of cognitive tasks (e.g.
Studies evaluating the persistence of cognitive
learning, spatial working memory, strategic thinking)
deficits among abstinent opiate addicts remain mixed.
known to be sensitive to cortical damage (including
A number of studies have found that abstinent
selective lesions of the temporal and frontal lobes)
[63]. Darke et al. reported that methadone-maintained groups of recovering addicts have no significant
heroin addicts performed more poorly on all neurop- cognitive deficits [60,62]. Guerra et al. reported that
sychological domains tested, including attention (in- individuals with current heroin abuse demonstrated
formation processing speed, attentional capacity), deficits in attention, working memory, episodic
memory (visual and verbal learning and memory) memory and verbal fluency, which normalized 7
14
and executive functioning (problem solving) com- days following rapid detoxification [62]. However,
pared with matched controls [66]. However, Darke two other studies of abstinent heroin users (8 and 14
et al. noted that the methadone group had high rates months, respectively) reported ongoing deficits in
of polysubstance use, overdose, head injury and executive function [61,65]. Using a more sophisticated
comorbid psychopathology [66]. They found that the battery of experimental neuropsychological tests,
neuropsychological deficits identified were more char- Ersche et al. reported that opiate-dependent indivi-
acteristic of those with associated comorbidities, duals demonstrated marked impairments in spatial
further raising issues regarding the specificity of planning, paired associate learning and visual pattern
findings reported. recognition compared with matched controls [70].
Chronic opiate users have been shown to have Performance of former opiate users (abstinent for 8
disturbances in prefrontal cortical activity when years on average) was not statistically different from
performing a reward-based decision task [67]. More- current users on any measure, suggesting that the
over, this disturbance was observed in a group of deficits observed did not simply reflect the current
drug users who had been abstinent for at least 1 year. effects of drug use. These findings are in keeping with
Further support for prefrontal dysfunction comes other studies describing prefrontal dysfunction in
from the large structural imaging study of Lyoo chronic drug users [1,3,5
7].
 M. YÜCEL, D.I. LUBMAN, N. SOLOWIJ, W.J. BREWER 961

Psychostimulants (cocaine, amphetamine/ methamphetamine-dependent subjects [87]. They

methamphetamine) also observed an inverse association between pre-
frontal white-matter NAA values and years of use,
Few studies have comprehensively examined cog- implying direct effects of this drug on the neuronal
nitive functioning among methamphetamine users. integrity of prefrontal tissue. Similar findings have
Some researchers point to studies that suggest been reported in the anterior cingulate cortex [88,89].
memory and executive problems, while others main- Recent neuroimaging studies have shown that frontal
tain that no firm evidence for a link exists [71]. Recent and temporal lobe white matter continues to increase
studies of chronic amphetamine/methamphetamine into the fifth decade of life [90]. However, Bartzokis
abusers have shown that they perform poorly on et al. found that cocaine-dependent subjects (aged 19

decision-making tasks that involve regions of the 47) do not demonstrate the normal pattern of age-
frontal cortex (specifically the ventromedial prefron- related increases in white matter within these brain
tal cortex), such that they make disadvantageous regions [90], suggesting that continued cocaine use
decisions that reflect valuing short-term gain over may arrest normal white matter maturation.
longer term losses [64,72]. Methamphetamine users Examination of cognitive function in abstinent
also appear to be more distractible and are unable to cocaine-dependent individuals after both 6 weeks
suppress processing task-irrelevant information [72], and 6 months abstinence shows persistent cognitive
which is consistent with their clinical presentation. impairment across a wide range of functions com-
Other work has also shown cognitive deficits related pared to controls at both time-points. Further, a close
to processing speed, learning, delayed recall and relationship between the degree of neuropsychologi-
inhibitory control and working memory [73
75]. cal impairments and dosage (i.e. quantity and dosage
Another recent study found methamphetamine abuse of peak usage) has also been reported [91]. Consistent
to be associated with deficient strategic (i.e. executive) with these neuropsychological findings, Fein et al.
control of verbal encoding and retrieval, which is also found that cocaine-induced brain volumetric
consistent with proposed prefrontostriatal circuit reduction in the prefrontal cortex persisted after 6
neurotoxicity [76]. Interestingly, comorbid cannabis weeks abstinence [92].
does not appear to exacerbate methamphetamine
neurotoxicity, but rather has been suggested to have
neuroprotective effects [75]. 3,4 methylenedioxymethamphetamine (MDMA,
Neuropsychological studies of chronic cocaine ecstasy)
users, as in chronic amphetamine users, also demon-
strate higher order cognitive impairments (e.g. in- A number of persisting cognitive problems have
hibitory dysregulation) that is consistent with been attributed to regular N-methyl-3,4-methylene-
abnormal blood flow in frontal brain regions [77]. dioxy-amphetamine (MDMA) use and suggest under-
Several studies have reported that cocaine abuse is lying serotonergic dysfunction [93
95]. For example,
associated with decrements on neurobehavioural tests impairments in memory (both visual and verbal) have
measuring executive control, visuoperception, psy- been shown to correlate with in vivo measurements of
chomotor speed, manual dexterity, verbal learning, brain serotonin function and levels of 5-hydroxyin-
and memory [78,79]. Ardila et al. found that neu- doleacetic acid (5-HIAA) in cerebrospinal fluid, as
ropsychological test scores were correlated with life- well as relating to the level of previous MDMA use
time amount of cocaine used, suggesting a direct (i.e. are dose related) [96]. Other neuropsychological
relationship between cocaine abuse and cognitive deficits that have been reported in regular ecstasy
impairment [80]. users include impairments of executive function and
Neuroimaging studies of methamphetamine users self-control (i.e. decreased inhibitory control and
have shown abnormalities of brain structure and increased impulsivity) [97,98]. McCardle et al. found
function relative to healthy controls including altera- that MDMA users exhibit difficulties in coding
tions of frontal, temporal and subcortical metabolism information into long-term memory, have impaired
[81
86]. Changes in neuronal biochemistry suggestive verbal learning, are more easily distracted, and are
of neuronal injury have also been found in the frontal less efficient at focussing attention on complex tasks
cortex and basal ganglia structures [87]. Using proton [97]. Interestingly, Spatt et al. have described a case of
magnetic resonance spectroscopy (1H-MRS), Ernst profound amnesia, associated with bilateral brain
et al. reported abnormally low levels of the neuronal changes on MRI, following a single exposure to
marker NAA in the basal ganglia of abstinent MDMA [99].
962 NEUROPSYCHOLOGY OF DRUG ABUSE

Although cognitive deficits among MDMA users addictive substances can adversely affect neuropsy-
have been well documented, little is known of the chological functioning. However, it is also clear that
neurobiological sequelae of MDMA use. In one there is marked inter-individual variability in the
study, MDMA use in adolescence was associated patterns of substance use (e.g. duration, frequency,
with difficulties in the ability to focus and divide dosage, type) and, with the exception of a few studies,
attention, as well as abnormal hippocampal activity most researchers were not able to definitively isolate
during performance of a working memory task [100]. the effects of a specific drug due to a history of
Other functional MRI studies have found abnormal polysubstance use. An under-investigated issue is
frontotemporal, parietal and subcortical activity dur- whether concurrent use of different substances (e.g.
ing performance of working memory tasks [101
104]. cannabis and alcohol) may potentiate the long-term
Additionally, Daumann et al. found that relative to a adverse effects of each drug. While synergistic or
group of controls and currently abstinent but pre-
additive effects are plausible, there is also speculation
viously moderate users, the currently abstinent but
that use of some substances may mask or protect
previously heavy users showed more prominent
against the neurocognitive sequelae of other sub-
frontal and temporal lobe activation abnormalities
stances. For example, it has been hypothesized that
during performance of a working memory task [104].
Structural MRI findings among MDMA polydrug the neuroprotective properties of cannabinoids may
users includes evidence of diffuse grey matter reduc- fortify against neurotoxic effects of MDMA or
tions across the cortex, cerebellum and brainstem amphetamines in general to preserve cognition in
structures [105]. Ecstasy users [93] or amphetamine users [75]. Work-
Little is known about the possible persistent ing memory-related neural activation in cannabis
neuropsychological effects of extensive MDMA use. users was found to be deficient only during nicotine
However, there is tentative evidence that these withdrawal (but not in tobacco users during nicotine
cognitive deficits persist for at least 6 months after withdrawal), suggesting that nicotine may mask
abstinence, whereas anxiety and hostility remit after 1 neuropsychological deficits associated with cannabis
year of abstinence [93,106]. Morgan et al. compared [107]. Nonetheless, there is consistent evidence that
four groups of participants: current regular recrea- almost all substances affect the domains of attention,
tional MDMA users; ex-regular MDMA users who learning and memory, visuospatial abilities and
had abstained from using the drug for an average of 2 executive functioning. However, the more robust
years; polydrug users who had never taken MDMA; findings relate to impairment in inhibitory control
and drug-naive controls [106]. They found that both (variously referred to as response inhibition, inhibi-
current and ex-MDMA users exhibited elevated tory regulation, self-control or impulsivity), working
psychopathology and behavioural impulsivity com- memory and decision-making. Accordingly, the neu-
pared with polydrug users and drug-naive controls, robiological findings from structural, functional and
but current MDMA users exhibited a broader range spectroscopic MRI studies suggest dysfunction in
of psychopathology than ex-users. Both groups of neural systems that subserve these functions, parti-
MDMA users also exhibited impaired working mem-
cularly frontotemporal and basal ganglia circuitry.
ory and verbal recall performance compared with
Nevertheless, the pathways into addiction are
drug-naive controls. These findings suggest that
invariably complex, making it difficult to disentangle
selective impairments of neuropsychological perfor-
the neuropsychological effects of substance exposure
mance associated with regular MDMA use are not
from associated risk factors. While in some instances,
reversed by prolonged abstinence. This is consistent
with evidence that MDMA may affect brain seroto- reported deficits have been found to be dose depen-
nergic systems in human users. Other studies have dent (implying direct effects of drug exposure), the
also found altered neural activations suggestive of fact that most studies are cross-sectional in nature
prefrontal neuronal injury in abstinent MDMA users means that it is not possible to categorically deter-
during performance of working memory tasks [102]. mine whether the identified deficits are a consequence
of the drugs specifically, relate to pre-existing vulner-
abilities, or are a combination of both. Specifically, it
Summary is not clear how broader individual characteristics
(e.g. developmental stage, psychopathology, genetic
This selective review of the available literature polymorphisms) may affect neuropsychological func-
suggests that chronic abuse of a wide range of tioning and contribute to the observed deficits.
 M. YÜCEL, D.I. LUBMAN, N. SOLOWIJ, W.J. BREWER 963

Executive control deficits: broader individual to reduce negative affectivity [121,122]. From a
considerations neurobiological and neuropsychological perspective,
this inability to internally regulate moods and the
Young people who have behavioural problems over-reliance upon external agents, such as psychoac-
early (e.g. a difficult temperament in infancy or tive substances, suggests inappropriate neural (parti-
childhood oppositional, aggressive or impulsive cularly prefrontal) and cognitive modulation of
behaviours) are at increased risk of developing emotions [123].
substance use disorders [108]. Indeed, childhood Another issue is that of premorbid neuropsycholo-
diagnoses of oppositional defiant disorder, conduct gical vulnerabilities. To this end, Tarter et al. and
disorder and attention deficit hyperactivity disorder Kirisci et al. recently conducted a cross-sectional and
are well-established risk factors [109
112]. In addi- longitudinal analysis of children at low and high risk
tion, a number of mental health disorders are of substance use (on the basis of parental substance
associated with high rates of comorbid substance use history) and found that deficits in behavioural
use, such as depression, anxiety, schizophrenia, regulation (referred to as ‘neurobehavioural inhibi-
bipolar disorder and obsessive
compulsive disorder tion’) at age 16 in high-risk children predicted a
[113
116]. Given that deficits in inhibitory control substance use disorder at age 19 with 85% accuracy
and affect regulation are found across many of these [117,124]. Their measure of behavioural regulation
disorders, together with disruption to brain regions was derived using primarily prefrontal tests of cogni-
subserving these functions (e.g. prefrontal and tion (e.g. Stroop interference task, Porteus mazes,
temporal areas), it is possible that they form a key motor restraint), affect (a temperament survey) and
component of liability to not only behavioural and behaviour (number of behavioural disorder symp-
mental health disorders, but also to addictive toms). The indices derived from these areas converge
behaviour. with other evidence to suggest that behavioural
Certain personality characteristics may also influ- dysregulation is a key component of liability to
ence an individual’s decision to use drugs, as well as drug addiction.
their liability to develop problematic use. Indeed, The initiation of substance use typically occurs
inhibitory-control and affect-regulation difficulties during adolescence, a critical period of neural,
may also be components of a premorbid personality cognitive, emotional, and social development. Nota-
style rather than the result of state-related cognitive
bly, adolescence is a period during which there is
affective processes. To this end, there is a growing increased affective reactivity together with significant
literature on temperament and personality as risk but more protracted neural maturation [125
129] in
factors for substance use disorders and addiction. areas associated with core executive and self-regula-
These studies highlight a relationship between mea- tory skills, including inhibitory control and affect
sures of impulsivity and related constructs (such as regulation [129]. Given that the frontotemporal
risk-taking, sensation-seeking) in childhood and the regions undergo dramatic developmental changes
development of later substance use disorders in from adolescence to adulthood, drug exposure during
adulthood [117]. In fact, studies of both adolescents adolescence may disrupt the functional maturation of
and adults consistently report an association between these regions (i.e. inhibitory control and affect
impulsivity (e.g. acting in a sudden and unplanned regulation). Indeed, there is growing evidence that
manner, acting without having all the necessary adolescent rodents appear to be more vulnerable than
information or failing to think through the pros and adults to the adverse neuropsychological and neuro-
cons of a decision) and substance-related problems biological effects of addictive substances [130,131],
[118
120]. Other personality traits such as negative although studies in human subjects have been limited
affectivity/neuroticism have also been identified as to date [132
136].
risk factors for substance use disorders. Negative Finally, genetic factors appear to account for 30

affect/neuroticism is characterized by a general ten- 60% of the overall variance in risk for developing a
dency to experience life as more negative and a drug addiction [137]. While the precise mechanisms
difficulty in controlling one’s mood (i.e. difficulties underlying this relationship remain unclear, recent
with affect regulation) and/or being less tolerant to work implicates the role of specific genetic poly-
stressful life events. There is growing evidence to morphisms. For example, the methionine poly-
suggest that adolescent substance use disorders may morphism of the catechol O-methyltransferase
not only result in disinhibited behaviour or impulsiv- (COMT) gene results in a slower breakdown of
ity (reviewed here), but may in fact reflect an attempt prefrontal dopamine, and is associated with better
964 NEUROPSYCHOLOGY OF DRUG ABUSE

prefrontal cortical function (including working between pre-existing neuropsychological vulnerabil-

memory and inhibitory control) in both children ities, the age of initiation of substance use (or
[138] and adults [139,140]. This polymorphism is less neurodevelopmental maturity), patterns of substance
common in drug-addicted populations, thereby po- use (type, dosage, duration, frequency) and asso-
tentially increasing vulnerability to prefrontally ciated adverse events (head injury, overdose, suicide).
mediated cognitive deficits with chronic drug use This latter issue is exemplified by Darke et al., who
[141,142]. found that these associated adverse events increased
the likelihood of neuropsychological impairment in
drug-using groups [66]. Similarly, Solomon and
Malloy critically reviewed how a head injury can
Pathways into drug addiction: implications for modulate the relationship between substance use and
neuropsychological interrelations neuropsychological functioning [19]. Clearly, each of
these areas can confound the association between
Long-term substance abuse is associated with
substance use and neuropsychological impairment, as
significant and persistent neuropsychological impair-
well as impact upon the development and functional
ments and neurobiological abnormalities, involving
integrity of prefrontal circuitry, which is postulated to
frontotemporal and basal ganglia circuits. However,
play an important role in the initiation and main-
it is not clear how broader individual characteristics
tenance of drug-use behaviours. These adverse effects
that are common to addicted populations (e.g.
psychopathology, genetic polymorphisms, head in- are likely to render the individual at increased risk for
jury), and that also affect neuropsychological func- making decisions that are impulsive, focused on
tioning, contribute to the reported findings. Age of short-term gains, and lack inhibitory control. Such
onset of substance use is also clearly important given impairments may underpin difficulties regulating
the plasticity of the developing brain, and may drug-seeking/taking behaviour, as well as increase
further accentuate the magnitude of neuropsycholo- the risk for the development of comorbid disorders.
gical and neurobiological impairments. We suggest However, the integrity of prefrontal circuitry is also
that future neuropsychological evaluations of long- likely to depend on a number of individual factors,
term substance abusing populations consider the ranging from genetic polymorphisms through to
potential influence of such factors. psychosocial variables. Such relationships need
As illustrated in Figure 1, the pathways leading to further investigation, especially as few prospective,
drug addiction are likely to be both multifaceted and longitudinal neuropsychological studies have been
complex. There is likely to be an intricate relationship conducted to date, and most previous studies have

Figure 1. Neuropsychological model illustrating how substance-associated neuropsychological sequelae may

interact with adolescent neurodevelopment and pre-existing neuropsychological vulnerabilities to increase risk for
addictive disorders. PFC, Prefrontal Cortex.
 M. YÜCEL, D.I. LUBMAN, N. SOLOWIJ, W.J. BREWER 965

sought to specifically exclude such confounds rather 8. Volkow ND, Hitzemann R, Wang GJ et al. Long-term
frontal brain metabolic changes in cocaine abusers. Synapse
than examine potential interactions. 1992; 11:184
190.
In closing, it should be noted that the selective 9. Yucel M, Lubman DI, Harrison BJ et al. A combined
review of studies highlighted in the present paper may spectroscopic and functional MRI investigation of the dorsal
anterior cingulate region in opiate addiction. Mol Psychiatry
have biased reporting toward positive findings with 2007; 12:691
702.
regard to neuropsychological sequelae of the major 10. Yucel M, Lubman DI, Harrison BJ et al. Neuronal,
substances of abuse. Nevertheless, we endeavoured to physiological and brain-behavioural abnormalities in opiate-
addicted individuals. Mol Psychiatry 2007; 12:611.
maintain a balance by also acknowledging negative 11. Fishbein DH, Herman-Stahl M, Eldreth D et al. Mediators
findings. A systematic and comprehensive review that of the stress-substance-use relationship in urban male
covers all of the published literature on neuropsycho- adolescents. Prev Sci 2006; 7:113
126.
12. Bowden-Jones H, McPhillips M, Rogers R, Hutton S, Joyce
logical sequelae of substance use in humans was E. Risk-taking on tests sensitive to ventromedial prefrontal
beyond the scope of this paper but would be a cortex dysfunction predicts early relapse in alcohol
welcome addition to the literature and would enable dependency: a pilot study. J Neuropsychiatry Clin Neurosci
a more rigorous exploration of the hypotheses we 2005; 17:417
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pose here. dependence. Curr Opin Psychiatry 2005; 18:319
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