4 • Add i c t i o n s c i e n c e & c l i n i c a l P r a c t i c e — D e c e m b e r 2 0 1 0

Addiction and Cognition

T he brain regions and neural processes that underlie addiction overlap extensively with those that support cognitive func-
tions, including learning, memory, and reasoning. Drug activity in these regions and processes during early stages of
abuse foster strong maladaptive associations between drug use and environmental stimuli that may underlie future cravings
and drug-seeking behaviors. With continued drug use, cognitive deficits ensue that exacerbate the difficulty of establishing sus-
tained abstinence. The developing brain is particularly susceptible to the effects of drugs of abuse; prenatal, childhood, and ado-
lescent exposures produce long-lasting changes in cognition. Patients with mental illness are at high risk for substance abuse,
and the adverse impact on cognition may be particularly deleterious in combination with cognitive problems related to their
mental disorders.

D
Thomas J. Gould, Ph.D. rug addiction manifests clinically as compulsive drug seeking, drug
Department of Psychology and Center for
Substance Abuse Research
use, and cravings that can persist and recur even after extended
Temple University periods of abstinence. From a psychological and neurological per-
Philadelphia, Pennsylvania
spective, addiction is a disorder of altered cognition. The brain regions and
processes that underlie addiction overlap extensively with those that are involved
in essential cognitive functions, including learning, memory, attention, rea-
soning, and impulse control. Drugs alter normal brain structure and function
in these regions, producing cognitive shifts that promote continued drug use
through maladaptive learning and hinder the acquisition of adaptive behaviors
that support abstinence.
In a 2005 review, Steven Hyman stated the current neurological conception
of drug abuse concisely: Characterizing addiction as a disease of “pathological
learning,” he wrote, “[A]ddiction represents a pathological usurpation of the
neural mechanisms of learning and memory that under normal circumstances
serve to shape survival behaviors related to the pursuit of rewards and the cues
that predict them.”
This article reviews current knowledge on the cognitive effects of drugs and their
neurological underpinnings. These effects may be particularly disruptive when
individuals are exposed to drugs during brain development, which lasts from the
prenatal period through adolescence, and in individuals with mental disorders.
An understanding of these issues will help substance abuse clinicians identify
and respond to cognitive changes that affect patients’ responses to treatment.
 R e s e a r c h R e v i e w — Add i c t i o n a n d C o g n i t i o n • 5

A MULTISTAGE PROCESS that their impact on cognition is potentially extremely

Recent reviews characterize addiction as a two-stage far-reaching.
process. In the first stage, the individual’s occasional
drug taking becomes increasingly chronic and uncon- cOGNITIVE EFFECTS OF ACUTE drug
trolled. The neurological source of these symptoms is ADMINISTRATION
drug-induced deregulation of the brain’s reward system Clinicians often observe that patients undergoing treat-
(Feltenstein and See, 2008). Normally, increased dopa- ment for addiction become highly vulnerable to relapse
mine signaling within this system—specifically, in the when they return to contexts or environments where
ventral striatum or nucleus accumbens (NAc)—produces their addiction developed (Hyman, 2005; See, 2005). Drugs act upon
pleasurable feelings that orient organisms to seek and Clinical research confirms that cues associated with sub- brain regions
perform life-sustaining conditions and activities, such stance abuse elicit physiological responses and cravings that underlie
as locating supportive environments, eating, and having for drugs (Franklin et al., 2007). Laboratory animals,
the memories
sex. Drugs of abuse hyperactivate this system, triggering too, develop powerful associations and cue-response
abrupt and large increases in NAc dopamine signaling, behaviors in the presence of drug-related stimuli. For that define us
producing intense sensations that motivate additional example, animals given a drug in one compartment of a as individuals.
drug taking, and promoting the formation of maladaptive double cage subsequently will gravitate to that compart-
drug-stimulus associations (Feltenstein and See, 2008). ment more than to the alternative compartment. This
Individuals in the second stage of the addictive phenomenon, known as conditioned place preference,
process present additional clinical features, including has been demonstrated in studies using nicotine, ethanol,
withdrawal symptoms during early abstinence, persistent amphetamine, methamphetamine, cocaine, morphine,
vulnerability to relapse, and alterations in decisionmaking cannabis, and caffeine (Bardo and Bevins, 2000).
and other cognitive processes. Although modification of
the dopaminergic reward system remains important at The Formation of Drug-Stimulus Associations
this stage, it probably is not sufficient to maintain these The multistage model of addiction attributes addicted
complex and long-lasting changes. Kalivas and Volkow individuals’ strong responses to drug cues to a learning
(2005) summarize evidence implicating drug-induced process that inculcates powerful drug-stimulus associa-
alterations in signals carried by the neurotransmitter tions (e.g., Robinson and Berridge, 2000). In this view,
glutamate from the brain area that is primarily associated the individual taking a drug perceives his or her present
with judgment—the prefrontal cortex—to the NAc. surroundings as highly significant (salient) and makes
Le Moal and Koob (2007) emphasize changes in brain exceptionally strong mental connections between features
stress circuits and negative reinforcement (i.e., effects of those surroundings and the intense pleasure of the
that motivate drug taking by causing discomfort during drug. Subsequently, when he or she re-encounters those
abstinence, such as the onset of withdrawal symptoms). features, the powerful associations reassert themselves,
Thus, whereas early drug use fosters maladaptive drug- consciously or subconsciously, and are experienced as
stimulus associations that contribute to drug seeking and prompts for drug seeking and drug taking. Consistent
use, later stages disrupt cognitive and other processes with this account, exposing addicted individuals to cues
that are important for successful abstinence. that they associate with substance abuse elicits, along with
The full extent of drugs’ impacts on cognition is physiological responses and drug cravings, changes in the
not yet known, but research indicates that addicted activity levels of brain regions involved in learning and
individuals have alterations in brain regions includ- memory (i.e., striatum, amygdala, orbitofrontal cortex,
ing the striatum, prefrontal cortex, amygdala, and hippocampus, thalamus, and left insula) (Franklin et al.,
hippocampus (Jones and Bonci, 2005; Kalivas and 2007; Volkow et al., 2006).
Volkow, 2005; Kelley, 2004; Le Moal and Koob, 2007). The acute effects of amphetamine, nicotine, and
These same regions underlie declarative memory—the cocaine fit straightforwardly into this scenario. Each of
memories that define an individual, without which it these drugs has been shown to acutely enhance learn-
would be difficult to generate and maintain a concept ing and/or attention (Del et al., 2007; Kenney and
of self (Cahill and McGaugh, 1998; Eichenbaum, Gould, 2008; Mattay, 1996). For example, the idea
2000; Kelley, 2004; Setlow, 1997). Drugs’ capacity to that smoking is a cognitive enhancer is well accepted by
act upon the substrates of declarative memory suggests researchers and the general public. Numerous studies
6 • A D D ICTION S CIENCE & CLINICAL P r a c t i c e — D e c e m b e r 2 0 1 0

have confirmed that laboratory animals’ cognitive pro- In contrast to the effects of opioids on cognition, those
cesses improve immediately following administration of of alcohol are clear, though bidirectional: High doses
nicotine (Kenney and Gould, 2008). Similar findings in disrupt cognitive processes (Ryback, 1971), while low
early studies with human smokers were not conclusive, doses can enhance learning (Gulick and Gould, 2007;
because the study participants were smokers who had Hernández, Valentine, and Powell, 1986).
received nicotine following a period of abstinence. The
observed enhancements might have reflected the reversal The Persistence of Drug-Stimulus Associations
of withdrawal effects, rather than improvements over Recent research has sought to account for the strik-
their normal cognitive powers. A subsequent review ingly long-lasting ability of maladaptive drug-stimulus
of the literature, however, suggests that acute nicotine associations to influence behavior and provoke relapse.
enhances reaction time and attention in nicotine-naïve Studies have shown that many abused substances can
individuals (Swan and Lessov-Schlaggar, 2007). Cocaine reshape the communication pathways between neurons
produced similar effects in a study of rats that were treated (synaptic plasticity), which could contribute to both
with the drug and then exposed to a sensory stimulus; the formation and the persistence of maladaptive drug-
the animals exhibited enhanced neural activation when stimulus associations.
High doses later re-exposed to the stimulus (Devonshire, Mayhew, Cocaine and nicotine can directly induce one form
of alcohol and Overton, 2007). of synaptic plasticity, the strengthening of neural con-
Although all drugs of abuse foster the learning of nections via a process known as long-term potentiation
disrupt cogni-
strong drug-stimulus associations and cue-induced drug (LTP; see Learning in the Mind and Brain on page 8
tive processes,
seeking, some appear to have mixed effects on other types and Table 1) (Argilli et al., 2008; Kenney and Gould,
while low of learning and cognition. For example, a clinical study of 2008). Amphetamine can enhance LTP (Delanoy, Tucci,
doses can the acute effects of morphine and oxycodone concluded and Gold, 1983). Marijuana activates the endocannabi-
enhance that these drugs have variable impacts on cognition: noid system, resulting in inhibition in some instances
Both improved men’s recall of prose just slightly, but and facilitation in others of both LTP and long-term
learning.
morphine slightly impaired both sexes’ performance depression (LTD), another form of synaptic plasticity
on a test of working memory in which they were asked in which connections between neurons become less
to repeat a set of digits in reverse order (Friswell et al., responsive (Carlson, Wang, and Alger, 2002; Nugent
2008). In another study, mice were given morphine or and Kauer, 2008; Sullivan, 2000). Ethanol consistently
saline and trained to run away when a light signaled that disrupts LTP while enhancing LTD (Yin et al., 2007).
a foot shock was impending; although the morphine- Morphine inhibits LTP of neurons that exhibit inhibi-
treated mice scored higher on the frequency and quick- tory control of neural activity via the neurotransmitter
ness with which they avoided shocks, the researchers gamma-aminobutyric acid (GABA) (Nugent and Kauer,
attributed this to increased motor activity rather than 2008). Inhibition of GABA activity could lead to an
enhanced learning (Aguilar, Miñarro, and Simón, 1998). overall increase in neural activity throughout the brain,
which might lead to the formation of stronger associa-
Table 1. Drug Effects on Synaptic Plasticity tions than would normally occur, including maladaptive
Drug Effects on plasticity
drug-context associations.
Strengthening the evidence that drugs foster long-
Amphetamine LTP lasting drug-stimulus associations by affecting synap-
tic plasticity, studies have demonstrated that the same
Cocaine LTP
proteins that participate in the sequential biochemical
Ethanol LTP, LTD reactions (cell signaling cascades) that control synaptic
plasticity (see Figure 1) come into play in drug-seeking
Marijuana LTP, LTD
behaviors. For example, in one experiment, researchers
Morphine LTP (of inhibitory synapses) showed that when rats went to a cage area that they
had been trained to associate with cocaine, the levels of
Nicotine LTP
proteins associated with learning—extracellular signal-
LTP, long-term potentiation of synaptic efficiency; LTD, long-term depression of regulated protein kinase (ERK), cyclic AMP response
synaptic efficiency. element-binding (CREB), Elk-1, and Fos—increased in
 R e s e a r c h R e v i e w — Add i c t i o n a n d C o g n i t i o n • 7

their NAc (Miller and Marshall, 2005). Moreover, when Figure 1. A Cell Signaling Cascade in Learning and Memory
the rats were treated with a compound that suppresses

Terese Winslow
ERK, they stopped preferring that cage area over one in VTA neuron

which they had received saline and showed a decrease in New

synapse
three biochemical participants in LTP (CREB, Elk-1, AMPA glutamate
receptor
and Fos) in the NAc. Glutamate

Cell nucleus
COGNITIVE DEFICITS IN CHRONIC DRUG CREB
Na+ DNA
ABUSE
Drug abusers who progress to the second stage of addic- CRE gene
Ca++
tion are subject to withdrawal when they initiate absti-
nence. Many drugs produce cognition-related withdrawal NMDA glutamate
MAPK/ERK
receptor Adenylate
symptoms that may make abstinence more difficult. cyclase

These include: ATP

• cocaine—deficits in cognitive flexibility (Kelley et al., cAMP
PKA

2005); PKA

• amphetamine—deficits in attention and impulse con-

trol (Dalley et al., 2005);
• opioids—deficits in cognitive flexibility (Lyvers and
Yakimoff, 2003);
• alcohol—deficits in working memory and attention Glutamate binds to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
(Moriyama et al., 2006); and N-methyl-d-aspartic acid (NMDA) receptors in the neuron membrane, open-
ing channels for sodium and calcium to flow into the cell; calcium influx induces
• cannabis—deficits in cognitive flexibility and attention adenylate cyclase to convert adenosine triphosphate (ATP) to cyclic adenosine
(Pope, Gruber, and Yurgelun-Todd, 2001); and monophosphate (cAMP). cAMP triggers activation, sequentially, of protein kinase
• nicotine—deficits in working memory and declarative A (PKA), mitogen-activated protein kinase/extracellular signal-regulated protein
kinase (MAPK/ERK), and cAMP response element-binding (CREB). CREB attaches
learning (Kenney and Gould, 2008).
to DNA, increasing DNA production of protein for the construction of new syn-
Nicotine provides a familiar example of cognitive apses. (For a detailed review of the cellular substrates of learning, see Abel and
changes in withdrawal. In both chronic smokers and Lattal, 2001.)
animal models of nicotine addiction, cessation of nico-
tine administration is associated with deficits in work- and the user’s genetic makeup (see Genes, Drugs, and
ing memory, attention, associative learning, and serial Cognition on page 11). In general, however, they impair Cognitive defi-
addition and subtraction (Bell et al., 1999; Blake and the ability to learn new patterns of thought and behavior cits may be par-
Smith, 1997; Davis et al., 2005; Hughes, Keenan, and that are conducive to successful response to treatment ticularly pro-
Yellin, 1989; Jacobsen et al., 2006; Mendrek et al., 2006; and recovery.
nounced during
Raybuck and Gould, 2009; Semenova, Stolerman, and For example, long-term cannabis users have impaired
Markou, 2007). Moreover, it has been shown that the learning, retention, and retrieval of dictated words, and early periods of
severity of decreases in cognitive performance during both long-term and short-term users show deficits in abstinence.
periods of smoking abstinence predicts relapse (Patter- time estimation (Solowij et al., 2002), although how
son et al., 2010; Rukstalis et al., 2005). Although these long these deficits persist is not yet known. As another
deficits usually dissipate with time, a dose of nicotine example, chronic amphetamine and heroin users show
will rapidly ameliorate them (Davis et al., 2005)—a deficits in a range of cognitive skills, including verbal
situation that may contribute to some relapses. Thus, fluency, pattern recognition, planning, and the ability
chronic substance abuse can lead to cognitive deficits to shift attention from one frame of reference to another
that are particularly pronounced during early periods (Ornstein et al., 2000). The decisionmaking deficits
of abstinence. resembled those observed in individuals with damage
While the cognitive deficits associated with with- to the prefrontal cortex, suggesting that both drugs alter
drawal from drugs are often temporary, long-term use function in that brain area (Rogers et al., 1999).
can also lead to lasting cognitive decline. The nature of A pair of recent studies suggests that some meth-
deficits varies with the specific drug, the environment, amphetamine-induced cognitive losses may be partially
8 • A D D ICTION S CIENCE & CLINICAL P r a c t i c e — D e c e m b e r 2 0 1 0

neuropsychological tasks. The deficits were associated

LEARNING IN THE MIND AND BRAIN with a comparative scarcity of dopamine transporters
A mind learns: It captures and stores information and impressions and (proteins that regulate dopamine) and reduced cellular
discovers relationships between them. For the mind to learn, events activity (metabolism) in the thalamus and NAc. When
must occur in the brain. Among the most compelling pieces of evidence
retested after 12 to 17 months of abstinence, the drug
for this idea are many cases of individuals who suffered drastic reduc-
abusers’ motor function and verbal memory had risen
tions of their ability to learn after incurring brain injuries. The most
famous, perhaps, is Henry Molaison, who, after surgical removal of to levels that approached those of the control group,
extensive brain tissue at age 27 to control his epilepsy, entirely lost his and the gains correlated with a return toward normal
long-term declarative memory (Penfield and Milner, 1958) so that for the transporter levels in the striatum and metabolic levels
remaining 55 years of his life he could not call to mind anything that hap- in the thalamus; however, other neuropsychological
pened to him more than a few minutes earlier. deficits remained, along with depressed metabolism
Neuroscience research has correlated learning with the elaboration of
in the NAc.
neural networks in the brain. Many experiments have established that, as In another study, abusers of 3,4-methylenedioxy-
learning takes place, selected neurons increase their levels of activity and methamphetamine (MDMA, ecstasy) continued to
form new connections, or strengthen established connections, with net- score relatively poorly in tests of immediate and delayed
works of other neurons. Moreover, experimental techniques that prevent recall of spoken words even after 2.5 years of abstinence
neuronal activity and networking inhibit learning. (Thomasius et al., 2006). In a study of polydrug abusers
Neuroscience research with animals is elucidating how the brain con- who had stated a primary preference for either cocaine
structs and maintains the neural networks that support learning. One or heroin, deficits in executive function—defined as
process identified, long-term potentiation (LTP), has features that paral- changes in fluency, working memory, reasoning, response
lel key aspects of learning. inhibition, cognitive flexibility, and decisionmaking—
remained after up to 5 months of abstinence (Verdejo-
• Once we learn to associate two ideas or sensations, the occurrence
of one is likely to invoke remembrance of the other. Similarly, in LTP, García, and Pérez-García, 2007).
a neuron that receives strong, or high-frequency, stimulation from An important question is whether nicotine’s cogni-
another neuron responds by becoming more sensitive to future stimu- tive benefit persists as smoking shifts from sporadic
lation from the same source; to chronic. In some studies with animals, chronic
nicotine administration improved cognitive capacities
• Newly learned material enters our short-term memory and may or may
not subsequently become established in our long-term memory. Simi-
such as attention, but other studies found that initial
larly, LTP has an early phase during which short-term physiological pro- improvements waned with chronic treatment (Kenney
cesses support the above-mentioned increase in neuronal sensitivity and Gould, 2008). Furthermore, several recent studies
and a late phase involving more long-lasting physiological processes; have shown that smoking and a past smoking history
are associated with cognitive decline. For example, in
• Animal studies have implicated some of the same sequences of
biochemical changes (cell signaling cascades) in LTP and learning.
one study with middle-aged men and women, smokers’
For example, researchers showed that suppressing production of an cognitive speed declined nearly twice as much as non-
enzyme (protein kinase A) in the hippocampi of mice prevented LTP smokers’ over 5 years; in addition, declines in smokers’
and inhibited the animals’ ability to retain previously learned informa- cognitive flexibility and global cognition occurred at 2.4
tion about a maze (Abel et al., 1997). times and 1.7 times the respective rates of nonsmokers
(Nooyens, van Gelder, and Verschuren, 2008). Recent
Although LTP has not been observed in every brain region, it has been
demonstrated in the nucleus accumbens, prefrontal cortex, hippocam- quitters’ scores in these areas were similar to smokers’,
pus, and amygdala—all regions involved in both addiction and learning and ex-smokers performed at levels intermediate between
(Kenney and Gould, 2008; Kombian and Malenka, 1994; Maren, 2005; smokers and nonsmokers.
Otani et al., 2003). Similarly, in another study, smokers’ performance
deteriorated more over 10 years than nonsmokers’ on
tests of verbal memory and speed of visual searching;
recouped with extended abstinence (Volkow et al., ex-smokers’ visual search speed slowed more than non-
2001; Wang et al., 2004). Evaluated when abstinent smokers’ as well (Richards et al., 2003). Although some
for less than 6 months, chronic methamphetamine early studies suggested that smoking might retard the
abusers scored lower than unexposed controls on tests of cognitive decline associated with Alzheimer’s disease
motor function, memory for spoken words, and other (van Duijn and Hofman, 1991), followup studies failed
 R e s e a r c h R e v i e w — Add i c t i o n a n d C o g n i t i o n • 9

to confirm this, and others correlated smoking quantity percent), globus pallidus (-27 to -30 percent), and hip-
and duration with higher risk for Alzheimer’s disease pocampus (-19 to -20 percent) among 15 children aged
(Swan and Lessov-Schlaggar, 2007). 3 to 16 years who were prenatally exposed to the stimu-
Laboratory studies have demonstrated nicotine- lant, compared with controls (Chang et al., 2004). The
related alterations in neuronal functioning that could drug-exposed children also exhibited poorer long-term
underlie cognitive decline that persists even after pro- spatial memory and visual/motor integration. Another
longed abstinence. For example, rats’ self-administration study documented structural changes in the frontal and
of nicotine was associated with a decrease in cell adhesion parietal cortex of 3- and 4-year-old children who had
molecules, a decrease in new neuron production, and been exposed prenatally to methamphetamine (Cloak
an increase in cell death in the hippocampus (Abrous et al., 2009). In laboratory studies, rats that were treated
et al., 2002). Such changes could result in long-lasting with methamphetamine during pregnancy gave birth to
cognitive changes that contribute to poor decisionmak- pups that, when they reached adulthood, were slow to
ing and addiction. learn spatial relationships and exhibited spatial memory
impairment (Acuff-Smith et al., 1996; Slamberová et
Drugs of Abuse and the Developing al., 2005).
Brain The effects of prenatal tobacco exposure are par-
The human brain continues to develop and consolidate ticularly concerning because so many expectant moth-
important neural pathways from the prenatal period ers smoke—by one estimate, over 10 percent in the
through adolescence. Throughout these years, the brain United States (Hamilton et al., 2007). In utero expo-
is highly malleable, and drug-induced alterations of sure to tobacco byproducts has been linked to cognitive
neural plasticity may deflect the normal course of brain deficits in laboratory animals and human adolescents
maturation. (Dwyer, Broide, and Leslie, 2008). Some studies sug-
gest that such exposure can lower general intelligence;
Prenatal Exposures for example, one found a 12-point gap in full-scale IQ
The consequences of prenatal alcohol exposure are well- between exposed and unexposed middle-class adolescents
known: Fetal alcohol spectrum disorders are the leading (e.g., Fried, Watkinson, and Gray, 2003). In another Cognitive defi-
cause of mental retardation in the United States (Centers study, the odds of having attention deficit hyperactivity cits following
for Disease Control and Prevention, 2009). In addition, disorder (ADHD) were more than three times as great
prenatal expo-
fetal alcohol exposure increases susceptibility to later for adolescents whose mothers smoked during pregnancy
sure to smok-
substance abuse problems (Yates et al., 1998). compared with children of nonsmoking mothers (Pauly
Prenatal exposures to a number of other drugs have and Slotkin, 2008). ing may reflect
significant deleterious effects on cognition and behavior Cognitive deficits following prenatal exposure to structural brain
that may not rise to the level of mental retardation. In smoking may reflect structural brain changes. In one changes.
one study, 5-year-olds whose mothers had used alcohol, study, prenatally exposed adolescent smokers had greater
cocaine, and/or opiates while pregnant ranked below visuospatial memory deficits in conjunction with changes
unexposed controls in language skills, impulse control, in parahippocampal and hippocampal function com-
and visual attention. There were no significant differ- pared with adolescent smokers not prenatally exposed
ences between the two groups of children in intelligence, (Jacobsen et al., 2006). Brain imaging of adolescent
visual/manual dexterity, or sustained attention; however, smokers and nonsmokers who were prenatally exposed
both groups placed below the normative means on these to smoking has revealed reduced cortical thickness (Toro
measures (Pulsifer et al., 2008). Another study docu- et al., 2008) and structural alterations in cortical white
mented memory deficits in 10-year-old children who matter (Jacobsen et al., 2007). Furthermore, in rats,
had been exposed prenatally to alcohol or marijuana prenatal exposure to nicotine decreased memory-related
(Richardson et al., 2002). neural activity in the hippocampus and resulted in defi-
Clinical and laboratory research has implicated pre- cits in active avoidance learning, with male and female
natal exposure to methamphetamine in both cognitive prenatally exposed rats showing significantly fewer cor-
deficits and altered brain structure. For example, one rect responses as young adults (Vaglenova et al., 2008).
study correlated shorter attention span and delayed These deficits persisted into later adulthood among the
memory with reduced volume in the putamen (-18 male rats, but not the females.
1 0 • A D D ICTION S CIENCE & CLINICAL P r a c t i c e — D e c e m b e r 2 0 1 0

Among the adverse consequences of prenatal drug (Thomas and O’Brien, 2008). A laboratory investigation
exposure is a heightened risk of becoming a drug abuser shed light on this relationship: Adult rats that had been
in later life (Fergusson, Woodward, and Horwood, exposed to nicotine during their adolescence proved less
1998). This is troubling, as it may lead to a downward sensitive than controls to rewarding/appetitive stimuli
spiral that manifests across generations and destroys and more responsive to stress and anxiogenic stimuli
family structures. Multiple factors could contribute (Iñiguez et al., 2009).
to the increased risk of future substance abuse, includ- Adolescent exposures to other substances of abuse,
ing the effects of prenatal drug exposure on cognition. such as alcohol, cannabis, and MDMA, also cause per-
As already reviewed, the risk of developing ADHD is sistent disruptions of cognition (Brown et al., 2000;
greatly increased in adolescents whose mothers smoked O’Shea, McGregor, and Mallet, 2006; Piper and Meyer,
during pregnancy (Pauly and Slotkin, 2008). ADHD 2004; Stiglick and Kalant, 1982). These findings indicate
Over half of is often comorbid with substance abuse (Biederman et that the adolescent brain, which is still developing, is
U.S. individu- al., 2008; Molina and Pelham, 2003), suggesting a link susceptible to insult from drug use and abuse, and such
between such changes in cognition and future drug abuse. insult can result in long-lasting changes in affect and
als with drug
Further work is needed to understand the mechanisms cognition.
disorders
that underlie the increased risk of drug abuse associated
(excluding with prenatal exposure. Drugs of Abuse and Mental Illness
alcohol) have Drug-related cognitive deficits may be particularly det-
co-occurring Adolescent Exposure rimental to the well-being of individuals whose cogni-
Adolescence is a high-risk period for substance abuse. tive performance is already compromised by a mental
mental
Most addicted smokers first formed the habit during disorder. Moreover, individuals who suffer from mental
disorders.
adolescence (Khuder, Dayal, and Mutgi, 1999). Ado- disorders abuse drugs at higher rates than the general
lescent smoking strongly affects cognition. Adolescent population. Substance abuse is almost twice as prevalent
smokers scored worse than age-matched nonsmokers on among adults with serious psychological distress or major
tests of working memory, verbal comprehension, oral depressive episodes as among age-matched controls
arithmetic, and auditory memory (Fried, Watkinson, (SAMHSA, 2007, p. 85), and it is estimated that over
and Gray, 2006; Jacobsen et al., 2005). These deficits half of U.S. individuals with drug disorders (excluding
resolved upon cessation of smoking with the excep- alcohol) also have mental disorders (Regier et al., 1990).
tions of working memory and arithmetic performance, In a 1986 study, smoking rates approximated 30 percent
which remained at comparatively low levels. In rats, in population-based controls, 47 percent in patients with
nicotine exposure during adolescence was associated anxiety disorder or major depressive disorder, 78 percent
with visuospatial attention deficits, increased impul- in patients with mania, and 88 percent in patients with
sivity, and increased sensitivity of medial prefrontal schizophrenia (Hughes et al., 1986).
cortical dopamine terminals in adulthood (Counotte The case of smoking and schizophrenia provides
et al., 2009). In addition, adolescent rats treated with one example of a mental disorder that features cognitive
nicotine had long-lasting changes in the sensitivity of the deficits in combination with abuse of a drug that causes
adenylyl cyclase cell signaling cascade (see Figure 1), a cognitive decline. As with many comorbidities, effective
second messenger pathway involved in many processes, treatment will likely require untangling the reasons why
including learning and memory (Slotkin et al., 2008). the two conditions so frequently co-occur:
These findings fit well with studies demonstrating that • Some evidence suggests that patients with schizophre-
nicotine initially can enhance some cognitive processes, nia smoke to self-medicate. For example, smoking
but with continued use adaptation can occur, leading to reverses schizophrenic patients’ deficits in the brain’s
dissipation of these effects and even deficits (for review, ability to adapt its responses to stimuli (sensory gating),
see Kenney and Gould, 2008). which could reduce the capacity to filter information,
Adolescent smoking can foster cognitive decline and might account for some of the cognitive disruption
indirectly, through the promotion of other disorders. For seen in the mental disorder. Researchers have traced
example, adolescent cigarette use is associated with later this feature of schizophrenia to a variant of the gene
episodes of depression (Choi et al., 1997), a malady which for the α7 nicotinic acetylcholinergic receptor subunit
in turn is associated with negative effects on cognition (Leonard et al., 2001). Consistent with this viewpoint
 R e s e a r c h R e v i e w — Add i c t i o n a n d C o g n i t i o n • 1 1

is an observation that patients smoke less when given

the antipsychotic clozapine, which independently GENES, DRUGS, AND COGNITION
alleviates this deficit, than when given haloperidol, An individual’s genetic makeup can influence the degree to which a drug
which does not (McEvoy, Freudenreich, and Wilson, of abuse alters his or her cognitive processes. For instance, an individu-
al’s cognitive response to acute amphetamine depends in part on which
1999).
of the alternative forms of the catechol-O-methyltransferase (COMT) gene
• It has also been proposed that patients with schizo-
he or she has inherited.
phrenia smoke to alleviate side effects of antipsychotic
medication (Goff, Henderson, and Amico, 1992). This gene encodes a protein that metabolizes dopamine and norepi-
An observation that supports this idea is that patients nephrine, among other molecules. A person inherits two copies of
with schizophrenia smoke more after receiving the the gene, one from each parent, and each copy has either a valine or a
methionine DNA triplet at codon 158: thus, a person may have two valine
antipsychotic haloperidol than when unmedicated
(Val/Val), two methionine (Met/Met), or a mixed pair (Val/Met or Met/
(McEvoy et al., 1995). Val) of codons at this location. Administration of acute amphetamine
• Another suggested explanation for the link between to individuals with the Val/Val pairing improved their performance on
smoking and schizophrenia is that smoking itself may the Wisconsin Card Sorting Task (a test of cognitive flexibility that acti-
precipitate schizophrenia in people predisposed to vates the dorsolateral prefrontal cortex) and increased efficiency in their
develop the disease. Among schizophrenics, smok- prefrontal cortical function, as measured by increased regional cerebral
ers have an earlier onset of illness, require hospital blood flow in the inferior frontal lobe (Mattay et al., 2003). However,
admissions more frequently, and receive higher doses acute amphetamine did not produce those advantages in individuals
with either the Val/Met or Met/Met pairing. Interestingly, the Val/Val
of antipsychotic medications (Goff, Henderson, and
pairing is also associated with increased impulsivity, a trait associated
Amico, 1992; Kelly and McCreadie, 1999; Ziedonis with addiction (Boettiger et al., 2007).
et al., 1994).
Another cognitive disorder that is strongly associ- Furthermore, smokers with the Val/Val pairing were more sensitive to
ated with smoking is ADHD. Interestingly, the cogni- the disruptive effects of nicotine withdrawal on working memory and
exhibited a greater cognitive response to tobacco (Loughead et al.,
tive symptoms associated with ADHD are similar to
2009). These results are important not only because they demonstrate
those displayed during nicotine withdrawal, and both a link between the effects of drugs of abuse on cognition and behavioral
have been attributed to alterations in the acetylcholin- traits associated with addiction, but also because they provide examples
ergic system (Beane and Marrocco, 2004; Kenney and of how genotype contributes to the addictive phenotype.
Gould, 2008). The high prevalence of smoking among
individuals with ADHD (Lambert and Hartsough,
1998; Pomerleau et al., 2003) may be an attempt to toms (Dopheide and Pliszka, 2009; Kollins, 2008) such
self-medicate, because acute nicotine use can reverse some as deficits in attention and working memory (Beane and The cognitive
ADHD attentional deficits (Conners et al., 1996). The Marrocco, 2004). Some of the distress of ADHD may symptoms
desire to avoid withdrawal may be a particularly strong reflect a reduction in dopaminergic function (Volkow associated
motivation for continued smoking in this population, as et al., 2009), which might be partially compensated by
with attention
individuals with ADHD suffer more severe withdrawal drugs of abuse (Feltenstein and See, 2008).
symptoms than age-matched controls without the dis- deficit hyperac-
order (Pomerleau et al., 2003), and increases in ADHD Clinical Implications tivity disorder
symptoms following smoking cessation are associated The literature reviewed here highlights the importance are similar to
with a greater risk of relapse (Rukstalis et al., 2005). As of considering past and present cognitive function when those displayed
noted above, however, continued smoking in itself can treating patients for addiction, as drug-related cognitive
during nicotine
lead to cognitive decline (Nooyens, van Gelder, and changes may bias patients toward responses and actions
Verschuren, 2008; Richards et al., 2003), and hence that contribute to the cycle of addiction. Clinicians withdrawal.
might exacerbate ADHD-related symptoms. face the challenge of helping patients master adaptive
Along with nicotine, ADHD is also associated strategies to overcome the strong associations that con-
with abuse of stimulants, such as amphetamine and tribute to relapse when patients return to environments
cocaine, and psychoactive drugs, such as cannabis (Elkins, associated with their prior substance use. In addition,
McGue, and Iacono, 2007; Galéra et al., 2008; Tang et cognitive deficits may hinder patients’ ability to benefit
al., 2007). Such abuse may also represent attempts at self- from counseling, and more sessions and/or reminders
medication, as stimulants are used to treat ADHD symp- may be necessary to aid these patients in incorporating
1 2 • A D D ICTION S CIENCE & CLINICAL P r a c t i c e — D e c e m b e r 2 0 1 0

abstinence-sustaining strategies into their daily routines. genetic background on the manifestation of symptoms is
Research into the changes in cognition that accom- a critical area for future research, holding the promise of
pany addiction and the neural substrates of learning and informing more effective treatments that can be tailored
addiction is still in its infancy but has potential to reshape to the individual’s genotype. Finally, understanding
views on addiction. For example, a recent discovery that how prenatal exposure to drugs of abuse changes neu-
has generated excitement in the addiction field is that ral development should be a high priority, as prenatal
smokers who suffered damage to the insula often lost exposure increases the new generation’s susceptibility
their desire to smoke (Naqvi et al., 2007). The authors to addiction and other problems.
of this finding proposed that the insula is involved in
the conscious urge to smoke and that therapies that Acknowledgments
modulate insula function may facilitate smoking cessa- The author would like to thank Dr. Sheree Logue and
tion. It may also be that damage to the insula will have members of the Gould Laboratory for critically reading
a similar effect on the desire to use other drugs of abuse an earlier version of this review and also to acknowledge
(for a review see Goldstein et al., 2009). support by grants from the National Institute on Alcohol
A better understanding of how substances of abuse Abuse and Alcoholism, the National Institute on Drug
change cognitive processes is needed to develop new Abuse, and the National Cancer Institute (AA015515,
therapeutic agents to treat addiction and ameliorate DA017949, DA024787, and P50 CA143187) for some
cognitive deficits. This is a complex issue, however, as of the studies reviewed.
different drugs of abuse appear to alter different cogni-
tive processes and cell signaling pathways. Even among Correspondence
users of the same drug, cognitive impacts will differ Thomas J. Gould, Department of Psychology, Weiss
depending on variations in environmental factors and Hall, Temple University, Philadelphia, PA 19122;
genetics. Understanding the influence of an individual’s e-mail: tgould@temple.edu.

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