Neuropsychol Rev (2007) 17:275–297
DOI 10.1007/s11065-007-9031-0
Neurocognitive Effects of Methamphetamine: A Critical
Review and Meta-analysis
J. Cobb Scott & Steven Paul Woods & Georg E. Matt &
Rachel A. Meyer & Robert K. Heaton &
J. Hampton Atkinson & Igor Grant
Published online: 13 August 2007
# Springer Science + Business Media, LLC 2007
Abstract This review provides a critical analysis of the
central nervous system effects of acute and chronic
methamphetamine (MA) use, which is linked to numerous
adverse psychosocial, neuropsychiatric, and medical prob-
lems. A meta-analysis of the neuropsychological effects of
MA abuse/dependence revealed broadly medium effect
sizes, showing deficits in episodic memory, executive
functions, information processing speed, motor skills,
language, and visuoconstructional abilities. The neuropsy-
chological deficits associated with MA abuse/dependence
are interpreted with regard to their possible neural mech-
anisms, most notably MA-associated frontostriatal neuro-
toxicity. In addition, potential explanatory factors are
considered, including demographics (e.g., gender), MA
use characteristics (e.g., duration of abstinence), and the
influence of common psychiatric (e.g., other substance-
J. C. Scott
Joint Doctoral Program in Clinical Psychology,
San Diego State University and University of California,
San Diego, CA 92120, USA
S. P. Woods : R. A. Meyer : R. K. Heaton : J. H. Atkinson :
I. Grant
Department of Psychiatry (0847), School of Medicine,
University of California,
San Diego, La Jolla,
CA 92093, USA
G. E. Matt
Department of Psychology, San Diego State University,
San Diego, CA 92182, USA
S. P. Woods (*)
HIV Neurobehavioral Research Center, Department of Psychiatry
(0847), University of California, San Diego,
150 West Washington Street, 2nd floor,
San Diego, CA 92103, USA
e-mail: spwoods@ucsd.edu
related disorders) and neuromedical (e.g., HIV infection)
comorbidities. Finally, these findings are discussed with
respect to their potential contribution to the clinical
management of persons with MA abuse/dependence.
Keywords Central nervous system . Methamphetamine .
Abuse . Dependence . Neuropsychological assessment .
Cognition
Methamphetamine (MA) is a potent, addictive psychostim-
ulant that has dramatic effects on the central nervous
system (CNS). This review provides a critical analysis of
the CNS sequelae of MA abuse and dependence, focusing
on studies from both the neuropsychological and neuro-
imaging literatures. First, we provide a brief introduction to
the prevalence, patterns, and history of MA use, a description
of the acute effects of MA, and an overview of its
neurotoxicity, including affected neural systems. Next,
results from neuroimaging studies are critically reviewed,
including those using structural (MR), functional (fMRI),
and metabolic (i.e., positron emission technology [PET] and
magnetic resonance spectroscopy [MRS]) techniques. Then
we present a meta-analysis of the neuropsychological
literature on persons with long-term MA abuse or depen-
dence. Extending prior qualitative reviews of this literature
(e.g., Meredith et al. 2005; Nordahl et al. 2003), we provide
novel information by arriving at quantitative estimates of
the potential effects of long-term MA abuse on various
neurocognitive functions. To this end, we provide effect
size estimates for each of nine neurocognitive ability
domains. The review concludes with a discussion of the
results from the meta-analysis, potential moderating factors
(e.g., demographics) and comorbidities (e.g., psychiatric
disorders), the limitations of previous studies, and areas in
which further research is urgently needed.
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Introduction
Scope of Methamphetamine Use
Although MA was first synthesized in the late 1800s in
Japan, it did not become widely used until World War II,
when Japanese, United States, and German military
personnel used it to combat fatigue and increase alertness.
In the U.S., MA was first illegally produced on a large scale
during the 1960s by underground labs on the West Coast,
and abuse of the substance quickly spread throughout that
area. This burgeoning illicit market was first controlled by
motorcycle gangs in the California Bay Area, only later to
be replaced by Mexican-based distributors, who, along with
a number of “super-labs” in California and the U.S.
Southwest capable of producing large quantities of MA in
a single production cycle, are the primary manufacturers of
the drug at the present time (see Anglin et al. 2000 for a
comprehensive review of the history of MA use and
distribution).
Methamphetamine abuse has recently been described as
an “epidemic” in the U.S. due to the rising prevalence rates
throughout the 1990s and into the present (Hunt 1995).
According to the U.S. 2005 National Survey on Drug Use
and Health, approximately 10 million people (around 4.5%
of the U.S. population) have tried MA at some point in their
lives, while 1.3 million persons reported using MA in the
past year (Substance Abuse and Mental Health Services
Administration 2006b). From 1995 to 2002, emergency
room visits due to MA use increased 88% for persons under
18 years old, and 54% across all age groups (Substance
Abuse and Mental Health Services Administration 2006a).
During this same period (1994–2004), there was also a
dramatic increase in individuals seeking substance abuse
treatment with MA as their primary substance of abuse
(Substance Abuse and Mental Health Services Administra-
tion 2006c). However, recent estimates also indicate that
the MA epidemic in the U.S. may have plateaued, as use
among the civilian, non-institutionalized population de-
clined between 2002 and 2005 (Substance Abuse and
Mental Health Services Administration 2006b). In addition,
the number of individuals using MA for the first time
decreased sharply from 318,000 in 2004 to 192,000 in
2005. Nonetheless, the MA problem is still rampant in the
Southwestern area of the U.S. (e.g., San Diego), and
indicators point to a spread into other areas of the country
(Community Epidemiology Work Group 2006; National
Drug Intelligence Center 2006). Legal measures have been
enacted specifically to counter the growing problem of MA
use, including the Comprehensive Methamphetamine Con-
trol Act of 1996 and the Combat Methamphetamine
Epidemic Act of 2005, both of which attempt to control
the precursor materials used for MA production (e.g.,
Neuropsychol Rev (2007) 17:275–297
pseudoephedrine). While data suggest that such measures
have been somewhat effective in reducing MA production
in the U.S., MA production in Mexico has concurrently
increased and threatens to offset the decline seen domesti-
cally (National Drug Intelligence Center 2006).
Currently, MA is primarily sold illicitly for recreational
use, although it has been available legally as a pharmaceu-
tical tablet under the trade name Desoxyn® since the 1940s.
There are a few accepted medical reasons for its use, such
as treatment of Attention-Deficit/Hyperactivity Disorder
(ADHD), narcolepsy, and obesity, although it is only
available as a prescription that cannot be refilled (Bray
1993; Mitler et al. 1993; National Institute on Drug Abuse
2006). The increasing prevalence of illicit MA is in part due
to its somewhat easy and cost-efficient synthesis in
clandestine laboratories with inexpensive, over-the-counter
ingredients. Prior to restrictions placed on phenyl-2-
propanone (P2P) with the Federal Chemical Diversion and
Trafficking Act of 1988, the most popular method for MA
synthesis was the “P2P method” of reduction. A number of
different methods currently exist for synthesizing MA from
legal precursor materials (with instructions widely available
over the Internet), but the most popular, cheap, and simple
method is the ephedrine/pseudoephedrine reduction. In the
U.S., the drug is most commonly found as a colorless
crystalline solid, sold under various street names (e.g.,
‘crystal meth,’ ‘ice,’ ‘tina’). However, the drug comes in
many forms and can be administered in a variety of ways,
such as injecting, snorting, smoking, or orally ingesting.
The amount administered for a single use varies widely,
depending on route of administration, drug purity, and
individual tolerance, although chronic users often use MA
in cycles of binges or “runs” that last for a few days,
followed by periods of abstinence.
Acute Effects of Methamphetamine Use
The timing, intensity, and spectrum of effects after MA
administration depend on both the amount of MA con-
sumed and the method of administration. Generally, acute
MA use results in a number of effects on the sympathetic
branch of the autonomic nervous system, including hyper-
tension, tachycardia, hyperthermia, increased breathing
rate, and constriction of blood vessels. The desired
cognitive and emotional effects include euphoria, enhanced
energy and alertness, feelings of increased physical and
mental capacity, and a surge in productivity (Cretzmeyer
et al. 2003; Hart et al. 2001). Elevated self-esteem and an
increase in libido are also fairly common. Effects from
smoking and injection tend to be almost instantaneous,
while ingestion and snorting have more delayed and less
intense effects with slower absorption into the body. Given
that the elimination half-life of MA ranges from 8 to 13 h,
Neuropsychol Rev (2007) 17:275–297
its effects typically last for a similar amount of time, which
is notably more than other stimulants such as cocaine
(Busto et al. 1989), and may partly explain the relatively
quicker progression from first use to addiction in MA users
(Gonzalez Castro et al. 2000).
Binge use, in which the drug is repeatedly administered
over a few hours or days, is common among chronic MA
users, resulting in highly elevated blood concentrations of
the drug. During a binge, individuals often exhibit an
increase in sexual behaviors and repetitive, focused
activities, such as mechanical work or intense periods of
cleaning, often accompanied by sleeplessness (Semple et al.
2003). The progressively higher doses required to maintain
a high (i.e., tachyphylaxis) can also result in heightened
anxiety, paranoia, hallucinations, and even delirium (Harris
and Batki 2000; Smith and Fischer 1970). As a binge
progresses, the positive effects of the drug generally
become less pleasurable, while toxic effects become more
prominent, and individuals eventually experience a phase
known as “tweaking,” characterized by increased anxiety,
irritability, insomnia, and confusion. A withdrawal syn-
drome can occur at the termination of binge use and can
include dysphoria, depression, irritability, anxiety, poor
concentration, hypersomnia, fatigue, paranoia, akathisia,
and drug craving (Barr et al. 2002; Zweben et al. 2004).
These symptoms usually lessen in intensity within a week
after cessation of use, although they are more likely to
occur and are more pronounced in long-term and injection
MA users (Davidson et al. 2001; McGregor et al. 2005;
Newton et al. 2004). While subjectively distressing,
withdrawal from MA (and other stimulants) is not asso-
ciated with the life-threatening symptoms that can accom-
pany withdrawal from alcohol or sedative-hypnotic agents
(see Trevisan et al. 1998 for a review).
Although a causal relationship has not been adequately
demonstrated, MA use is frequently associated with
increased impulsive, violent, and even homicidal behavior,
as well as unsafe automobile driving. Japan instituted a
strict ban on MA in the 1950s when its use had increased
concurrently with MA-associated crimes and homicides
(Anglin et al. 2000). In one study, a large majority of
patients entering treatment reported that their use of MA
resulted in violent behavior (von Mayrhauser et al. 2002).
Similarly, Zweben et al. (2004) reported that 43% of
individuals in treatment either reported a history of legal
charges for violent crimes or stated that they had difficulty
controlling violent behavior. In a population of adult male
California parolees, MA use was predictive of both
recidivism (i.e., a return to custody for any reason) and
violent behavior (Cartier et al. 2006). Logan et al. (1998)
found that approximately 45% of deaths involving MA use
were associated with either suicidal or homicidal violence.
In an earlier review, Logan (1996) examined 28 reports of
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MA-associated automobile accidents or violations, finding
that all of the accidents were caused by the MA-using
drivers, whose blood concentrations were generally well
above the therapeutic dose. Moreover, emergency room
visits associated with MA use are more likely to present
with various traumas (e.g., injury from assault) and to
require greater utilization of services than the visits of the
average emergency room patient (Richards et al. 1999).
Clinical studies present a complex picture regarding the
acute effects of MA on cognition. A number of studies have
reported an enhancement of cognitive performance with
acute administration of therapeutic doses, especially in
information processing speed, psychomotor functioning,
and attention, in both non-drug using volunteers (Johnson
et al. 2000; Mohs et al. 1978, 1980; Silber et al. 2006) and
stimulant-dependent individuals (Johnson et al. 2005).
However, other studies have shown equivocal effects
(e.g., Comer et al. 2001), while still others suggest that
MA leads to deficits in inhibition and filtering out irrelevant
information upon acute administration (Mewaldt and
Ghoneim 1979). Users who are sleep deprived show better
performance on most tasks with MA administration (Hart
et al. 2005), although the effects generally diminish as more
of the drug is metabolized (Wiegmann et al. 1996).
Interpretation of this literature remains difficult, in part
due to differing MA dosing regimens, the variety of
cognitive tests administered, and variable quality in
experimental design. In addition, it is unclear how relevant
these cognitive enhancements may be for abusers, who
mostly use well above the therapeutic dose and often smoke
or inject the drug (as opposed to oral administration, which
is the norm in acute studies). Nonetheless, the existing
literature on acute cognitive effects of MA, combined with
qualitative reports regarding MA use and the literature from
other amphetamines (e.g., Soetens et al. 1995), tend to point
to an increase in attentiveness and speed of processing
accompanied by decreases in ability to filter information
with therapeutic doses of MA.
Effects of Chronic Methamphetamine Use
Long-term MA abuse or dependence can result in a host of
medical, psychiatric, and psychosocial consequences. A
number of cardiovascular effects from chronic MA use
have been reported, including pulmonary hypertension
(Chin et al. 2006), acute aortic dissection (e.g., Davis and
Swalwell 1994), myocardial infarction (e.g., Hong et al.
1991), and ischemic and hemorrhagic strokes (e.g., Olsen
1977; Yen et al. 1994). In addition, a number of other
detrimental physical and mental health consequences can
occur, including nutritional deficiencies, sleep deprivation,
and rapid tooth decay, known as “meth mouth” (ADA
Division of Communications 2005; National Institute on
278
Drug Abuse 2006). A number of cases of MA-related
mortality have been reported, not only due to excessive use
or overdosing, but also because of hypersensitivity to MA
or the drug’s prominent hypertensive effects (e.g., Delaney
and Estes 1980; Hall et al. 1973). In addition, MA abusers
have significantly elevated infection rates for diseases such
as human immunodeficiency virus (HIV) and hepatitis C
virus (HCV) as a result of both injection drug use (i.e.,
needle sharing) and risky sexual behavior (e.g., unprotected
sex), especially among the population of men who have sex
with men (Bluthenthal et al. 2001; Gonzales et al. 2006;
Halkitis et al. 2001; Shoptaw 2006).
Chronic MA abusers also have high rates of affective
distress and psychiatric disorders, which can be especially
severe during withdrawal (Newton et al. 2004). Psychosis,
including both negative and positive symptoms, is more
likely to occur in MA abusing individuals compared to non-
abusing populations, even after adjusting for history of
psychotic disorders (Buffenstein et al. 1999; Harris and
Batki 2000; Iwanami et al. 1994; McKetin et al. 2006;
Srisurapanont et al. 2003). This psychosis is more likely to
be seen in MA dependent injection users (Hall et al. 1996;
McKetin et al. 2006), but individuals with predispositions
to psychotic symptoms, including schizotypal or schizoid
traits and family histories of psychotic disorders, also have
an increased risk of MA-associated psychosis (Chen et al.
2003, 2005). The presence of psychosis is usually transient,
occurring during use or withdrawal and normally abating in
a period of days. However, susceptibility to psychotic
episodes may persist for years after cessation of MA use
(e.g., Sato 1986; Ujike and Sato 2004). Moreover, this
increased susceptibility may be associated with a polymor-
phism in the hDAT1 gene (SLC6A3) encoding the
dopamine transporter (Ujike et al. 2003) and/or noradren-
ergic hyperactivity (or other metabolite alterations) in
response to mild stressors (Iyo et al. 2004; Yui et al.
2002). Methamphetamine abusers are also at increased risk
of depression and suicidal ideation during active use,
withdrawal, and abstinence, and this risk is amplified in
women and injection users (Domier et al. 2000; Kalechstein
et al. 2000; Zweben et al. 2004). Abnormalities in the
amygdala or anterior cingulate, areas largely modulated by
dopamine, may contribute to the increase in depressive
symptoms seen in MA abusers (London et al. 2004). MA
users may also have increased rates of antisocial personality
disorder (Chen et al. 2003), as well as mania and bipolar
disorder (Shoptaw et al. 2003), but the differential
diagnosis of MA-induced mood disorders and primary
mania can be problematic.
Recently, high rates of comorbidity have been observed
between MA dependence and ADHD (Jaffe et al. 2005;
Matsumoto et al. 2005; Sim et al. 2002), which is a
neurodevelopmental disorder characterized by marked
Neuropsychol Rev (2007) 17:275–297
inattention (e.g., difficulty focusing), hyperactivity (e.g.,
fidgety behavior), and impulsivity (e.g., often interrupts
others) (American Psychiatric Association 1994). ADHD can
persist into adulthood, mostly with a symptom profile of
inattention and distractibility (Faraone et al. 2000), and is a
risk factor for subsequent substance abuse (Wilens et al.
1995). Although its neuropathogenesis is not completely
understood, ADHD is currently conceptualized as a disorder
resulting from hypoactivity of dopaminergic systems and
imbalance in noradrenergic systems (Biederman 2005; di
Michele et al. 2005), implicating cognitive and behavioral
dysfunction characteristic of an underlying frontal-striatal
pathophysiology (Hervey et al. 2004). Moreover, current
pharmacologic treatments for ADHD (e.g., methylphenidate)
target dopaminergic systems, and, similar to MA, operate by
blocking reuptake of dopamine and norepinephrine (Pliszka
2007). This has led some researchers to propose that
individuals with ADHD may experience more beneficial
effects from initial MA use, leading to repeated use and
potentially to dependence (Jaffe et al. 2005). Most studies,
however, are cross-sectional in nature, and therefore are not
able to establish cause and effect relationships. Thus,
whether MA use results in a similar symptom profile to
ADHD, or whether individuals with these symptoms have a
predilection for MA due to its initial effects on concentration
abilities remains debated.
Considering its highly addictive potential, it is not
surprising that chronic MA use leads to adverse psychoso-
cial and behavioral outcomes. MA users are likely to be
unemployed and uninsured (Baberg et al. 1996). Given that
illicit MA use often results in irritability, agitation, and
numerous other forms of psychiatric distress, chronic MA
abusers experience myriad interpersonal problems, includ-
ing poor coping skills, limited social support, and disorga-
nized lifestyles (Cretzmeyer et al. 2003; Halkitis and Shrem
2006). Impulsive behavior on the part of MA abusers may
exacerbate their psychosocial difficulties and promote
maintenance of drug-seeking behavior, and this impulsivity
may be greater in depressed, younger users, those with low
educational levels, and those who use large amounts of MA
(Semple et al. 2004, 2005).
Methamphetamine and the Brain
Methamphetamine is a synthetic derivative of amphet-
amine, but due to the addition of a methyl group in its
chemical structure, it has a relatively high lipid solubility,
allowing more rapid transport of the drug across the blood–
brain barrier (Barr et al. 2006). Thus, compared with its
parent drug, amphetamine, MA exerts more profound
effects on the CNS. Methamphetamine use principally
results in a cascading release of dopamine, but also of
other monoamine neurotransmitters, including norepineph-
Neuropsychol Rev (2007) 17:275–297
rine and serotonin (Kokoshka et al. 1998). Animal models
suggest that MA administration stimulates the release of
dopamine via a number of different molecular mechanisms,
including displacement of storage vesicles and inhibition of
monoamine oxidase (Zaczek et al. 1990), although the
dopamine transporter (DAT) may be the primary site of
action (Giros et al. 1996). In addition to increasing the
efflux of dopamine, MA enhances DAT-mediated reverse
transport of dopamine across the plasma membrane,
thereby further increasing the dopamine concentration into
the synapse (Khoshbouei et al. 2003).
Methamphetamine-induced neurotoxicity is evident in
several neurotransmitter systems, but it is most notable in
nigrostriatal dopaminergic pathways, thus altering the
function of the dopamine rich fronto-striato-thalamo-
cortical loops (Cass 1997). Although an acute, moderate
dose of MA is unlikely to reduce dopamine stores
permanently (e.g., Chan et al. 1994), a series of high-dose
administrations in experimental animals results in a
significant reduction in levels of dopamine and serotonin
and their metabolites, as well as tyrosine hydroxylase and
tryptophan hydroxylase activity, enzymes involved in the
synthesis of dopamine and other catecholamines (Axt and
Molliver 1991; Bakhit et al. 1981; Hotchkiss and Gibb
1980; Morgan and Gibb 1980). Both high dose and chronic
administration of MA can result in depletion of dopamine,
destruction of dopamine nerve terminals, and long-term
reduction in other markers of dopamine terminal integrity,
although dopaminergic neuron cell bodies themselves do
not seem to be destroyed (Harvey et al. 2000; Miller and
O’Callaghan 2003; Ricaurte et al. 1982; Wagner et al.
1980). A number of pathways have been implicated in MA-
induced neurotoxicity, including production of reactive
oxygen and nitrogen species, hyperthermia, or triggering
of an apoptotic cascade dependent upon mitochondria, but
the exact processes are still unclear (see Cadet et al. 2005;
Davidson et al. 2001 for more thorough reviews). More-
over, evidence from experimental animal studies indicates
that MA neurotoxicity brought about by binge-like admin-
istration might be partially reversible with time, although
this recovery is likely dependent on the amount and dosing
of MA exposure (Friedman et al. 1998; Harvey et al. 2000)
and is likely incomplete (Woolverton et al. 1989). The
mechanisms of recovery are unclear, but may be partly
explained by the sprouting of remaining axons or a
compensatory increase in monoamine levels (Cass and
Manning 1999; Friedman et al. 1998).
Studies of MA-associated neurotoxicity in humans have
been limited until recent years. Wilson et al. (1996) found a
reduction in levels of dopamine, DAT, and tyrosine
hydroxylase in postmortem striatum of chronic MA
abusers, although they did not find reductions in levels of
other dopamine transporters and synthetic enzymes (e.g.,
279
vesicular monoamine transporter type-2 [VMAT2]),
changes that might be expected with damage to dopamine
nerve terminals. Interestingly, a later study from the same
group found that dopamine levels were more severely reduced
in the caudate than in the putamen at autopsy, an opposite
pattern as is seen in Parkinson’s disease, perhaps explaining
the relatively low prevalence of parkinsonian motor symp-
toms observed in chronic MA abusers (Moszczynska et al.
2004). One possible implication of these findings is that
cognitive functions may be affected more so than motoric
abilities in MA abuse compared to Parkinson’s disease,
because the caudate has more cognitive pathways (i.e.,
the three prefrontal-caudate-globus pallidus/substantia
nigra-thalamo-cortical loops) than the putamen (i.e., the
supplementary motor-putamen-globus pallidus/substantia
nigra-thalamo-cortical loop; Alexander et al. 1986).
Neuroimaging of Methamphetamine Abuse
and Dependence
Given the effects of MA on dopaminergic, as well as
perhaps serotonergic and GABAergic (e.g., Burrows and
Meshul 1999) systems, a number of studies have investi-
gated the impact of MA abuse and dependence on the
structure and function of frontostriatal and limbic systems.
For example, studies using positron emission tomography
(PET), which utilizes ligands that bind to transporters,
provide in vivo insights into dopaminergic and serotonergic
dysregulation in MA users. One study reported that MA
abusers evidence reduced serotonin transporter density (a
marker of the number or integrity of serotonin terminals),
which may be associated with increased aggressive behav-
ior (Sekine et al. 2006). Regarding the effect of MA on the
dopaminergic system, McCann et al. (1998) first demon-
strated a reduction in striatal DAT levels in a small sample
of abstinent MA abusers. Similar findings were reported by
Volkow et al. (2001c) and Sekine et al. (2001, 2003), who
observed low DAT availability in the striatum and prefron-
tal cortex of MA users ranging from 20% to 33% relative to
healthy comparison participants. Although these DAT
reductions are generally lower than those found in
Parkinson’s disease (e.g., McCann et al. 1998), they are
nonetheless associated with impaired psychomotor and
episodic memory functioning (Volkow et al. 2001c),
increased severity of psychiatric symptoms (Sekine et al.
2001, 2003), and longer duration of MA use (Sekine et al.
2001, 2003; Volkow et al. 2001c). Whether these DAT
changes reflect down-regulation in transporter expression,
as suggested by reduced DAT with relative sparing of
VMAT2 (i.e., a more stable indicator of the structural
integrity of dopamine terminals; Wilson et al. 1996), or
actual dopamine terminal degeneration (e.g., Johanson et al.
2006) remains unclear. Importantly, however, DAT avail-
280
ability may recover in a time-dependent fashion with
extended abstinence from MA (Volkow et al. 2001b) but
not necessarily to pre-MA levels (Johanson et al. 2006) or
with parallel cognitive normalization (Volkow et al. 2001b).
Several studies have also employed 1H magnetic
resonance spectroscopy (MRS) methods to investigate the
possible metabolic alterations in chronic MA use. A
majority of these studies indicate that individuals with
MA dependence show low levels of N-acetylaspartate
(NAA), a marker of neuronal integrity, relative to age-
and gender-matched comparison volunteers. Low NAA is
apparent in the basal ganglia, frontal white matter, and
anterior cingulate (Ernst et al. 2000; Nordahl et al. 2002;
Sung et al. 2006; cf. Sekine et al. 2002) and is associated
with greater lifetime MA use (Ernst et al. 2000; Sung et al.
2006). However, a recent study of 44 well-characterized
MA dependent persons who were abstinent for an average
of 3 months found no differences in NAA (Taylor et al.
2007), raising questions about the persistence of the NAA
effects. MA users also show reduced basal ganglia levels of
creatine (a marker of metabolic [e.g., mitochondrial]
disturbance), which is correlated with duration of use
(Sekine et al. 2002) and psychiatric symptom severity
(Iyo et al. 2004; Sekine et al. 2002). Elevated choline (a
marker of cellular membrane synthesis and turnover) in the
anterior cingulate and frontal grey matter is also evident in
MA dependent individuals (Ernst et al. 2000; Salo et al.
2007) and may correlate with duration of MA use (Taylor et
al. 2007). Finally, some studies showed abnormally high
levels of myo-inositol (a marker of glial activation) in the
frontal grey (Ernst et al. 2000) and left frontal white (Sung
et al. 2006) matter. Taken together, these MR spectroscopy
studies suggest that a variety of different neuropathological
processes may be associated with MA dependence, includ-
ing neuronal injury or death, astrocytosis, cellular mem-
brane alterations, and dysregulation of energy metabolism.
Not all studies have shown MA effects on these metabo-
lites, however (e.g., Taylor et al. 2007), perhaps due to
differences in MA use severity and prevalence of comorbid
conditions across study cohorts, which raises the possibility
that brain metabolite changes occur when MA use rises
over some threshold or that certain populations of MA
users might be unusually resistant to MA-associated
neurotoxicity. Given the possible role of glutamergic
alterations in MA-associated neurotoxicity (Brown et al.
2005), future studies of MA users might use 13C spectros-
copy to provide a dynamic evaluation of glutamate-
glutamine cycling (for further reading on this method, see
Mason and Rothman 2004; Ross et al. 2003).
More recently, attention has turned to the possible effects
of MA-associated neurotransmitter (e.g., dopaminergic) and
metabolic (e.g., NAA) disturbances on the structural
integrity of brain parenchyma. Structural MRI studies of
Neuropsychol Rev (2007) 17:275–297
MA users consistently reveal grey matter volumetric
abnormalities, but have differed in directionality (i.e.,
smaller versus larger volumes) and their associations with
MA use characteristics, demographics, and neuropsycho-
logical impairment. Thompson et al. (2004) first published
on structural brain alterations in MA-dependent persons in
a study that showed abnormally small limbic (e.g.,
cingulate) and hippocampal volumes, with the latter being
associated with word recall impairment. Using a compre-
hensive morphometric approach, Jernigan et al. (2005)
reported that MA dependence was associated with abnor-
mally large volumes in the striatum, nucleus accumbens,
and parietal lobes. Greater cortical volumes were not related
to psychiatric comorbidity or MA use characteristics, but
were associated with greater severity of global neuro-
cognitive impairment. Similarly, Chang et al. (2005a) found
larger basal ganglia (i.e., putamen and globus pallidus)
volumes in chronic MA users; however, in contrast to
Jernigan et al. (2005), smaller striatal volumes were
associated with greater severity of cognitive impairment
and greater cumulative MA use. Although somewhat
surprising, the larger basal ganglia volumes apparent in
MA users may represent a functional compensatory
response, inflammatory mechanisms, neuritic growth, or
glial activation (Chang et al. 2005a; Jernigan et al. 2005).
In addition to grey matter abnormalities, several studies
have revealed evidence of white matter pathology in
persons dependent on MA. Perhaps reflecting underlying
cerebrovascular disease (e.g., decreased perfusion of brain
parenchyma), male MA abusers demonstrate greater sever-
ity of white matter hyperintensities, which correlate with
lifetime quantity of MA use in the deep white matter (Bae
et al. 2006). Volumetric analyses have shown bilaterally
greater temporal, occipital, and cingulate white matter
volumes in MA dependent individuals, with the latter being
more pronounced in the right hemisphere (Thompson et al.
2004). Chronic MA users have also been found to
demonstrate corpus callosum irregularities, including great-
er curvature in the genu and smaller width in posterior
regions (e.g., isthmus; Oh et al. 2005). In the only diffusion
tensor imaging study of MA to date, Chung et al. (2006)
found lower fractional anisotropy (i.e., less directional
diffusivity of water, possibly indicating decreased parallel
ordering of axons) bilaterally in the frontal white matter of
32 MA abusers compared with 30 healthy comparison
subjects. The reduced white matter anisotropy was more
prominent in men, particularly the right frontal region,
which was associated with a greater number of errors on the
Wisconsin Card Sorting Test (WCST; Chung et al. 2006).
Considering the marked cardiovascular and neurotoxic
effects of MA use, changes in regional cerebral blood flow
(rCBF) may accompany MA dependence. Iyo et al. (1997)
reported qualitative “focal perfusion deficits” in six out of
Neuropsychol Rev (2007) 17:275–297
nine chronic MA users. Using quantitative perfusion MR
imaging techniques, Chang et al. (2002) demonstrated
lower relative rCBF in the frontal cortex and basal ganglia
of 20 MA dependent individuals as compared with age- and
gender matched comparison volunteers. Commensurate
with previously reported metabolite (Nordahl et al. 2002)
and gray matter density (Thompson et al. 2004) abnormal-
ities in the anterior cingulate, an area with a high density of
dopamine fibers, Hwang et al. (2006) observed lower
relative rCBF in the right anterior cingulate cortex in MA
users. These changes were less pronounced in individuals
with prolonged abstinence from MA when compared to
recently abstinent users, although rCBF was still lower than
healthy comparison participants. As measured by fMRI,
chronic MA users show alterations in blood-oxygen-
dependent level (BOLD) signals in both prefrontal and
parietal brain regions during decision-making when com-
pared with healthy comparison volunteers (Monterosso et
al. 2006; Paulus et al. 2002, 2003). These BOLD signal
changes are particularly evident in the dorsolateral and
orbitofrontal cortices (Paulus et al. 2002), which may be
mediated by low levels of dopamine D2 receptors (Volkow
et al. 2001a). Interestingly, prefrontal, parietal, and insular
hypoactivation during decision-making is also predictive of
incident MA relapse, thus demonstrating the potential
relevance of MA-related CNS effects to treatment outcomes
(Paulus et al. 2005).
It is unknown whether the changes in brain structure and
function evident in persons with MA dependence are
reversible. Large-scale outcome studies that have followed
MA users over longer periods of time (i.e., years) do not
exist, and therefore we do not know if any or all of the
brain changes will remit with prolonged abstinence. If
research in the CNS effects of alcoholism is a reasonable
guiding model (e.g., Grant 1987), then one might predict
that sustained abstinence from MA would be associated
with substantial recovery in brain structure and function.
Neuropsychological Aspects of Methamphetamine Abuse
and Dependence
Extending the neurobiological and neuroimaging litera-
tures, a number of studies have suggested that chronic MA
use is often associated with mild-to-moderate neuropsycho-
logical impairment. Current estimates suggest that approx-
imately 40% of persons with MA dependence demonstrate
global neuropsychological impairment (Rippeth et al.
2004). However, interpretation of the neuropsychological
literature remains difficult due to a number of methodolog-
ical factors. First, only a handful of studies have used a
comprehensive neuropsychological battery that assesses
functioning in a number of cognitive domains, and such
studies have used divergent tests within their batteries and
281
have yielded contradictory findings. Second, both the
demographic (e.g., age) and drug use characteristics of the
participants studied have varied widely. For example, some
studies assess treatment-seeking samples that have been
abstinent for at least 30 days (with wide variability in actual
abstinence length), whereas other studies assess individuals
who are currently using MA and are only abstinent on the
day of testing. Such discrepancies create difficulty in
estimating and interpreting the effects of chronic MA use
on neuropsychological functioning. Meta-analyses repre-
sent one potentially powerful way to clarify contradictory
findings and possible explanatory variables across a
literature, and may more accurately reveal the effects of
chronic MA use on cognition. Thus, we conducted a meta-
analysis to evaluate the hypothesis that chronic MA use is
associated with deficits in neuropsychological functioning.
In addition, we proposed the following exploratory ques-
tions: (1) To what extent do demographic characteristics
and comorbid drug use influence differences between
groups? and (2) What are the effects of MA use variables
(e.g., abstinence from MA, duration of MA use) on the
neuropsychological sequelae of chronic MA use?
Meta-analysis
Studies and Variables
Before initiating a literature search, we identified a set of
inclusion criteria that would allow us to best answer the
principal research question: “What are the neuropsycholog-
ical sequelae of long-term methamphetamine abuse and
dependence?” These study inclusion criteria were (1)
assessed human adults aged 18 years and older; (2)
published in English; (3) members of the MA group were
classified specifically as having lifetime histories of MA
dependence or abuse (studies that only included amphet-
amine or stimulant dependent/abusing participants were
eligible only if they reported separate statistics for a MA
group) and identified MA as their primary substance of use;
(4) healthy comparison participants did not have a history
of stimulant dependence or any severe neurologic or
psychiatric illnesses; (5) MA was not administered by the
experimenters; (6) outcome measures included at least one
standardized neuropsychological test; and (7) sufficient data
were provided to calculate effect sizes. These criteria were
intentionally liberal in order to be more inclusive, which
has the benefits of providing a more complete representa-
tion of the existing research on the cognitive effects of MA
and using an empirical approach to examine the relation-
ships between various methodologies and study findings.
Preliminary literature searches using terms such as
amphetamine, methamphetamine, cognition, neuropsycho-
282
logical, and domain-specific keywords (e.g., memory,
attention) were independently conducted by two of the
investigators (JCS and RAM) through several online data-
bases, including PubMed, PsychInfo, and ISI Web of
Science. Any article published prior to January 2007 was
considered eligible. All articles identified as potentially
eligible were manually reviewed to ensure that the criteria
for inclusion (specified above) were met. We also manually
reviewed each article to examine for any potential omis-
sions in our literature search. In addition, all possibly
eligible studies published by the same group of authors
were carefully reviewed to minimize the inclusion of
overlapping data from a single participant cohort. After
narrowing down the pool of possibly eligible studies, a total
of 18 studies with 951 participants, including 487 partic-
ipants with MA abuse/dependence and 464 normal com-
parison participants, were deemed eligible for inclusion.
The following information was extracted from each study:
(1) demographic variables (e.g., age and education); (2)
MA use characteristics (e.g., length of MA use and average
length of abstinence from MA); (3) cohort factors (e.g.,
comorbid substance use); (4) sample size; and (5) summary
statistics for the calculation of effect sizes. Two authors
(JCS and SPW) independently coded each study, and any
disagreements (e.g., due to a lack of clarity in studies
regarding participant characteristics) were resolved by
conference consensus.
Effect Size Calculation
For each neuropsychological test that was administered in
these 18 studies, an effect size and its variance were
calculated. The effect size used in this meta-analysis was
the standardized mean difference statistic (d). When
possible, this statistic was calculated as d=(Me −Mc)/Sp,
where M e and M c are the mean raw scores on a
neuropsychological test for the MA using and normal
comparison groups, respectively, and Sp is the pooled
within-group standard deviation. Where these data were
not reported, standardized mean difference effect sizes were
derived from t-values based on independent t-tests or F-
ratios from a two-group one-way analysis of variance
(Shadish et al. 1999). Hedges and Olkin’s (1985) correction
for small sample bias was applied to all effect sizes. The
variance for each d value was then calculated and used to
determine a weighting factor for the unbiased effect size.
We coded 157 effect sizes from the 18 studies, with a
range of 1 to 19 effect sizes and a mean of 8.72 (SD=7.38)
per study. When studies offered results from multiple
neurocognitive tests, the battery was independently
reviewed by the raters who classified the tests into domains.
In the event of disagreement, the raters determined the
domains for each test by consensus. These domains were:
Neuropsychol Rev (2007) 17:275–297
(1) simple reaction time; (2) attention/working memory
(e.g., Wechsler Adult Intelligence Scale, 3rd Edition
[WAIS-III] Digit Span, N-Back tasks); (3) executive
functions (e.g., WCST, Stroop Color-Word interference
condition); (4) learning (e.g., California Verbal Learning
Test [CVLT] trials 1–5); (4) memory (e.g., CVLT Delayed
Recall); (5) motor (e.g., Grooved Pegboard); (6) language
(e.g., Verbal Fluency, WAIS-III Vocabulary); (7) speed of
information processing (e.g., WAIS-III Digit Symbol); and
(8) visuoconstruction (i.e., Rey Complex Figure Copy). If
multiple subtests assessing the same cognitive construct
were reported (e.g., CVLT Delayed Free Recall and Cued
Recall), the subtest with the best evidence of construct
validity (based on consensus) was chosen for inclusion
(e.g., CVLT Delayed Free Recall). Table 1 lists the tests
that were included in each cognitive domain along with
their frequency. Measures for which low scores indicate
better performance were adjusted accordingly to assure that
a negative d indicated that the MA group performed worse
than the normal comparison group.
Statistical Analyses
A mixed-effects multivariate model was used in our meta-
analysis computations for a number of theoretical and
practical reasons (for a more thorough review of these
models, see Arends et al. 2003; Kalaian and Raudenbush
1996). Multivariate meta-analysis allows more than one
outcome per study (i.e., more than one test per neuro-
cognitive domain per study) by modeling the correlation
between multiple dependent variables in a study (i.e., by
modeling both fixed and random elements). In addition, the
model is flexible in allowing different numbers of effect
sizes per study. Furthermore, a multivariate mixed-effects
model for meta-analysis allows us to increase generaliz-
ability and make inferences about the population of studies
on the neurocognitive effects of chronic MA use, including
ones that differ from the included studies in such factors as
participants, MA use characteristics, and outcome mea-
sures, instead of solely allowing inferences about this
particular set of studies (a limitation of fixed effects
models).
A two-level mixed-effects model was used to examine
the variability of effect sizes between studies (random
factor) and the association between explanatory variables
(fixed factors) and effect sizes. We first tested the following
simple model without explanatory variables to estimate an
overall mean effect size and the between-study variance:

  
yij ¼ α þ uj þ eij uj  N 0; σ2u eij  N 0; s2ij
where yij refers to effect sizes (i) within studies (j), α is a
constant (i.e., the overall mean), uj are the study-level
Neuropsychol Rev (2007) 17:275–297 283

Table 1 Neuropsychological tests categorized by cognitive domain Table 1 (continued)

Domain Domain

Test k % Test k %

Attention/Working memory WAIS-III symbol search 1 5.26

CalCAP choice reaction time 2 11.11 WAIS-R digit symbol 2 10.53
RAVLT trial 1 1 5.56 Symbol digit 2 10.53
PASAT 1 5.56
WAIS-III letter-number sequencing 1 5.56 Verbal
Delayed match to sample 2 11.11 Letter fluency 6 54.55
Woodcock–Johnson backward digit span 2 11.11 Category fluency 2 18.18
WCST failure to maintain set 1 5.56 Shipley vocabulary 3 27.27
Continuous performance test RT 1 5.56
WMS-III letter-number sequencing 1 5.56 Motor skills
WMS-III visual memory span 1 5.56 Timed gait 1 16.67
N-Back (1 and 2) 2 11.11 Grooved pegboard 4 66.67
CVLT trial 1 1 5.56 Finger tapping 1 16.67
CANTAB spatial working memory 1 5.56
RVIP CANTAB 1 5.56 Reaction time
CalCAP simple reaction time 2 66.66
Abstraction/Executive functions Continuous performance test 1 33.33
CalCAP response reversal 1 3.23
Trail making test, part B 7 22.58 Visuoconstruction
Stroop interference 8 25.81 Rey complex figure copy 3 100.00
Category test 1 3.23
WCST 4 12.90 % = Percent of journal articles within each domain that included the
Shipley abstract thinking 2 6.45 neuropsychological test in the primary source, k = number of studies,
Response inhibition/switching task 1 3.23 CalCAP = California Computerized Assessment Package, RAVLT =
Rey Auditory Verbal Learning Test, PASAT = Paced Auditory Serial
Two-choice prediction task 1 3.23
Addition Test, WAIS = Wechsler Adult Intelligence Test, WCST =
Delay discounting task 2 6.45
Wisconsin Card Sorting Test, RT = Reaction Time, WMS = Wechsler
Stop signal reaction time 1 3.23 Memory Test, CVLT = California Verbal Learning Test, CANTAB =
Ruff figural fluency 1 3.23 Cambridge Automated Neuropsychological Assessment Battery, RVIP =
CANTAB extradimensional shift 1 3.23 Rapid Visual Information Processing, HVLT-R = Hopkins Verbal Learning
Stockings of Cambridge 1 3.23 Test-Revised, BVMT-R = Brief Visuospatial Memory Test-Revised, PAL =
Paired Associates Learning.
Memory
RAVLT delay 3 18.75
Rey complex figure recall 3 18.75
random effects, and eij is the effect-size level residual. s 2u is
HVLT-R delay 1 6.25
the variance parameter to be estimated for the between-
BVMT-R delay 1 6.25
Repeated memory word 2 12.50 study variance, and s2ij are the known conditional variances
Repeated memory picture 2 12.50 of the effect sizes. This analysis revealed that the overall
WMS-III logical memory 1 6.25 mean effect size was d=−0.558 (SE=0.034) and the
Babcock story 1 6.25 between-study variance estimate was 0.037 (SE=0.012,
CVLT delay 1 6.25 p<0.01), indicating that the variance between studies was
CANTAB PAL 1 6.25 significantly more than what could be explained solely by
sampling error alone.
Learning
HVLT-R total 1 14.29
The significance of the between-study variance prompt-
BVMT-R total 1 14.29 ed an exploration as to whether research group, neuro-
RAVLT total 3 42.86 cognitive test domain, average gender proportion, average
Babcock story immediate 1 14.29 education level, or comorbidity could account for some of
CVLT trial 5 1 14.29 the between-study variance. Because the relatively small
number of studies did not provide enough degrees of
Speed of information processing freedom, we could not jointly examine main or interaction
Trail making test, part A 7 36.84
effects. Therefore, the explanatory variables were examined
Stroop color/word 5 26.32
WAIS-III digit symbol 2 10.53 separately, and findings from these analyses should be
interpreted cautiously.
284 Neuropsychol Rev (2007) 17:275–297

To examine single explanatory variables, we fit the dependence and 445 normal comparison participants, with an
following model: average of 53.88 participants per study (range=19–130).
Table 2 presents the included participants’ demographic data
yij ¼ α þ βxij þ uj þeij  and MA use characteristics, and Table 3 presents a summary


uj  N 0; σ2u eij  N 0; s2ij of the studies used in the meta-analysis.

where β is the regression slope associated with the

explanatory variable.
All models were fit using program gllamm of Stata
version 9.2 (Grilli and Rampichini 2006; Rabe-Hesketh et
al. 2004; StataCorp 2006). The level 1 variances of the
effect sizes were fixed to the estimates of the conditional
effect-size variances.
Research Groups
Preliminary analyses indicated that effect size estimates
differed significantly between research groups (χ2(10)=30.1,
p<0.001), which reduced the between study variance to
0.026 (SE=0.023). Thus, differences between research
groups accounted for a significant proportion of between-
study differences, and the remaining between-group variance
was predominantly due to sampling error. Among the
research groups, effect sizes reported by one research group
(Gonzalez et al. 2007) were the largest overall (d=−1.37,
SE=0.248), and significantly larger than all but those of two
research groups (p<0.05). We cannot statistically address the
reasons for these differences, as analyses to test these
hypotheses were not possible due to diminishing degrees of
freedom. Several possibilities may account for this discrep-
ancy, including significant demographic differences (i.e., a
higher proportion of men in the MA group) and the high
prevalence of polysubstance use disorders in the MA group.
Due to these divergent study characteristics and the potential
influence of the unusually large effect sizes, we chose to
exclude this study from subsequent analyses and limit our
analyses to the remaining research groups. However, the
results outlined below did not change appreciably when this
study was included in analyses. This exclusion left 17 studies
containing 916 participants: 471 participants with MA abuse/
Results
Overall, significant differences in mean effect size estimates
were found across neurocognitive test domains (χ2 =23.6,
p<0.01). Figure 1 displays the mean weighted effect sizes
and 95% confidence intervals for each neurocognitive
domain across studies. The mean effect sizes for each
domain across the 17 studies ranged from −0.34 to −0.66.
With the exception of simple reaction time, the 95%
confidence interval surrounding the mean effect size for
each domain did not contain zero, and thus all effect sizes
in each domain were significantly different from zero. By
convention, d-values of 0.2, 0.5, and 0.8 correspond to
small, medium, and large effect sizes, respectively (Cohen
1988), although it should be noted that these categoriza-
tions are broad and do not necessarily signify levels of
practical significance. As illustrated in Fig. 1, the largest
effect sizes were seen in the domains of learning (d=−0.66),
executive functions (d=−0.63), and memory (d=−0.59),
which were all in the medium-to-large range. Effect sizes
of a medium magnitude were observed in the domains of
speed of information processing (d=−0.52) and motor
skills (d=−0.48), with slightly smaller effects in attention/
working memory (d=−0.39), visuoconstruction (d=−0.37),
and language (d=− 0.34). Visual inspection of a funnel
plot (Duval and Tweedie 2000) showed no significant
evidence of publication bias.
Demographic Variables
Analyses examining the associations between study char-
acteristics and effect size estimates were performed with a
number of explanatory variables, including participant

Table 2 Participants’ demographic data and methamphetamine use characteristics

k MA group NC group

N Mean (SD) Range N Mean (SD) Range

Age 17 471 34.62 (7.83) 31.1–41.4 425a 32.75 (8.44) 25.7–38.7

Education 15 443 12.47 (1.59) 10–13.7 390 13.87 (1.69) 12.8–15.3
% male 17 471 65.21 36.1–100 445 61.8 33.3–100
Length of MA use (months) 14 395 123.58 (60.62) 30.7–207
Length of MA abstinence (days) 12 395 294.89 (359.37) 0–1241

k=Number of studies, MA = methamphetamine, N=number of participants, NC = normal comparison.

a
k=16.
Neuropsychol Rev (2007) 17:275–297 285

Table 3 Summary of studies used in the meta-analysis

Authors Year MA group NC group NP domains assessed

(N) (N)

Chang, Ernst, Speck, et al. 2002 18 20 Attention/WM, simple RT, executive functions
Chang, Cloak, Patterson, 2005 43 28 Attention/WM, executive functions, learning, memory, motor, verbal, SIP,
et al. visuoconstruction
Gonzalez, Bechara, and 2007 16 19 Attention/WM, executive functions
Martina
Hoffman, Moore, Templin, 2006 41 41 Executive functions, learning, memory, motor, verbal, SIP,
et al. visuoconstruction
Johanson, Frey, Lundahl, 2006 16 18 Attention/WM, executive functions, learning, memory, motor, verbal, SIP
et al.
Kalechstein, Newton, and 2003 27 18 Attention/WM, executive functions, learning, memory, verbal, SIP,
Green visuoconstruction
Kim, Lyoo, Hwang, et al. 2005 33 21 Executive functions
London, Berman, Voytek, 2005 17 16 Attention/WM, simple RT
et al.
Monterosso, Ainslie, Xu, 2006 12 17 Executive functions
et al.
Monterosso, Aron, 2005 11 29 Executive functions
Cordova, et al.
Newton, Kalechstein, 2004 9 10 Attention/WM, simple RT
Hardy, et al.
Paulus, Hozack, Frank, 2003 14 14 Executive functions
et al.
Rippeth, Heaton, Carey, 2004 47 60 Attention/WM, executive functions, learning, memory, motor, verbal, SIP
et al.
Salo, Nordahl, Moore, et al. 2005 34 20 Executive functions
Salo, Nordahl, Natsuaki, In 36 16 Executive functions
et al. press
Salo, Nordahl, Possin, et al. 2002 8 12 Executive functions
Simon, Domier, Carnell, 2000 65 65 Attention/WM, executive functions, memory, verbal, SIP
et al.
Simon, Domier, Sim, et al. 2002 40 40 Attention/WM, executive functions, memory, verbal, SIP

MA = methamphetamine, N=number of participants, NC = normal comparison, NP = neuropsychological, RT = reaction time, SIP = speed of
information processing, WM = working memory.
a
Study excluded from final analyses.

demographics (e.g., mean age, mean years of education,
gender proportion) and drug use characteristics (e.g.,
average length of abstinence from MA, exclusion of
comorbid drug use). Including gender in a model with the
neurocognitive test domains showed that for every 1%
increase of men in the MA group, the magnitude of the
effect size estimate (i.e., the difference between the groups)
increased by −0.01 (b b =−0.01; p<0.001), indicating greater
performance discrepancy between the groups. Similarly,
with every 1% increase of men in the normal comparison
group, the magnitude of the effect size estimate became
slightly more positive (b b =+0.01; p<0.01). Results also
revealed that for each unit increase (i.e., year) in the
average age of the MA group in a study the magnitude
of the effect size estimate increased by −0.04 (b b =−0.04;
p<0.05). Similarly, with increasing age in the normal
comparison group, the magnitude of the effect size became
more positive at a trend level, indicating less performance
difference between the groups (bb =+0.05; p=0.09). Finally,
as a majority of studies (76%) did not match MA and
normal comparison groups on education (see Table 2), a
variable representing the raw difference in years of
education between these groups was created for each study
to examine the influence of this difference on the
magnitude of effect size. This analysis revealed that there
was not a significant influence of educational discrepancy
on study effect sizes (b
b =0.06; p=0.13).
Methamphetamine Use Variables
Analyses of MA use variables revealed that neither average
length of abstinence from MA nor average duration of
lifetime MA use had an appreciable influence on the
magnitude of the effect size (ps>0.10). We also created a
286
Fig. 1 Mean effect sizes and
95% confidence intervals for
each neurocognitive test do-
main. *k=18, mean=grand
mean effect size, LB = lower
bound, UB = upper bound,
SIP = speed of information
processing, WM = working
memory, CI = confidence
interval
dichotomous variable to indicate whether studies had
excluded individuals from the MA group with prior
substance-related disorders other than MA (excluded,
k=6; did not exclude, k=11). This variable also exhibited
no significant change on the magnitude of effect sizes
(p>0.10).
Discussion
A wealth of animal and human literature implicates chronic
MA use in metabolic and neurotransmitter abnormalities,
structural brain alterations, and deficits in everyday func-
tioning, which are most often attributed to neurotoxicity in
dopaminergic and serotonergic fronto-striatal-thalamo-
cortical circuits. It has been hypothesized that these
alterations may also contribute to significant neuropsycho-
logical impairment. The results of this meta-analysis gener-
ally support this contention, revealing an overall medium
effect size, which was somewhat greater than the generally
small effects reported in meta-analyses of the cognitive
sequelae of cocaine (d=−0.35; Jovanovski et al. 2005) and
marijuana (d=−0.15; Grant et al. 2003). Significant deficits
of a medium magnitude were observed in several different
cognitive processes dependent upon frontostriatal and limbic
circuits, including episodic memory, executive functions
(e.g., response inhibition, novel problem solving), complex
information processing speed, and psychomotor functions.
Slightly smaller effects were also evident in attention/
working memory, language, and visuoconstruction.
Neuropsychol Rev (2007) 17:275–297
Cognitive and Motor Processes Affected
in Methamphetamine Users
Of particular interest, MA use was associated with marked
detrimental effects on episodic memory, which is also
among the most susceptible cognitive functions to MA
relapse (Simon et al. 2004). Interpretation of the medium-
to-large effects in MA users is complicated by the fact that
episodic memory is a multifactorial ability (e.g., encoding,
consolidation, and retrieval) subserved by multiple brain
regions (e.g., frontal and temporal systems). Nevertheless,
we hypothesize that the MA effect on episodic memory is
driven by deficient executive aspects of encoding and
retrieval, likely related to MA-associated neurotoxicity in
the frontostriatal circuits. In support of this hypothesis, a
slightly larger effect was observed on learning as compared
with delayed recall, suggesting that impairment in learning
(and perhaps retrieval) rather than consolidation (i.e.,
retention) difficulties underlie the overall episodic memory
deficit. To this end, Woods et al. (2005b) recently
demonstrated impairment in overall learning, free recall,
utilization of semantic clustering strategies, repetitions, and
non-semantically related intrusion errors in 87 persons with
MA dependence, who were nevertheless normal in reten-
tion and recognition discrimination. Moreover, Volkow
et al. (2001c) showed associations between reduced striatal
dopamine terminal function and deficits in list learning and
recall in MA users. Taken together, these cognitive and
neurobiological data support the notion that MA use
disrupts the organizational and tactical components of
Neuropsychol Rev (2007) 17:275–297
memory encoding and retrieval that are dependent upon
frontostriatal networks, although the potential contribution
of medial temporal abnormalities on MA-associated epi-
sodic memory impairment cannot be entirely dismissed
(Thompson et al. 2004). Given the magnitude of the
learning and memory deficit in chronic MA users and its
apparent relationship to frontostriatal circuits, exploration
of other aspects of episodic memory (e.g., prospective
memory), perhaps as well as nondeclarative (e.g., proce-
dural) memory will be important areas for future research.
Also supporting the hypothesized strategic contribution
to episodic memory deficits evident in MA abusers, the
current meta-analysis revealed evidence of significant
executive dysfunction in this population. Based on the tests
that comprised this domain (e.g., Stroop Color-Word
Interference, WCST perseverations, and Trail Making Test,
Part B), one might argue that cognitive set shifting and,
perhaps to a greater extent (Salo et al. 2005), response
inhibition may be particularly affected in MA users.
Although executive functions are subserved by distributed
neural networks, research generally supports their strong
reliance upon the frontal cortex and frontostriatal systems
(e.g., Stuss and Alexander 2007). In MA users specifically,
WCST errors are associated with lower frontal grey matter
density (Kim et al. 2006), as well as hypometabolism (Kim
et al. 2005) and lower fractional anisotropy (Chung et al.
2006) in the frontal white matter. Furthermore, recovery in
DAT binding after MA abstinence is related to reductions
in WCST errors (Chou et al. 2007). Interestingly, deficits in
selective inhibition in MA abusers may also be related to
frontal systems dysregulation, as evidenced by its associa-
tion with low anterior cingulate levels of N-acetyl aspartate
(NAA), a brain metabolite regarded as a marker of neuronal
integrity (Salo et al. 2007).
An important future direction for executive function
research in MA dependent individuals is examination of
impulsivity and decision-making abilities. Similar to other
stimulant using populations (e.g., Coffey et al. 2003), MA
dependent individuals evidence risky decision-making and
impulsivity, as assessed by their sensitivity to delayed
versus immediate rewards (Hoffman et al. 2006; Monterosso
et al. 2006), selection of disadvantageous and/or impulsive
choices when compared to normal comparison participants
(Gonzalez et al. 2007), and self-report of impulsive
behavior patterns (Semple et al. 2004, 2005). In fact,
decision-making impairment may be linked to the execu-
tive aspects of working memory deficits (Bechara and
Martin 2004), which were also evident in this meta-
analysis of MA users. In combination, the decision-making
and working memory deficits may predispose MA users
toward “real world” risky behaviors, such as needle
sharing or unprotected sex, that increase the risk of HIV
and HCV transmission, which (as discussed below) are
287
associated with poorer medical, neuropsychological, and
psychosocial outcomes. Indeed, it has been hypothesized
that MA dependent individuals may evidence fundamental
dysfunction in decision-making, including a predilection
for stimulus-driven behavior (Paulus et al. 2002). This
hypothesis is bolstered by findings that hypoactivation in
prefrontal, parietal, and insular cortex during a decision-
making task, potentially signifying reduced processing
resources, predicted incident relapse to MA (Paulus et al.
2005).
A number of early preclinical studies reported pro-
nounced motor effects with high doses of MA, which
initially raised fears about the widespread prevalence of
gross motor abnormalities in MA abusers, including
parkinsonism. However, the prevalence of severe move-
ment abnormalities in both clinical practice and in the
neuropsychological literature has been less than what might
be expected given the vulnerability of the striatum to MA-
associated neurotoxicity (Caligiuri and Buitenhuys 2005;
Moszczynska et al. 2004). The current meta-analysis
revealed medium effect sizes for basic motor functioning
(e.g., fine-motor speed and coordination) and information
processing speed, with the latter domain being of a slightly
greater magnitude. One possible explanation for the minor
discrepancy between these domains is that subtle motor
difficulties will be more prominent on psychomotor tasks
that require higher-level cognitive abilities (Caligiuri and
Buitenhuys 2005). In support of this contention, the Digit
Symbol test was generally associated with considerably
larger effect sizes than either TMT A or the noninterference
trials of the Stroop Test within the processing speed
domain, although a direct statistical comparison was not
possible. Furthermore, this hypothesis is consistent with
reports of more pronounced dopaminergic depletion in
cognitive (i.e., caudate) versus motor (i.e., putamen)
regions of the striatum of MA users (Moszczynska et al.
2004). Given the relatively smaller putamen effects, use of
more sophisticated and sensitive neuromotor paradigms
(e.g., motor programming, velocity scaling, forced steadi-
ness, and contraction time) may be useful in demarcating
motor abnormalities in MA users (Caligiuri and Buitenhuys
2005).
Clinical descriptions of patients dependent on MA
frequently highlight the apparent inattentiveness and dis-
tractibility of this population. In support of such observa-
tions, this meta-analysis suggests that MA dependent
individuals demonstrate impairment on laboratory tasks of
attention and working memory. It has been hypothesized
that this effect may depend on the type of task employed,
such that basic attentional and processing abilities (e.g.,
digit recognition) are unaffected (Chang et al. 2002), with
more pronounced deficits emerging with increasingly
complex processing demands, especially when working
288
memory and decision-making abilities are taxed (e.g., N-
back task). Sustained attentional abilities may also be
particularly susceptible to MA, perhaps related to MA-
associated neuronal damage in the anterior cingulate and
insular cortices (London et al. 2005).
The moderate language impairment demonstrated in MA
users may be partially explained by the information
processing speed and executive deficits described above.
The language domain was primarily comprised of measures
of verbal fluency, which require the rule-guided generation
of words under time constraints (typically 60 s). As such,
normal fluency performance taxes the integrity of the
lexicosemantic memory stores, as well as executive and
speeded processes, such as rapid, constrained search,
retrieval, switching, and production abilities. In light of
the prominent frontostriatal neurotoxicity of MA, one might
hypothesize that the apparent verbal fluency deficit reflects
executive dyscontrol of search and retrieval strategies and/
or slowed information processing, rather than degraded
lexicosemantic memory stores, as has been observed in
other clinical populations with frontostriatal involvement
(e.g., Troyer et al. 1998; Woods et al. 2004). Furthermore,
considering the motor and executive deficits apparent in MA
users, one possible direction for future research is examina-
tion of action (verb) fluency, which prior research shows to
be particularly sensitive to frontal systems pathology (Piatt
et al. 1999a, b), perhaps reflecting inefficiencies engaging
motor representations (Woods et al. 2005a).
Although visuospatial abilities have not been extensively
studied in chronic MA users, the current meta-analysis found
a small-to-medium effect size within the visuoconstruction
domain. Unfortunately, this domain consisted exclusively of
effect sizes from studies that used the copy trial from the Rey
Complex Figure (e.g., Kalechstein et al. 2003), which limits
the conclusions that can be drawn from this finding.
Nevertheless, the posterior parietal cortex and parieto-
striato-frontal circuits play an important role in spatial
cognition (Lawrence et al. 2000), including visuoconstruc-
tional abilities. In this regard, MA users show reduced
relative regional cerebral blood flow (Chang et al. 2002) and
greater volumes (Jernigan et al. 2005) in the parietal cortex.
Yet whether the visuoconstructional deficits observed herein
are related to perceptual organizational impairment, execu-
tive dysfunction (e.g., planning), or constructional dyspraxia
remains to be determined. Future research may examine
these, along with other aspects of spatial cognition (e.g.,
mental rotation) in MA users, particularly with respect to
their cognitive and neurobiological mechanisms.
Demographic Factors
Analyses of demographic explanatory variables revealed
that gender had a relatively minor, but nonetheless
Neuropsychol Rev (2007) 17:275–297
significant, influence on the magnitude of the MA-
associated effect sizes. Specifically, a larger proportion of
men in the MA sample was associated with greater overall
levels of neuropsychological impairment. Although this
effect was generally small (b b =−0.01), it should be noted
that a 50% change in the gender composition of an MA
group would be associated with a difference in the effect
size of 0.5 standard deviation units. Moreover, these data
raise a number of interesting hypotheses regarding gender
and MA-associated neurotoxicity. For example, this finding
may reflect differential CNS effects of MA use in men,
which is supported by prior studies showing including
reduced fractional anisotropy in the frontal cortex (Kim
et al. 2006) and correlations between frontal hypometabo-
lism and WCST errors (Kim et al. 2005) in male, but not
female MA users. To this end, animal models suggest that
the gonadal steroid hormone, estrogen, may be protective
against frontostriatal dopamine depletion associated with
MA use (see Dluzen and McDermott 2006 for a review).
Another possible explanation is that men may use MA
more frequently or in greater amounts (Brecht et al. 2004),
leading to more severe addiction and increased CNS
effects. Men who use MA also have a higher prevalence
of comorbid substance-related disorders (e.g., alcohol),
antisocial personality disorder, and closed head injuries,
which may also adversely impact cognition and should be
considered in future studies of CNS functioning in MA
users.
Several other demographic factors deserve consideration
in interpreting these data. Older age in the MA sample was
associated with a modest increase in cognitive effect size;
practically speaking, an increase of 12 years in the age of
an MA group would result in a half standard deviation
change in the effect size. Normal aging is associated with
structural and functional changes in prefrontal systems
(e.g., Mielke et al. 1998), which are often accompanied by
cognitive decline (e.g., Craik and Bialystok 2006), and
therefore it may be that normal aging leads to additive
neural and cognitive effects in MA users. However, one
notable limitation is that participants in this meta-analysis
were generally young to middle-aged, with the largest mean
age of 41.4 years. It is also possible that older MA
dependent individuals had been using MA for a longer
period of time, although length of use was not correlated
with the magnitude of effect in our analyses. Despite the
relatively lower educational attainment of the MA sample
relative to the comparison group, neither education nor the
between-group discrepancy in education had a significant
influence on the effect size estimates. The possibility that
premorbid neurocognitive differences may exist between
MA using and healthy comparison individuals should also
be considered. In particular, substance users may evidence
poorer intellectual abilities, or certain cognitive factors may
Neuropsychol Rev (2007) 17:275–297
predispose individuals to seek out or abuse substances
(Block et al. 2002). However, data regarding these types of
factors (e.g., SES, premorbid IQ, and ethnicity) were not
consistently reported across studies and therefore could not
be considered as possible explanatory variables. Accordingly,
future study groups (and relevant MA subgroups) should be
demographically comparable and neuropsychological test
selection might give special consideration to measures with
demographically-adjusted normative standards.
Methamphetamine Use Factors
It remains unresolved whether the extent of neuropsycho-
logical impairment is related to MA use characteristics
(e.g., abstinence, lifetime quantity of consumption, and
route of use). A few studies have reported that rates of
cognitive impairment correlate with frequency (Simon et al.
2000) or amount (Monterosso et al. 2005) of MA use, while
others have found no associations with measures assessing
the severity of MA dependence or MA use frequency,
amount, or duration (Chang et al. 2002; Hoffman et al.
2006; Johanson et al. 2006; Rippeth et al. 2004). This
ambiguity may be due to the unreliability of self-report
substance use data or may reflect the influence of other,
often unmeasured factors (e.g., psychiatric symptomatolo-
gy). It may also reflect the divergence in studies regarding
the actual MA use variables that are collected and/or
reported; for example, some studies report average amount
of MA administered per day, while others report days per
week of use. Unfortunately, the current meta-analysis cannot
shed much light on this issue, due to inconsistent (and often
incomplete) reporting of MA use characteristics across
studies.
Although still limited, sufficient data were available on
reported length of abstinence and duration of MA use,
which our analyses showed did not correspond to neuro-
psychological impairment. This was somewhat surprising
because, as mentioned above, a number of studies have
shown relationships between duration of MA use and
extent of dopaminergic dysfunction (Sekine et al. 2001,
2003; Volkow et al. 2001c), as well as at least partial
recovery of dopamine terminal function, brain metabolism,
and rCBF with extended abstinence (e.g., Hwang et al.
2006; e.g., Volkow et al. 2001b; Wang et al. 2004).
However, it is still unclear whether this recovery results in
any substantive changes in neuropsychological function,
daily living skills, and other functional outcomes. Previous
studies suggest that cognitive deficits extend into absti-
nence, are gradual to recover, and may even become worse
with initial abstinence when compared to continuing users.
In early stages of abstinence, deficits are, at the least,
equivalent to those seen in currently abusing individuals,
especially in the domains of episodic and working memory
289
(Hoffman et al. 2006; Kalechstein et al. 2003; Simon et al.
2004; cf. Chang et al. 2005a, b). Volkow et al. (2001b)
found that psychomotor and memory deficits persisted for
at least 9 months after last MA use, albeit in a less severe
form, despite a significant degree of recovery in dopamine
terminal function. Longer periods of abstinence may lead to
further recovery of cognitive function, although some
deficits still remain, most notably in episodic memory and
cognitive inhibition (Johanson et al. 2006). Nevertheless,
while this meta-analysis found that neither average length
of abstinence nor duration of MA use significantly changed
the effect sizes observed across studies, it did not allow for
more fine-grained analyses of abstinence or recovery (e.g.,
subgroup analyses). Large-scale, longitudinal cohort studies
are needed to examine whether sustained abstinence is
associated with full or partial recovery of cognitive
functioning in persons with MA dependence.
Clinical Relevance
Regarding the possible clinical relevance of this study, MA-
associated cognitive impairment, and particularly the
medium-to-large negative effect sizes in episodic memory
and executive functions, may influence daily functioning
outcomes, as has been shown in both normal and clinical
populations (e.g., HIV infection; Heaton et al. 2004). To our
knowledge, however, only one study to date has examined
the possible impact of MA-associated cognitive impairment
on everyday functioning (Sadek et al. in 2007), revealing
that MA dependence is associated with elevated cognitive
complaints and self-reported dependence in IADL (e.g.,
preparing meals, managing money). IADL impairments
were strongly associated with depressive symptoms, where-
as cognitive complaints were related to both depressive
symptoms and objective neuropsychological impairment
(Sadek et al. in 2007). Of additional interest is the possible
link between cognitive impairment and poor treatment
outcomes in MA users, again, especially in terms of
executive and memory deficits, which are theorized con-
tributors to the maintenance of drug-seeking behaviors
(Bechara and Damasio 2002). Neuropsychological func-
tioning plays an important role in state-of-the-art MA abuse
treatments, which commonly involve cognitively-based
interventions (e.g., developing strategies to avoiding use
and prevent relapse; Schuckit 1994), as well as targeted
pharmacotherapies (Meredith et al. 2005). In fact, substance
users with neuropsychological deficits are more likely to
achieve poorer treatment outcomes, including high rates of
program rule violations, poor cognitive skill acquisition,
and premature drop-out (Aharonovich et al. 2003; Fals-
Stewart 1993). Clearly, additional research is needed to
better understand the effects of MA-associated neuropsy-
chological impairment on these important functional out-
290
comes. In addition, given evidence that cognitive impairment
is an important feature of chronic MA use, future studies of
MA treatment efficacy should consider including neuropsy-
chological functioning as an outcome variable of interest.
Medical and Psychiatric Comorbidities
Interpretation of the etiology of the neuropsychological
deficits in MA users is confounded by the prevalence of
numerous premorbid (e.g., ADHD) and incident comorbid
(e.g., cardiovascular disease) conditions, which make it
difficult to ascribe the observed impairment exclusively to
MA use. Comorbid neuromedical (e.g., cardiovascular
disease) conditions may exacerbate MA-associated cogni-
tive impairment but were not sufficiently characterized
across studies to examine their statistical effects on the
meta-analytic results. For example, MA users are at
increased risk of cardiovascular disease (e.g., hypertension),
including hemorrhagic and ischemic stroke (Perez et al.
1999). Furthermore, HIV infection is associated with
additive neural injury (Chang et al. 2005b; Taylor et al.
2007) and neuropsychological impairment (Carey et al.
2006; Rippeth et al. 2004) in MA dependent individuals.
HCV infection is another important medical factor that is
common in MA users and is known to carry CNS effects
(Forton et al. 2003; Hilsabeck et al. 2003). In fact, HCV is
an independent predictor of white matter injury (i.e., lower
NAA; Taylor et al. 2004) and cognitive impairment (i.e.,
learning, executive functions, and motor skills) in MA users
(Cherner et al. 2005; Letendre et al. 2005). Several
psychiatric factors (e.g., psychosis, major depressive disor-
der, bipolar disorder, and ADHD) that can affect cognitive
functioning frequently co-occur in MA dependent popula-
tions. For example, ADHD is associated with greater
psychiatric symptom severity among MA users (e.g., Jaffe
et al. 2005) and may worsen deficits in language, working
memory, and executive functions (Jaffe et al. 2005; Sim
et al. 2002). Moreover, both mood (London et al. 2004) and
psychotic (Sekine et al. 2002) symptoms are associated
with cerebral metabolism abnormalities in MA users,
raising questions as to whether these psychiatric comorbid-
ities are associated with greater prevalence and severity of
cognitive impairment. Future neuropsychological studies of
MA dependence are encouraged to characterize their
cohorts on these psychiatric and neuromedical co-factors
and carefully examine their potential effects on cognitive
outcomes. Relatedly, future studies should consider the
contribution of various host genetic factors, such as
catechol-O-methyltransferase (COMT) to the expression
of MA-associated neuropsychological impairment (see
Goldberg and Weinberger 2004).
It is also unknown whether the abuse of other substances
(e.g., alcohol or cocaine) imparts additive risks of neural
Neuropsychol Rev (2007) 17:275–297
injury and neurocognitive impairment in persons with MA
dependence. This is an important question because individ-
uals rarely use MA in isolation and many illicit (and licit)
drugs are associated with cognitive deficits. For example,
although between 20 and 35% of chronic MA users are also
dependent on alcohol (e.g., Simons et al. 2005), we are
unaware of any studies that have prospectively examined
the additive effects of these comorbid neurotoxic substances
on CNS functioning specifically in MA dependent indi-
viduals. Approximately 15% of MA users have comorbid
marijuana abuse (Rippeth et al. 2004), which may not
exacerbate MA-associated neuropsychological impairment
(Gonzalez et al. 2004), but could further compromise
cerebral glucose metabolism (Voytek et al. 2005). Another
commonly used drug, nicotine (e.g., Monterosso et al.
2005), is hypothesized to be protective against the
neurotoxic effects of MA (Maggio et al. 1998) and may
even lessen MA cravings (Hiranita et al. 2006). Yet no
studies have thoroughly examined the effects of nicotine
on cognitive functioning or neurobiological markers of
cerebral function in human MA abusers. Unfortunately, our
meta-analysis was unable to provide any insights into the
effects of current substance comorbidities, since the studies
examined were not designed to answer such questions
(e.g., most excluded persons with current comorbid non-
MA substance abuse). A post-hoc analysis demonstrated
that the presence of prior non-MA substance use disorders
did not significantly change the effect size estimates, which
may be attributable to inconsistencies in the prevalence of
past substance-related disorders across studies. Thus, well-
controlled, prospective studies are needed to adequately
examine the combined or interactive risk of comorbid use
of substances other than MA.
Summary and Conclusions
Illicit MA use has grown increasingly prevalent over the
past 10 years and is now linked to a host of adverse
psychosocial (e.g., unemployment), psychiatric (e.g., de-
pression), and medical (e.g., cardiovascular) complications.
Methamphetamine is also neurotoxic, and chronic use is
associated with detrimental effects on neurotransmission
(e.g., dopamine depletion), as well as the neural structure
and functional integrity of limbic and frontostriatal circuits.
In addition, the results of the present meta-analysis indicate
that, at the group level, MA dependence is associated with
overall moderate neuropsychological impairment. Effect
size estimates of the MA literature revealed broadly
medium group differences across several domains of
functioning, with the largest impairments in episodic
memory, executive functions, and information processing
speed, which were accompanied by slightly smaller impair-
ments in motor skills, language, and visuoconstructional
Neuropsychol Rev (2007) 17:275–297
abilities. Considering the neural systems most susceptible
to MA and their known cognitive sequelae, this pattern of
neuropsychological impairment is most consistent with a
frontostriatal neuropathogenesis, along with perhaps more
modest contributions from neurotoxicity in the posterior
parietal and medial temporal cortices. Candidate mecha-
nisms for MA-associated neuropsychological deficits in-
clude both necrotic and apoptotic etiologies resultant from
such factors as cerebrovascular injury, oxidative stress,
gliosis, and neuritic growth. Analysis of possible moderat-
ing factors revealed a potential interplay between MA
dependence and demographic factors (i.e., male gender and
older age) in the expression of cognitive deficits. Although
there was no evidence supporting the moderating effects of
MA use characteristics (i.e., length of abstinence and
duration of use) or remote non-MA substance-related
disorders on the observed neuropsychological effect sizes,
interpretation of these analyses is tempered by methodo-
logical limitations of the existing literature. Understanding
the etiology of the cognitive deficits in chronic MA users is
also complicated by numerous common psychiatric (e.g.,
ADHD and depression) and medical (e.g., HIV and HCV
infection) cofactors with known CNS effects, which will be
critical targets for future neuropsychological and neurobi-
ological research. Despite these interpretive caveats, the
nature and magnitude of cognitive deficits associated with
chronic MA use ostensibly increase the risk of poorer
health outcomes, including dependence in daily functioning
(e.g., unemployment), high-risk behaviors, and treatment
nonadherence and relapse. Accordingly, consideration of
neuropsychological functioning has clear implications for
the clinical management of persons with MA dependence.
Acknowledgement The research described was supported by
DA12065 and MH62512 from the National Institutes of Health. The
views expressed in this article are those of the authors and do not
reflect the official policy or position of the Department of the Navy,
Department of Defense, or the United States Government.
The authors thank Drs. Raul Gonzalez and John Monterosso for
kindly providing supplementary data for analyses.
The following studies were included in the meta-analysis: Chang
et al. 2002, 2005a; Gonzalez et al. 2007; Hoffman et al. 2006; Johanson
et al. 2006; Kalechstein et al. 2003; Kim et al. 2005; London et al. 2005;
Monterosso et al. 2005, 2006; Newton et al. 2004; Paulus et al. 2003;
Rippeth et al. 2004; Salo et al. 2002, 2005, 2007; Simon et al. 2000,
2004.
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