Tag: ADHD

Shaheen E. Lakhan & Annette Kirchgessner
Global Neuroscience Initiative Foundation, Los Angeles, California

disorder, oppositional-de´¼üant disorder, antisocial person-
ality, substance use, and anxiety) (Faraone et al. 1997;
Rasmussen and Gillberg 2000; Kollins et al. 2005; Bieder-
man et al. 2006). However, early treatment may decrease
negative outcomes of ADHD including the rate of con-
duct disorder and adult antisocial personality disorder
(Dopheide and Pliszka 2009).
There are both pharmacological and nonpharmacologi-
cal (e.g., cognitive behavioral therapy [CBT]) treatments
of ADHD. Stimulants, such as methylphenidate (MPH;
Ritalin and Concerta) and dextroamphetamine-AMP
(d-AMP; Adderall) are the most common pharmacologic
treatments (The MTA Cooperative Group 1999) and
abundant data support the potentially positive effects of
prescription stimulants for the majority of children, ado-
lescents, and adults with ADHD. Experts estimate that
approximately 60% of children with ADHD are treated
with prescription stimulants (Center for Disease Control
and Prevention 2005a); therefore, approximately three
million children in this country take stimulants for prob-
lems with focusing. At the same time, many studies have
revealed the numerous adverse effects associated with pre-
scription stimulants when they are used inappropriately.
Stimulants are classi´¼üed as Schedule II drugs (i.e., pro-
viding positive medicinal effects but also considerable
abuse potential). The nonmedical use of prescription
stimulants represents the second common most form of
illicit drug use in college, second only to marijuana use
(Johnston et al. 2004). Indeed, many consider stimulants
ÔÇô whether obtained by prescription or illicitly ÔÇô a conve-
nient option to improve performance or to induce
euphoria (get ÔÇ£highÔÇØ). Major daily newspapers such as
The New York Times have reported a trend toward grow-
ing use of prescription stimulants, commonly called
ÔÇ£smart pills,ÔÇØ by high school and college students for
enhancing school or work performance (Jacobs 2005).
Unfortunately, media reports appear to condone this
behavior as 95% of articles mentioned at least one possi-
ble bene´¼üt of using a prescription stimulant for neuroen-
hancement, but only 58% mentioned any risks/side effects
(Partridge et al. 2011). Stimulant misuse is often pre-
dicted on individualsÔÇÖ misconceptions or simple lack of
knowledge of associated risks.
This review discusses recent studies regarding the use
and misuse of stimulants among high school and college
students, including athletes, with and without ADHD.
Given the widespread belief that prescription stimulants
are ÔÇ£smart pills,ÔÇØ we address if these drugs actually
enhance cognition in a healthy individual. Athletes may
see stimulants as a way to help maintain physical ´¼ütness
for their competitive sport or to improve their concentra-
tion. Finally, we elaborate on the long-term effects of
chronic stimulant use. Addiction and tolerance are major
concerns, as are psychosis and cardiovascular effects. Sur-
prisingly, these associated risks of stimulant misuse are
not frequently addressed in the media and literature.
Clearly, the widespread misuse of prescription stimulants
represents an important public health issue faced by stu-
dents, school of´¼ücials, health centers, and parents.
Methods
This review was initiated with a PubMed search of the
US National Library of Medicine with combinations of
the following key words: ÔÇ£Adderall,ÔÇØ ÔÇ£amphetamine,ÔÇØ
ÔÇ£methylphenidate,ÔÇØ ÔÇ£dexamphetamine,ÔÇØ ÔÇ£ADHD,ÔÇØ ÔÇ£mis-
use,ÔÇØ ÔÇ£illicit use,ÔÇØ ÔÇ£non-prescription use,ÔÇØ ÔÇ£non-medical
use,ÔÇØ ÔÇ£diversion,ÔÇØ ÔÇ£students,ÔÇØ and ÔÇ£athletes.ÔÇØ A review of
all titles was conducted to include only pertinent publica-
tions. A hand search of psychiatry journals was performed
and reference lists from relevant studies were searched.
Prescription stimulant use in ADHD
It is estimated that about two-thirds of the children diag-
nosed with ADHD receive pharmacological treatment
(Centers for Disease Control and Prevention 2010) and
the majority of medications used are stimulants (Center
for Disease Control and Prevention 2005b). The pre-
scribed use of stimulant medications to treat ADHD in
children age 18 and younger rose steadily from 1996 to
2008, from an estimated 2.4% in 1996 to an estimated
3.5% of US children in 2008 (Zuvekas and Vitiello 2011).
Overall, prescription stimulant use among 6- to 12-year-
olds is highest, going from 4.2% in 1996 to 5.1% in 2008;
however, the fastest growth rate occurred among
13ÔÇô18 year olds, going from 2.3% in 1996 to 4% in 2008.
Prescription stimulant use remained consistently low in
the West than in other US regions and in lower racial/
ethnic minorities.
MPH and d-AMP are the most widely used prescrip-
tion stimulants approved by the US Food and Drug
Administration (FDA) for the treatment of ADHD. MPH
is a short-acting stimulant drug. Generic MPH is available
in many forms, and several versions of the long-acting
MPH have been introduced, with Concerta getting the
largest share of the market. According to the U.S. Drug
Enforcement Administration (DEA), MPH has been the
fourth most prescribed controlled substance in the United
States since 2003, with over 58,000 Americans purchasing
MPH in 2006 (Department of Justice: Drug Enforcement
Administration 2008). Both the production and prescrip-
tion of MPH has risen as the diagnosis of ADHD has
concurrently increased. In addition, with the realization
that ADHD is a lifelong disorder, MPH has become more
commonly prescribed for adolescents and adults, and
662 ?¬ 2012 The Authors. Published by Wiley Periodicals, Inc.
Stimulants in Individuals With and Without ADHD S. E. Lakhan & A. Kirchgessnertreatment duration has increased (Horrigan 2001). Both
MPH and d-AMP are ef´¼ücacious and well-tolerated medi-
cations and remain the ´¼ürst choice for short duration
management in adolescent and adult ADHD (Faraone
and Glatt 2010). Although the precise mechanisms under-
lying the action of these medications are not completely
understood, they appear to increase the availability of
dopamine, which could account for their therapeutic
effects.
Although ADHD is a multifactorial disorder, disrupted
dopamine (DA) neurotransmission plays an important
role in its pathophysiology. In addition, polymorphisms
in the dopamine D1 receptor (DRD1) are associated with
the disorder (Misener et al. 2004). MPH and d-AMP both
enhance DA signaling in the brain. MPH increases DA by
blocking dopamine transporters (DATs) and AMP by
releasing DA from the nerve terminal using the DAT as
carrier (Kuczenski and Segal 1997). In healthy controls
and in adolescents and adults with ADHD (Rosa-Neto
et al. 2005; Volkow et al. 2007), MPH signi´¼ücantly
increased DA in the ventral striatum (VS) (Volkow et al.
2012), a crucial brain region involved with motivation
and reward (Wise 2002). Moreover, intravenous MPH-
induced increases in DA in the VS were correlated with
improvement in symptoms of inattention after long-term
oral MPH treatment. Historically, the core feature of
ADHD has been characterized as one of attention de´¼ücit,
but increasing evidence suggests that a reward and moti-
vation de´¼ücit may be of equal importance. It has been
proposed that increasing DA in the VS would enhance
the saliency of the task, thus improving attention in
ADHD (Volkow et al. 2012). Intravenous MPH also sig-
ni´¼ücantly increased DA in the prefrontal and temporal
cortices that were associated with decreased ratings of
inattention, which may be therapeutically relevant.
The widespread use of prescription stimulants for
ADHD has not been without critics. In recent months,
we have heard speculation about whether ADHD is a real
disease, and if it is real, whether it is being grossly over-
diagnosed. Disorders often become widely diagnosed after
drugs come along that can alter a set of suboptimal
behaviors. In this way, Ritalin and Adderall helped make
ADHD a household name. If there is a pill that can clear
up the wavering focus of sleep-deprived youth, then those
rather ordinary states may come to be seen as syndrome.
A recent opinion piece entitled ÔÇ£Ritalin Gone WrongÔÇØ in
the New York Times (Sroufe 2012) by psychology profes-
sor L. Alan Sroufe argues that attention-de´¼ücit drugs do
more harm than good over the long term, a conclusion
other professionals in his ´¼üeld dispute. Studies have
shown that children who take MPH can show reductions
in ADHD symptomatology (inattention, hyperactivity,
and impulsivity) and gains in social and classroom
behaviors. Studies of adults with ADHD have con´¼ürmed
its usefulness for this population as well. However, the
bene´¼üts of prescription stimulants on ADHD symptom-
atology do not appear to last long.
The Multimodal Treatment Study of Children with
ADHD (MTA) compared four distinct treatment strate-
gies during childhood for children diagnosed with DSM-
IV ADHD, Combined Type (The MTA Cooperative
Group 1999). Children were randomly assigned to
14 months of (a) systematic medication management
(MedMgt), which was initial placebo-controlled titration,
three times a day dosing, 7 days a week, and monthly
30-min clinic visits, (b) multicomponent behavior therapy
(Beh), which included 27-session group parent training
supplemented with eight individual parent sessions, an
8-week summer treatment program, 12 weeks of
classroom administered behavior therapy with a half-time
aide, and ten teacher consultation sessions, (c) their
combination (Comb), or (d) usual community care (CC).
This randomized, six-site, controlled clinical trial featured
rigorous diagnostic criteria at study entry and compared
the relative effectiveness of treatments of well-established
ef´¼ücacy. The initial MTA ´¼ündings reported that all groups
showed improvement over baseline at the end of the
14-month treatment period; however, the Comb and
MedMgt group participants showed signi´¼ücantly greater
improvements in ADHD symptoms than did the Beh or
CC participants. By the next follow-up, 3 years after
enrollment, there were no longer signi´¼ücant treatment
group differences in ADHD symptoms or functioning
(Jensen et al. 2007). Molina et al. (Molina et al. 2009)
reported the next two follow-up assessments of the MTA
sample at 6 and 8 years after random assignment, when
the sample ranged in age from 13 to 18 years and found
similar ´¼ündings.
Prevalence of prescription stimulant
misuse
The misuse of a stimulant medication ÔÇô taking a stimu-
lant not prescribed by a physician or in a manner not in
accordance with physician guidance ÔÇô has been growing
over the past two decades. In fact, in the past 10 years
there has been a surge in prevalence rates of non-
prescription stimulant use among both adolescents and
young adults. In general, nonprescription use of MPH in
2000 was reported as 1.2% and in 2006 this number had
risen to 2%. Breaking the sample down by age, nonpre-
scription use among adolescents (ages 12ÔÇô17) went from
2.2% to 1.8% between 2000 and 2006, a slight decrease.
Among college-aged individuals (ages 18ÔÇô25), however,
usage increased signi´¼ücantly from 3.6% in 2000 to 5.4%
by 2006. Finally, among those 26 and older, usage is the
?¬ 2012 The Authors. Published by Wiley Periodicals, Inc. 663
S. E. Lakhan & A. Kirchgessner Stimulants in Individuals With and Without ADHDlowest of any group, but rates are rising. In 2000, only
0.7% reported any lifetime usage of MPH, but this num-
ber had doubled to 1.5% by 2006 (Bogle and Smith
2009).
The majority of research on the misuse of prescription
stimulants has focused on undergraduate college students.
The nonprescription use of stimulants has increased in
this population, to the extent that the misuse of prescrip-
tion stimulants is second only to marijuana as the most
common form of illicit drug use among college students
(Johnston et al. 2004). A 2001 nationwide self-reported
survey of more than 10,000 students from 4-year univer-
sities in the United States reported a 6.9% lifetime preva-
lence of nonprescription stimulant misuse, including a
past-year prevalence of 4.1% and a past-month prevalence
of 2.1% (McCabe et al. 2005). Colleges with the highest
past-year prevalence rates were typically located in the
northeastern United States, which is corroborated by
other reports (McCabe et al. 2005). A study by Teter
et al. (2005) of 9161 undergraduates reported an 8.1%
lifetime nonprescription stimulant misuse rate among col-
lege students, including 5.4% over the past year. Accord-
ing to a 2002 survey of a single US college, 35.5% of
undergraduates reported using stimulants without a pre-
scription, with greater frequency occurring in males com-
pared with females (Low and Gendaszek 2002).
The majority of nonprescription stimulant users
reported obtaining the drugs from a peer with a prescrip-
tion ÔÇô a process termed diversion. The diversion of stim-
ulants is very common and can begin in childhood,
adolescence, or young adulthood. A study conducted by
Wilens et al. (2008) reported that lifetime rates of diver-
sion ranged from 16% to 29% of students with stimulant
prescriptions asked to give, sell, or trade their medications
(Wilens et al. 2008). One survey reported that 23.3% of
middle and high school students taking prescribed stimu-
lants had been solicited to divert their medication to oth-
ers at a rate that increased from middle school to high
school (McCabe et al. 2004). A review of 161 elementary
and high school students prescribed the stimulant MPH
revealed that they had been asked to give or sell their
medication to others (Musser et al. 1998). Data has
shown that the diversion continues among college stu-
dents. McCabe et al. found 54% of college students who
were prescribed stimulants for ADHD had been
approached to divert their medication (McCabe and Boyd
2005). Nearly 29% of 334 college students had sold or
given their medication to others (Upadhyaya et al. 2005).
McCabe et al. (2005) examined the prevalence rates
and correlates of nonprescription use of stimulants (Rita-
lin, Adderall, or Dexedrine) among US college students
and found evidence that misuse is more prevalent among
particular subgroups of US college students and types of
colleges. The lifetime prevalence of nonprescription
stimulant use was 6.9%, past-year prevalence was 4.1%,
and past-month prevalence was 2.1%. Multivariate
analysis indicated that nonprescription use was higher
among college students who were male, white, members
of fraternities and sororities and earned lower grade point
averages. Wilens et al. (2008) reported similar ´¼ündings.
Rates were higher at colleges located in the northeastern
region of the United States and colleges with more
competitive admission standards. Nonprescription
stimulant users were more likely to report use of alcohol,
cigarettes, marijuana, ecstasy, cocaine, and other risky
behaviors. Among college students, available evidence
suggests that individuals who misuse MPH were more
likely to be white, male, af´¼üliated with a formally
organized fraternity, and more likely to use other illicit
and illegal substances (Bogle and Smith 2009).
A descriptive, nonexperimental, cross-sectional study
examined the nonprescription use of stimulants among
student pharmacists (Lord et al. 2003). Lifetime preva-
lence of stimulant misuse was 7% and was more likely in
students who were white, older, and fraternity or sorority
members, whereas past-year misuse was more likely in
whites and low academic achievers. A recent survey found
that the misuse of prescription stimulants is also rampant
among dental and dental hygiene students (McNiel et al.
2011). The survey, which was mailed to dental education
institutions in the south-central region of the United
States, found that 12.4% of these students used a stimu-
lant without a prescription and, of those, 70% took it to
improve attention and/or concentration. The most com-
monly reported stimulant medication used was Adderall
(77%). The majority (87%) of the students obtained the
medication through friends, and 90% began using the
drug in college. Interestingly, 17% of the students sur-
veyed felt it was easy to obtain stimulant medication for
use at their school, and 17% thought it was a problem
within their institution. The use, misuse, and diversion of
prescription stimulants among middle and high school
students were also examined by McCabe et al. (2005). In
this study, the odds for nonprescription stimulant use
were lower among African American students and higher
among those students with no plans for attending college.
These students also had the highest rates of alcohol and
other drug use.
The prevalence of prescription stimulant misuse in
medical students is also high. In fact, discussion based
websites such as Facebook, Medical School Forum, and
The Student Doctor Network are rife with Adderall
ÔÇ£expertsÔÇØ and informal question-and-answer sessions on
the drug. An anonymous survey was administered to
388 medical students (84.0% return rate) across all
4 years of education at a public medical college. More
664 ?¬ 2012 The Authors. Published by Wiley Periodicals, Inc.
Stimulants in Individuals With and Without ADHD S. E. Lakhan & A. Kirchgessnerthan 10% of medical students reported using stimulants
to improve academic performance. ADHD was diag-
nosed in 5.5% of students and 72.2% of those students
were diagnosed after the age of 18 years (Tuttle et al.
2010). This study suggests that medical students appear
to be a relatively high-risk population for prescription
stimulant misuse. Several of´¼ücials now say the problem
is increasing in medical schools (Harris 2009). ÔÇ£During
the last few years, the number of requests for ADD
evaluations has hugely increased,ÔÇØ Paula Stoessel, Ph.D.,
director of mental health services for physicians in
training at the University of California, Los Angeles,
David Geffen School of Medicine. ÔÇ£We make them
[medical students] go through a lot before we hand out
medication, but IÔÇÖve heard them talk about [obtaining
Adderall prescriptions] in passing.ÔÇØ Clearly, the results
emphasize the need for education about stimulants and
their adverse side effects.
Why are prescription stimulants
misused?
The reasons why prescription stimulants are misused are
numerous and include achieving euphoria, and helping
cope with stressful factors related to their educational
environment. According to a survey of 334 ADHD-
diagnosed college students taking prescription stimulants,
25% misused their own prescription medications to get
ÔÇ£highÔÇØ (Upadhyaya et al. 2005). Like cocaine, MPH
inhibits the DAT, which increases synaptic levels of DA,
and this is presumed to mediate MPHÔÇÖs reinforcing effects
and abuse potential. In laboratory studies, it has been
shown that animals will repeatedly administer MPH as
they do cocaine (Kollins 2003), and humans receiving
both drugs indicate a similar ÔÇ£highÔÇØ (Volkow et al. 1995).
A frequent concern regarding the use of stimulants for
ADHD is their mechanism of action, which increases DA
and thus may increase the risk for overt, illicit drug use.
However, research points to the conclusion that people of
any age receiving a stimulant for ADHD have no greater
risk for illicit substance abuse compared with the general
population (Wilens 2003).
Stimulants are especially popular at the end of a school
term when students will often use the drugs to stay awake
through the night to study for exams or complete aca-
demic projects. In fact, prescription stimulants are most
commonly misused to enhance school performance.
According to a Web survey of 115 ADHD-diagnosed col-
lege students, enhancing the ability to study outside of
class was the primary motive for misuse (Rabiner et al.
2009). Pressures such as a persistent desire to succeed
academically, poor sleep habits due to large workloads,
and the persistence of underlying social and ´¼ünancial
demands may place students at an increased risk for mis-
use of various drugs, including stimulants (Kadison 2005;
Teter et al. 2005). Students who misused ADHD medica-
tions generally felt that doing so was helpful. Thus, pre-
scription stimulants developed to help children with
ADHD improve their focus and attention are often mis-
used by the patient, especially ADHD patients with con-
duct disorder or comorbid substance abuse (Kollins
2008). Moreover, students without ADHD misuse stimu-
lants to improve performance or to induce euphoria. A
web-based survey administered to medical and health
profession students found that the most common reason
for nonprescription stimulant use was to focus and con-
centrate during studying (93.5%) (Herman et al. 2011).
In this study, approximately 10.4% of students surveyed
(45.2% female; 83.9% male; 83.9% Caucasian) have either
used a stimulant or are currently using prescription stim-
ulants, and the most commonly abused stimulant
(71.4%) was d-AMP. A recent survey found that 70% of
dental and dental hygiene students used a prescription
stimulant nonmedically to improve attention and/or con-
centration (McNiel et al. 2011). Student pharmacists
(Lord et al. 2003) and medical students (Tuttle et al.
2010) are also using stimulants to improve concentration
and academic performance.
Effects of prescription stimulants on
cognition in ADHD
Neuropsychological studies of ADHD children and adults
indicate impairments in many cognitive areas including
selective attention, memory, reaction time, information
processing speed, and executive control function such as
set-shifting, and working memory. The bene´¼üts of pre-
scription stimulants for enhancing classroom manageabil-
ity and increasing attention and academic productivity in
children are well established. Prescription stimulants may
increase the quality of note taking, scores on quizzes and
worksheets, writing output, and homework completion.
Nevertheless, they do not normalize the ability to learn
and apply knowledge (Advokat 2010). In fact, it has been
recognized over 30 years that there is little evidence that
prescription stimulants such as MPH and AMP improve
the academic achievement of ADHD-diagnosed children.
Children with ADHD have a consistently lower full-scale
IQ than normal controls. They score signi´¼ücantly lower
on reading and arithmetic tests, use more remedial aca-
demic services, and are more likely to be placed in a spe-
cial education class, or repeat a grade compared with
controls. They also take more years to complete high
school and have lower rates of college attendance
(Advokat 2010). Thus, prescription stimulants have only
a modest impact on these outcomes.
?¬ 2012 The Authors. Published by Wiley Periodicals, Inc. 665
S. E. Lakhan & A. Kirchgessner Stimulants in Individuals With and Without ADHDThe ´¼ürst review to describe the general academic func-
tioning of adults with ADHD summarized the results
from 23 studies (Weyandt and DuPaul 2006). ADHD-
diagnosed college students were found to have signi´¼ü-
cantly lower grade point averages, report more ÔÇ£academic
problemsÔÇØ and to be less likely to graduate from college.
Nevertheless, ADHD-diagnosed college students did not
differ in IQ from those without ADHD, and were shown
to be able to meet the demands of college courses. On
psychological tests, they showed signi´¼ücant de´¼ücits in
attention, but were not different from normal students on
other measures, such as the ability to be ´¼éexible and to
maintain performance, as task demands varied (Weyandt
and DuPaul 2006). More recent reports have reached sim-
ilar conclusions. Interestingly, like elementary and high
school students, college students with ADHD are less
likely to reach the same academic level as their non-
ADHD counterparts, even when they use stimulant medi-
cations. Thus, stimulant medications do not necessarily
equalize academic achievement in the typical adult with
ADHD.
A recent controlled, cross-sectional study evaluated the
effects of stimulants on cognition in adults with ADHD
and found that treated ADHD subjects had signi´¼ücantly
better scores on measures of IQ than did untreated
patients (Biederman et al. 2012). Thus, either good cogni-
tive functioning may be a determinant of seeking treat-
ment or stimulant treatment may improve cognition in
adults with ADHD. When ADHD studies address the
issue of cognition, they usually demonstrate that treated
patients perform better than untreated patients on neuro-
psychological tests or measures after they are treated.
Whether treatment normalizes neurocognitive perfor-
mance is rarely addressed. In fact, adults with ADHD are
less likely to attain the same educational levels as those
without the diagnosis relative to what would be predicted
based on their IQ, and this outcome does not appear to
be improved by stimulant medication. In one recent
study, for example, although 84% of ADHD-diagnosed
adults were statistically expected to be college graduates,
only 50% reached this level of education (Biederman
et al. 2008a,b). Gualtieri and Johnson (2008) conducted a
cross-sectional study of ADHD patients treated with
different ADHD drugs (Adderall XR, atomoxetine,
Concerta) (Adderall XR is an extended-release formu-
lation with duration of action of approximately 10ÔÇô12 h.
This is signi´¼ücantly longer than the duration of action of
most methylphenidate formulations, with the exception of
Concerta. Immediate-release methylphenidate lasts at
most for 6 h). PatientsÔÇÖ performance on a computerized
neurocognitive screening battery was compared with
untreated ADHD patients and normal controls. Signi´¼ü-
cant differences were detected between normal and
untreated ADHD patients. Treated patients performed
better than untreated patients but remained signi´¼ücantly
impaired compared with normal subjects. Thus, even after
optimal treatment, neurocognitive impairments persisted
in the ADHD patients.
It has never been established that the cognitive effects
of stimulant drugs are central to their therapeutic utility.
In fact, although ADHD medications are effective for the
behavioral components of the disorder, little information
exists concerning their effects on cognition. Barkley and
Cunningham (1978) summarized 17 short-term research
studies ranging from 2 weeks to 6 months, and found
stimulant medications produced little improvement in the
academic performance of hyperkinetic ADHD children.
The drugs appeared to reduce disruptive behavior rather
than improve academic performance. Stimulant drugs do
improve the ability (even without ADHD) to focus and
pay attention. One function, which is reliably improved
by stimulant medications, is sustained attention, or vigi-
lance. Stimulants improve sustained, focused attention,
but ÔÇ£selective attentionÔÇØ and ÔÇ£distractibilityÔÇØ may be
worsened, possibly because of a drug induced increase in
impulsivity. Both AMP and MPH do not improve (and
may even impair) short-term acquisition of information.
In addition, AMP and MPH do not improve, and may
impair ÔÇ£cognitive ´¼éexibilityÔÇØ as assessed with tests such as
the Wisconsin Card Sort and Attentional Set-Shifting
tasks. MPH has been shown to improve performance on
an auditory arithmetic task, the Paced Auditory Serial
Addition Task, in adults with ADHD relative to control
subjects (Schweitzer et al. 2004). AMP and MPH might
improve long-term retention of information, if the drugs
are active during a period in which memory is being
ÔÇ£consolidated.ÔÇØ However, this may only occur in situa-
tions where retention is already suboptimal.
Effects of stimulants on cognition in
individuals without ADHD
Recognition that ADHD persists into adulthood has sub-
stantially increased the prescription stimulant treatment
of adults with the disorder (see above). It has also
resulted in a corresponding escalation of nonprescription
stimulant use in many college students con´¼ürmed by
numerous surveys. Studies consistently show that students
report using stimulant medications, legally or illicitly, to
improve academic performance, speci´¼ücally to increase
concentration and the ability to stay up longer and study.
Intuitively, it would seem logical that drugs that improve
attention and concentration should also promote learning
and academic achievement. Inherent in terms like ÔÇ£cogni-
tive enhancers,ÔÇØ ÔÇ£smart drugs,ÔÇØ and ÔÇ£neuroenhancersÔÇØ is
the assumption that MPH and d-AMP enhance cognition.
666 ?¬ 2012 The Authors. Published by Wiley Periodicals, Inc.
Stimulants in Individuals With and Without ADHD S. E. Lakhan & A. KirchgessnerMajor magazines such as The New Yorker have reported a
trend toward growing use of prescription stimulants by
college students for ÔÇ£neuroenhancementÔÇØ. In fact, some
students are faking ADHD to gain access to prescription
stimulant medication, which has led to a shortage of
ADHD drugs such as Adderall (Mitchell 2012). Unfortu-
nately, media reports appear to condone this behavior as
95% of articles mentioned at least one possible bene´¼üt of
using prescription drugs for neuroenhancement, but only
58% mentioned any risks or side effects (Partridge et al.
2011). Duke University recently enacted a new policy pro-
hibiting the nonmedical use of prescription stimulants for
any academic purposes (McLaughlin 2012). Students
received an email stating policy changes including, ÔÇ£The
unauthorized use of prescription medication to enhance
academic performance has been added to the de´¼ünition
of Cheating.ÔÇØ In the past, the use of such drugs without a
prescription was only a violation under the UniversityÔÇÖs
drug policy. Oddly, the assumption that prescription
stimulants are truly ÔÇ£cognitive enhancersÔÇØ is not really
questioned. Stimulants reduce hyperactivity, impulsivity,
and inattention in children and adults with ADHD, so it
has been assumed that these drugs enhance long-term
intellectual performance. However, contrary to simple
implicit assumptions found in bioethics and media dis-
courses, there are actually only a few studies on the
enhancement effects of ÔÇ£cognitive enhancersÔÇØ in individu-
als without ADHD.
Smith and Farah (2011) reviewed data on prescription
stimulants as neuroenhancers from over forty laboratory
studies involving healthy, nonelderly adults. Most of the
studies looked at one of three types of cognition: learn-
ing, working memory, and cognitive control. Effects of
d-AMP or MPH on cognition were assessed by a variety
of tasks (Table 1). A typical learning task asks subjects
to memorize a list of paired words; an hour, a few days,
or a week later, subjects are presented with the ´¼ürst
words in the pairs and asked to come up with the sec-
ond. In general, with single exposures of verbal material,
the studies on learning showed that no bene´¼üts are seen
immediately following learning, but later recall and rec-
ognition are enhanced. Of the six articles reporting on
memory performance (Rapoport et al. 1978; Soetens
et al. 1993; Camp-Bruno and Herting 1994; Fleming
et al. 1995; Unrug et al. 1997; Zeeuws and Soetens
2007), encompassing eight separate experiments, only
one of the experiments yielded signi´¼ücant memory
enhancement on short delays (Rapoport et al. 1978). In
contrast, retention was reliably enhanced by d-AMP
when subjects were tested after longer delays, with recall
improved after 1 h through 1 week (Soetens et al. 1993,
1995; Zeeuws and Soetens 2007). These data suggest that
when people are given rote-learning tasks their perfor-
mance is improved by stimulants. The bene´¼üts were
more apparent in studies where subjects had been asked
to remember information for several days or longer.
However, studies only found a correlation with rote
memory tasks, not complex memory, which is more
likely to appear on college exams.
In contrast to the types of memory, which are long
lasting and formed as a result of learning, working mem-
ory is a temporary store of information that plays a role
in executive function. Several studies have assessed the
effect of MPH or d-AMP on tasks examining various
aspects of working memory (Sahakian and Owen 1992;
Oken et al. 1995; Elliott et al. 1997; Mehta et al. 2000;
Barch and Carter 2005; Silber et al. 2006; Clatworthy
et al. 2009) (see Table 1). One classic approach to the
assessment of working memory is the span task, in which
a series of items is presented to the subject for repetition,
transcription, or recognition. A spatial span task, in which
the subjects must retain and reproduce the order in which
boxes in a scattered spatial arrangement change color was
employed by Elliott et al. (1997) to assess the effects of
MPH on working memory. For the subjects in the group
who received placebo ´¼ürst, MPH increased spatial span.
However, for the subjects who received MPH ´¼ürst, there
was a nonsigni´¼ücant opposite trend. The authors noted
that the subjects in the ´¼ürst group performed at an overall
lower level, and so, this may have contributed to the lar-
ger enhancement effect for less able subjects. Barch and
Carter (2005) obtained similar results and Mehta et al.
(2000) found evidence of greater accuracy with MPH. In
the study by Mehta et al. (2000), the effect depended on
subjectsÔÇÖ working memory ability: the lower a subjectÔÇÖs
score on placebo, the greater the improvement on MPH.
In contrast to the three previous studies, Bray et al.
(2004) reported that MPH does not improve the cogni-
tive function of sleep-deprived young adults. In sum, the
evidence concerning stimulant effects of working memory
is mixed, with some ´¼ündings of enhancement and some
null results, although no ´¼ündings of overall performance
impairment (Smith and Farah 2011). However, the small
effects were mainly evident in subjects who had low
cognitive performance to start with, showing that the
drug is more effective at correcting de´¼ücits than
ÔÇ£enhancing performance.ÔÇØ Farah et al. (2009) recently
examined the effect of Adderall upon creativity, a
component of cognition stimulants are suspected of sti-
´¼éing, in a double-blind, placebo-controlled trial. They
found that the drug enhanced creativity on speci´¼üc tasks,
but the amount of enhancement depended upon the
baseline performance of individuals: lower-performing
individuals were more enhanced than high-performers.
Thus, the drugs do not offer as much help to people with
greater intellectual abilities.
?¬ 2012 The Authors. Published by Wiley Periodicals, Inc. 667
S. E. Lakhan & A. Kirchgessner Stimulants in Individuals With and Without ADHDTable 1. Overview of effects of prescription stimulants on cognitive performance in adults without ADHD.
Study Tests Finding
Barch and Carter
(2005)
Spatial working memory Decrease in reaction time
Stroop test Decrease in response time
Breitenstein et al.
(2004)
Probabilistic learning Steeper increase in hits and decrease in misses across learning sessions;
increase in retention after more than 1 year
Breitenstein et al.
(2006)
Probabilistic learning Steeper learning curve
Brignell et al.
(2007)
Single-exposure verbal learning At 1 week improved recognition
Brumaghim and
Klormart (1998)
Associative learning: word pairs No effect
Burns et al. (1967) Associative learning: location of stimulus and
response
Slower rate of learning
Callaway (1983) Item recognition No effect
Camp-Bruno and
Herting (1994)
Repeated-exposure verbal learning 1 h: no effect; 2 h: borderline effect
Camp-Bruno and
Herting (1994)
Single-exposure verbal learning Up to 2.5 h: no effect
Clatworthy et al.
(2009)
Spatial working memory No effect
Reversal learning No effect
Cooper et al.
(2005)
Continuous performance test (double version) 5 min: decrease in reaction time; decrease in errors of omission
de Wit et al.
(2000)
Stop-signal task No effect
de Wit et al.
(2002)
Repeated-exposure verbal learning 25 min: no effect
Digit span Increase in performance
Go/no-go Decrease in number of false alarms
Delay of grati´¼ücation No effect
Dodds et al.
(2008)
Reversal learning No effect
Elliott et al. (1997) Spatial span Decrease in errors
Spatial working memory Decrease in errors
Attentional set-shifting No effect
Verbal ´¼éuency No effect
Sequence generation No effect
New Tower of London No effect
Tower of London Relative decrease in accuracy
Fillmore et al.
(2005)
Stop-signal task No effect
n-back Increase in processing rate
Fitzpatrick et al.
(1988)
Item recognition: stimulus evaluation/
response selection task
Decrease in reaction time
Fleming et al.
(1995)
Single-exposure verbal learning 20 min: no effect on single-exposure verbal learning
Continuous performance test 5 min: decrease in reaction time
Spatial working memory No effect
Wisconsin Card Sorting Test No effect
Verbal ´¼éuency No effect
Hurst et al. (1969) Associative learning: word pairs Increase in retention after 1 week delay
Kennedy et al.
(1990)
Item recognition No effect
Grammatical reasoning No effect
Klorman et al.
(1984)
Continuous performance test (BX version) 45 min: decrease in reaction time; 12.5/45 min: decrease in errors of
omission
Koelega (1993) Vigilance performance Improves the overall level of vigilance performance and prevents the
decrement that occurs over time under normal circumstances
Kumari et al.
(1997)
Motor sequence learning No effect
Motor sequence learning No effect
(Continued)
668 ?¬ 2012 The Authors. Published by Wiley Periodicals, Inc.
Stimulants in Individuals With and Without ADHD S. E. Lakhan & A. KirchgessnerThe third type of cognition is cognitive control. Cogni-
tive control is a broad concept that refers to guidance of
cognitive processes in situations where the most natural,
automatic, or available action is not necessarily the cor-
rect one (Smith and Farah 2011). Attention and working
memory are thought to rely on cognitive control and loss
of cognitive control is a major component of many neu-
ropsychiatric diseases such as schizophrenia. The effects
of MPH and d-AMP have been determined on several
tests used to study cognitive control, including the go/no-
go task, the stop-signal task, and the Flanker test. In gen-
eral, the effects of stimulants on cognitive control are not
robust, but MPH and d-AMP appear to enhance cogni-
tive control in some tasks for some people, especially
those less likely to perform well on cognitive control tasks
(Smith and Farah 2011). The results of these studies cur-
rently provide limited support for the enthusiastic por-
trayals of cognitive enhancement.
The neural basis of error processing has become a key
research interest in cognitive neuroscience. Recently, a
single dose of MPH was shown to improve the ability of
healthy volunteers to consciously detect performance
errors (Hester et al. 2012). Furthermore, this behavioral
effect was associated with a strengthening of activation
Table 1. Continued.
Study Tests Finding
Makris et al.
(2007)
Item recognition Proportion correct sustained across multiple trials
Mattay et al.
(1996)
Wisconsin Card Sorting Test No effect
Mattay et al.
(2000)
n-back No effect
Mattay et al.
(2003)
n-back No effect
Wisconsin Card Sorting Test No effect
Mehta et al.
(2000)
Spatial working memory Decrease in between-search errors
Mintzer and
Grif´¼üths (2007)
Single-exposure verbal learning 2 h: improved recognition; no effect on recall
n-back No effect
Item recognition No effect
Oken et al. (1995) Digit span No effect
Rapoport et al.
(1978)
Single-exposure verbal learning; continuous
performance test (BX version)
10 min: improved recall; decrease in errors of omission
Rogers et al.
(1999)
Attentional set-shifting Increase in intradimensional shift errors; decrease in extradimensional shift
errors; increase in response latencies
Schmedje et al.
(1988)
Digit span No effect
Pattern memory No effect
Schroeder et al.
(1987)
Strategic choice task Decrease in changeover rate
Servan-Schreiber
et al. (1998)
Flanker task Decrease in response time; increase in accuracy
Silber et al. (2006) Digit span No effect
Trail Making Test No effect
Soetens et al.
(1993)
Single-exposure verbal learning 20 min: no effect; 1 hÔÇô3 days: improved long-term retention
Soetens et al.
(1995)
Single-exposure verbal learning 1 hÔÇô1 week: improved long-term retention in free recall; 1 week: improved
recognition
Strauss et al.
(1984)
Associative learning: word pairs; continuous
performance test (double version)
No effect; 45 min: decrease in reaction time; 45 min: decrease in errors of
omission
Unrug et al.
(1997)
Single-exposure verbal learning 20 min: no effect
Ward et al. (1997) Motor sequence learning; item recognition No effect; decrease in reaction time
Weitzner (1965) Associative learning: word pairs Improved performance only when pairs were uniquely semantically related
Willett (1962) Repeated-exposure verbal learning Decrease in number of trials to reach criterion
Zeeuws and
Soetens (2007)
Single-exposure verbal learning 30 min: no effect; 1 hÔÇô1 day: improved long-term retention
Table adapted with permission from Smith and Farah (2011), Copyright 2011 by the American Psychological Association. The use of APA informa-
tion does not imply endorsement by APA.
?¬ 2012 The Authors. Published by Wiley Periodicals, Inc. 669

differences in the dorsal anterior cingulate cortex and
inferior parietal lobe during the MPH condition for
errors made with versus without awareness. How the
brain monitors ongoing behavior for performance errors
is a central question of cognitive neuroscience. Dimin-
ished awareness of performance errors limits the extent to
which humans engage in corrective behavior and has been
linked to loss of insight in ADHD and drug addiction.
As it remains unclear whether stimulant medication
has the same effect on healthy individuals as for those
with ADHD, it is possible that many reported effects of
prescription stimulants in healthy individuals may stem
from placebo effects. Looby and Earleywine (2011) exam-
ined whether placebo effects in´¼éuence reports of subjec-
tive mood and cognitive performance among college
students who endorsed several risk factors for prescription
stimulant misuse (e.g., low grade point average, frater-
nity/sorority involvement, binge drinking). Interestingly,
participants believed that they had better ability to focus
and persevere, particularly for a sustained amount of
time, when they expected to receive MPH (Looby and
Earleywine 2011). This is similar to circumstances in
which participants may engage in nonmedical-stimulant
use to study or cram for extended hours. On the other
hand, when experimental participants did not expect to
receive MPH, their attention appeared disrupted resulting
in inconsistent reaction times throughout the CPT. Inter-
estingly, subjective feelings of being high and stimulated
were produced solely by expecting to receive MPH. This
´¼ünding is important to consider when examining initia-
tion and maintenance of nonmedical prescription stimu-
lant use. As motives for nonprescription stimulant use
include the desire to feel high (Barrett et al. 2005), it is
likely that individuals who use a stimulant for this pur-
pose will consequently feel high due to these demon-
strated placebo effects, which will likely maintain misuse
of the drug.
Prescription stimulant misuse in
athletes
ADHD is a controversial problem in sport as participants
with this disorder often require banned stimulants while
competing. Many of the governing bodies of competitive
sports have developed regulations that limit the use of
stimulant medications to treat ADHD. In other cases,
stimulant use is allowed in the setting of a documented
diagnosis of ADHD. Most sports organizations around
the world now follow the guidelines set forth by the
World Anti-Doping Agency (WADA). According to this
document, the diagnosis of ADHD is to be made by
ÔÇ£experienced cliniciansÔÇØ and in accordance to the DSM-
IV. Stimulant medications are considered to be a
ÔÇ£medical best practice treatmentÔÇØ that do require the
athlete to ´¼üle a therapeutic use exemption (TUE). A TUE
gives athletes with medical diagnoses an exemption to
use a drug normally prohibited by MLB, to treat a
legitimately diagnosed medical condition. WADA
recommends reassessments of continued treatment every
3ÔÇô4 months. Other organizations, such as the National
College Athletic Association (NCAA) and individual
professional leagues, such as the National Football League
(NFL) and Major League Baseball (MLB), have developed
their own regulations.
The NCAA does not require that physicians prescribe a
trial of nonstimulant medications before prescribing stim-
ulants, only that the prescribing physician considers non-
stimulants ´¼ürst. The NCAA acknowledges that
nonstimulant medication may not be as effective as stim-
ulant medications in treating ADHD. In contrast to the
NCAA regulations, athletes who are also participating in
events governed by the International Olympic Committee
(IOC) and/or WADA are not allowed to use stimulant
medications, even with a TUE. These organizations
require that the athlete with ADHD on stimulant medica-
tions stop taking these medication or risk disquali´¼ücation
(Putukian et al. 2011).
It has been reported that MLB players are using an
ADHD diagnosis to evade the AMP ban (Associated Press
2009). According to records MLB of´¼ücials turned over to
congressional investigators as part of George MitchellÔÇÖs
probe into steroid use in baseball, the number of players
getting ÔÇ£therapeutic use exemptionsÔÇØ from baseballÔÇÖs AMP
ban jumped in 1 year from 28 to 103 ÔÇô which means that,
suddenly, 7.6% of the 1354 players on major-league rosters
have been diagnosed with ADHD. MLB banned AMP in
2006. The prevalence of ADHD in athletes has not been
studied, although there is no reason to believe it would dif-
fer from the general population. Thus, 2ÔÇô3 times the usual
adult rate of ADHD in baseball players is alarming. Ath-
letes may see stimulants as a way to help maintain physical
´¼ütness for their competitive sport or to improve their con-
centration. Certainly some of the players getting prescrip-
tions for ADHD medications may have a legitimate
medical need and without treatment, players manifesting
the symptoms of untreated ADHD would be at a disadvan-
tage to non-ADHD players. A therapeutic dose of MPH
will bene´¼üt concentration, and may improve motor coor-
dination. Prescription stimulants to treat ADHD could be
used as performance enhancing drugs (PEDs); however, a
proper diagnosis would prevent athletes from abusing the
TUE status to ÔÇ£cheat within the rules.ÔÇØ
Some athletes will only take medications episodically for
school testing or for studying purposes. Others may feel
that their sport performance is improved on stimulants,
whereas others may temporarily stop taking them so
670 ?¬ 2012 The Authors. Published by Wiley Periodicals, Inc.
Stimulants in Individuals With and Without ADHD S. E. Lakhan & A. Kirchgessnerthat their sports play is more random and unfocused,
which they feel improves their performance (Pelham et al.
1990).
Potential adverse affects of chronic
stimulant use
ADHD is now recognized as a chronic disorder that con-
tinues into adulthood; therefore, some individuals take
stimulants such as MPH and d-AMP for years. The medi-
cal literature provides abundant data to support the
potentially positive effect of stimulants for the majority of
children, adolescents, and adults with ADHD, and stimu-
lants have been considered to be relatively safe (Elia et al.
1999; Brown et al. 2005). However, reports of adverse
events in conjunction with the use of these drugs have
raised concern about their safety.
Large doses of stimulants can lead to psychosis, sei-
zures, and cardiovascular events. The induction of schizo-
phrenic-like states in AMP abusers is well documented,
although the onset of such states in children on pre-
scribed doses of stimulant medication is observed far less
often (Polchert and Morse 1985; Masand et al. 1991;
Murray 1998). Surles et al. (2002) published a case report
of psychotic reactions to AMP (10 mg/day) in an adoles-
cent ADHD patient. The patient displayed many of the
characteristics of AMP-induced psychosis including visual
hallucinations, delusions, anorexia, ´¼éattening of affect,
and insomnia. It is thought that the mechanism of AMP-
induced psychosis is mediated by dopaminergic excess. As
the patientÔÇÖs symptoms disappeared when taken off the
stimulant medication, it suggests that the psychosis was
indeed secondary to AMP.
The most commonly observed cardiovascular effects
linked with ADHD stimulant medications include hyper-
tension and tachycardia. In addition, cardiomyopathy,
cardiac dysrhythmias, and necrotizing vasculitis have been
described. In February 2005, the brand medication Adder-
all XR (Shire BioChem Inc, Quebec, Canada) was with-
drawn from the Canadian market by Health Canada. Case
reports on serious cardiovascular adverse drug reactions
(ADRs), sudden death, and psychiatric disorders led regu-
latory agencies to warn against the use of MPH in the
pediatric population in 2006 and 2007 (European Medi-
cines Agency 2007). In 2006, warnings were also linked to
atomoxetine use due to reports of hepatotoxicity and
suicidal thoughts in children. These concerns received
glaring attention in 2006 and led the US Food and Drug
Administration advisory committee to propose placing a
black box warning concerning sudden death on
psychostimulants in response to ADR reports.
Adderall use is associated with myocardial infarction
and even sudden death (Gandhi et al. 2005; Jiao et al.
2009). Gandhi et al. (2005) reported the case of a
15-year-old male subject who suffered a myocardial
infarction after taking two 20 mg tablets of Adderall. Jiao
et al. (2009) reported a second case of a 20-year-old
ADHD college freshman with myocardial infarction after
taking two 15-mg tablets of Adderall XR. Recently,
Sylvester and Agarwala (2012) reported another case of a
15-year-old male subject who suffered a myocardial
infarction after starting Adderall XR. The patient was
otherwise in good health with no previous cardiac abnor-
malities and improved with cessation of medication. The
´¼ündings of the case have been disputed (Rosenthal 2012).
In addition, a recent report by Alsidawi et al. (2011)
discusses the case of a 19-year-old female subject with
Adderall overdose induced inverted-Takotsubo cardiomy-
opathy, also known as stress-induced cardiomyopathy.
The patient was brought to the emergency department
after ingesting 30 Adderall tablets. She complained of
pressure like chest pain and shortness of breath. Her car-
diac enzymes were elevated, but the electrocardiogram
was unremarkable. Echocardiography identi´¼üed a low
ejection fraction of 25ÔÇô35% with severe hyperkinetic apex
and akinetic base consistent with the diagnosis of
inverted-TTC. Her symptoms resolved in 24 h. Drug-
induced-Takotsubo cardiomyopathy has been previously
reported and is mainly attributed to sympathetic oversti-
mulation (Amariles 2011). In this case, the patient over-
dosed on Adderall, which is a sympathomimetic drug.
The mechanisms for AMP-induced cardiac injury are pos-
tulated to be similar to those seen with cocaine, which
include coronary spasm, prothrombotic state, accelerated
atherosclerosis due to endothelial injury, and direct myo-
cardial (Chen 2007). Inappropriate dosing or taking with
alcohol increases the risk of serious cardiovascular side
effects like myocardial infarction, even without underlying
cardiovascular risk factors.
Unfortunately, there are few long-term studies (i.e.,
longer than 24 months) on the use of stimulants for the
management of ADHD; therefore, the precise long-term
effects ÔÇô either adverse or positive ÔÇô remain unknown.
A recent study (Vitiello et al. 2011) suggests that the
chronic use of stimulant medication to treat ADHD in
children does not appear to increase the risk for high
blood pressure in the long term, but it may have modest
effects on heart rate. The MTA study found that stimulant
medication does not appear to increase the risk for
abnormal elevations in blood pressure or heart rate over a
10-year period; however, the effect of stimulants on heart
rate can be detected even after years of use (Vitiello et al.
2011). The effect on heart rate may be clinically signi´¼ücant
for individuals who have underlying heart conditions.
A cohort study sought to determine whether use of
MPH in adults is associated with elevated rates of serious
?¬ 2012 The Authors. Published by Wiley Periodicals, Inc. 671
S. E. Lakhan & A. Kirchgessner Stimulants in Individuals With and Without ADHDcardiovascular events compared with rates in nonusers
(Schelleman et al. 2012). All new MPH users with at least
180 days of prior enrollment were identi´¼üed. Initiation of
MPH was associated with a 1.8-fold increase in risk of sud-
den death or ventricular arrhythmia; however, the lack of a
dose response relationship suggested that this association
might not be a causal one. A recent study by Habel and
colleagues (Habel et al. 2011), which compared approxi-
mately 150,000 adults prescribed ADHD medication with
approximately 300,000 nonusers, found no evidence of a
link between ADHD medication and cardiovascular risk
(myocardial infarction, sudden death, or stroke). Although
the student enrolled adults, the same group also has
reported a similar lack of signi´¼ücant association between
serious cardiovascular events and use of ADHD medica-
tions in children and younger adults (Cooper et al. 2011).
These ´¼ündings support the ´¼ünal decision of the US Food
and Drug Administration committee to not to place a
black box warning for all children and adults, but to
pursue further research. However, the study by Habel et al.
(2011) has limitations stemming from its focus on the
most severe cardiovascular event. The databases were not
used to examine other cardiovascular adverse effects, such
as palpitations and dyspnea, which, although less severe,
are nonetheless alarming to patients.
Additional potential ADRs associated with stimulant use
are important to note including abdominal pain, anorexia,
constipation, dizziness, dry mouth, headache, insomnia,
jitteriness, irritability, nausea, and palpitations (Greydanus
and Strasburger 2006). College students with ADHD who
misuse prescribed stimulants also reported hyperactivity
symptoms as a common adverse event. Of particular
signi´¼ücance to athletes, many stimulants utilized in treat-
ing ADHD may increase core temperature (Piper et al.
2005), possibly increasing risk of heart injury. These agents
may also mask signs and symptoms of fatigue and allow
for a longer duration of exercise with elevated temperature
in excess of 40??C. Thus, in situations of increased exoge-
nous heat stress, stimulants should be used with caution.
Conclusion
Although prescription stimulants have been shown to be
relatively safe and effective in managing the symptoms of
ADHD, there exists a signi´¼ücant potential for misuse. The
data are clear that individuals with and without ADHD,
including athletes misuse stimulants to enhance perfor-
mance. Although stimulants may improve an individualÔÇÖs
performance when given a rote-learning task, they do not
offer as much help to people with greater intellectual abil-
ities. Stimulants do not increase IQ (Advokat et al. 2008).
In fact, very little is known about the effects of nonpre-
scription stimulants on cognitive enhancement outside of
the student population, although it is frequently reported
in newspaper articles. Thus, the rumored effects of ÔÇ£smart
drugsÔÇØ may be a false promise, as research suggests that
stimulants are more effective at correcting de´¼ücits than
ÔÇ£enhancing performance.ÔÇØ Moreover, students are taking
unnecessary risks including the potential for harmful side
effects, which may cause sudden death. This requires edu-
cation on the proper use of stimulants and on the signs
and symptoms of misuse and the health risks associated
with misuse. It is important that students with prescription
stimulants understand that they are the main source of
diversion to other students, and should receive education
in the prevention of stimulant diversion. Health centers
should aim to recognize students who are misusing stimu-
lants because they may present with a variety of signs
including insisting on a larger dose, and demanding more
drug during times within the academic year, such as dur-
ing ´¼ünals. Students with past or active drug abuse patterns
should not be prescribed stimulants, as they are more
likely to divert their prescription stimulants. It is also
important that athletes be warned that the NCAA, the US
Olympic Committee, and the IOC ban MPH. As a result,
education on the proper use of stimulants and on the signs
and symptoms of misuse is an imperative.
Acknowledgments
The development of this work was supported by the
Global Neuroscience Initiative Foundation (GNIF).
Con´¼éict of Interest
The authors declare that they have no competing interests.
Authors contributions: All authors participated in the
preparation of the manuscript, and read and approved
the ´¼ünal manuscript.
References
Advokat, C. 2010. What are the cognitive effects of stimulant
medications? Emphasis on adults with attention-de´¼ücit/
hyperactivity disorder (ADHD). Neurosci. Biobehav. Rev.
34:1256ÔÇô1266.
Advokat, C. D., M. S. Guidry, and B. A. Martino. 2008. Licit
and illicit use of medications for attention de´¼ücit
hyperactivity disorder in undergraduate college students.
J. Am. Coll. Health 56:601ÔÇô607.
Alsidawi, S., J. Muth, and J. Wilkin. 2011. Adderall induced
inverted-Takotsubo cardiomyopathy. Catheter. Cardiovasc.
Interv. 78:910ÔÇô913.
Amariles, P. 2011. A comprehensive literature search: drugs as
possible triggers of Takotsubo cardiomyopathy. Curr. Clin.
Pharmacol. 6:1ÔÇô11.
672 ?¬ 2012 The Authors. Published by Wiley Periodicals, Inc.
Stimulants in Individuals With and Without ADHD S. E. Lakhan & A. KirchgessnerAmerican Psychiatric Association. 2000. DSM-IV-TR.
American Psychiatric Association, Washington, DC.
Associated Press. 2009.ADHD exemptions on rise in MLB.
ESPN, New York, NY.
Barch, D. M., and C. S. Carter. 2005. Amphetamine improves
cognitive function in medicated individuals with
schizophrenia and in healthy volunteers. Schizophrenia Res.
77:43ÔÇô58.
Barkley, R. A., and C. E. Cunningham. 1978. Do stimulant
drugs improve the academic performance of hyperkinetic
children? A review of outcome studies. Clin. Pediatr.
(Phila.) 17:85ÔÇô92.
Barrett, S. P., C. Darredeau, L. K. Brody, and R. O. Pihl. 2005.
Characteristics of methylphenidate misuse in a university
student sample. Can. J. Psychiatry 50:457ÔÇô461.
Biederman, J., M. C. Monuteaux, E. Mick, T. Spencer, T. E.
Wilens, J. M. Silva, et al. 2006. Young adult outcome of
attention de´¼ücit hyperactivity disorder: a controlled
10 year prospective follow-up study. Psychol. Med.
36:167ÔÇô179.
Biederman, J., C. R. Petty, R. Fried, R. Kaiser, C. R. Dolan, S.
Schoenfeld, et al. 2008a. Educational and occupational
underattainment in adults with attention-de´¼ücit/
hyperactivity disorder: a controlled study. J. Clin. Psychiatry
69:1217ÔÇô1222.
Biederman, J., L. J. Seidman, C. R. Petty, R. Fried, A. E. Doyle,
D. R. Cohen, et al. 2008b. Effects of stimulant medication
on neuropsychological functioning in young adults with
attention de´¼ücit/hyperactivity disorder. J. Clin. Psychiatry
69:1150ÔÇô1156.
Biederman, J., R. Fried, C. R. Petty, A. Henin, J. Wozniak, L.
Corkum, et al. 2012. Examining the association between
stimulant treatment and cognitive outcomes across the life
cycle of adults with attention-de´¼ücit/hyperactivity disorder:
a controlled cross-sectional study. J. Nerv. Ment. Dis.
200:69ÔÇô75.
Bloom, B., and R. A. Cohen. 2007. Summary health statistics
for U.S. children: National Health Interview Survey, 2006.
Statistics VH 234:1ÔÇô79.
Bogle, K. E., and B. H. Smith. 2009. Illcit methylphenidate
use: a review of prevalence, availability, pharmacology,
and consequences. Curr. Drug Abuse Rev. 2:157ÔÇô
176.
Bray, C. L., K. S. Cahill, J. T. Oshier, C. S. Peden, D. W.
Theriaque, T. R. Flotte, et al. 2004. Methylphenidate does
not improve cognitive function in healthy sleep-deprived
young adults. J. Invest. Med. 52:192ÔÇô201.
Breitenstein, C., S. Wailke, S. Bushuven, S. Kamping, P.
Zwitserlood, E. B. Ringelstein, et al. 2004. D-amphetamine
boosts language learning independent of its cardiovascular
and motor arousing effects. Neuropsychopharmacology
29:1704ÔÇô1714.
Breitenstein, C., A. Floel, C. Korsukewitz, S. Waike, S.
Bushuven, and S. Knecht. 2006. A shift paradigm: from
noradrenergic to dopaminergic modulation of learning? J.
Neurol. Sci. 248:42ÔÇô47.
Brignell, C. M., J. Rosenthal, and H. V. Curran. 2007.
Pharmacological manipulations of arousal and memory for
emotional material: effects of a single dose of
methylphenidate or lorazepam. J. Psychopharmacol.
21:673ÔÇô683.
Brown, R. T., R. W. Amler, W. S. Freeman, J. M. Perrin, M.
T. Stein, H. M. Feldman, et al. 2005. Treatment of
attention-de´¼ücit/hyperactivity disorder: overview of the
evidence. Pediatrics 115:e749ÔÇôe757.
Brumaghim, J. T., and R. Klormart. 1998. MethylphenidateÔÇÖs
effects on paired-association learning and event-related
potentials of young adults. Psychophysiology 35:73ÔÇô85.
Burns, J. T., R. F. House, F. C. Fensch, and J. G. Miller. 1967.
Effects of magnesium pemoline and dextroamphetamine on
human learning. Science 155:849ÔÇô851.
Callaway, E. 1983. Presidential address. 1982: the
pharmacology of human information processing.
Psychophysiology 20:359ÔÇô370.
Camp-Bruno, J. A., and R. L. Herting. 1994. Cognitive effects
of milacemide and methylphenidate in healthy young adults.
Psychopharmacology 115:46ÔÇô52.
Center for Disease Control and Prevention. 2005a. Mental
health in the United States. Prevalence of diagnosis and
medication treatment for attention-de´¼ücit/hyperactivity
disorder ÔÇô United States, 2003. MMWR Morb. Mortal.
Wkly. Rep. 54:842ÔÇô847.
Center for Disease Control and Prevention. 2005b. Prevalence
of diagnosis and medication treatment for attention de´¼ücit/
hyperactivity disorder ÔÇô United States, 2003. MMWR
Morbid. Mortal. Wkly. Rep. 54:842ÔÇô847.
Centers for Disease Control and Prevention. 2010. Increasing
prevalence of parent-reported attention-de´¼ücit/hyperactivity
disorder among children ÔÇô United States, 2003 and 2007.
MMWR Morb. Mortal. Wkly. Rep. 59:1439ÔÇô1443.
Chen, J. P. 2007. Methamphetamine-associated acute
myocardial infarction and cardiogenic shock with normal
coronary arteries: refractory global coronary microvascular
spasm. J. Invasive Cardiol. 19:E89ÔÇôE92.
Clatworthy, P. L., S. J. Lewis, L. Brichard, Y. T. Hong, D.
Izquierdo, L. Clark, et al. 2009. Dopamine release in
dissociable striatal subregions predicts the different effects of
oral methylphenidate on reversal learning and spatial
working memory. J. Neurosci. 29:4690ÔÇô4696.
Cooper, N. J., H. Keage, D. Hermens, L. M. Williams,
D. Debrota, and C. R. Clark. 2005. The dose-dependent
effect of methylphenidate on performance, cognition,
and psychophysiology. J. Integrative Neurosci. 4:
123ÔÇô144.
Cooper, W. O., L. A. Habel, C. M. Sox, K. A. Chan, P. G.
Arbogast, T. C. Cheetham, et al. 2011. ADHD drugs and
serious cardiovascular events in children and young adults.
N. Engl. J. Med. 365:1896ÔÇô1904.
?¬ 2012 The Authors. Published by Wiley Periodicals, Inc. 673
S. E. Lakhan & A. Kirchgessner Stimulants in Individuals With and Without ADHDDepartment of Justice: Drug Enforcement Administration.
2008. ARCOS2-report 7, United States summary for retail
drug purchases by grams weight.
Dodds, C. M., U. Muller, L. Clark, A. van Loon, R. Cools, and
T. W. Robbins. 2008. Methylphenidate has differential
effects on blood oxygenation level-dependent signal related
to cognitive subprocesses of reversal learning. J. Neurosci.
28:5976ÔÇô5982.
Dopheide, J. A., and S. R. Pliszka. 2009. Attention-de´¼ücit-
hyperactivity disorder: an update. Pharmacotherapy 29:
656ÔÇô679.
Elia, J., P. J. Ambrosini, and J. L. Rapoport. 1999. Treatment
of attention-de´¼ücit-hyperactivity disorder. N. Engl. J. Med.
340:780ÔÇô788.
Elliott, R., B. J. Sahakian, K. Matthews, A. Bannerjea, J.
Rimmer, and T. W. Robbins. 1997. Effects of
methylphenidate on spatial working memory and planning
in healthy young adults. Psychopharmacology 131:196ÔÇô206.
European Medicines Agency. 2007. Meeting highlights from
the committee for medicinal products for human use, 16ÔÇô19
July 2007, European Medicines Agency, London.
Farah, M. J., C. Halmm, G. Sankoorikal, M. E. Smith, and A.
Chatterjee. 2009. When we enhance cognition with Adderall,
do we sacri´¼üce creativity? A preliminary study
Psychopharmacology 202:541ÔÇô547.
Faraone, S. V., and S. J. Glatt. 2010. A comparison of the
ef´¼ücacy of medications for adult attention-de´¼ücit/
hyperactivity disorder using meta-analysis of effect sizes. J.
Clin. Psychiatry 71:754ÔÇô763.
Faraone, S. V., J. Biederman, J. G. Jetton, and M. T. Tsuang.
1997. Attention de´¼ücit disorder and conduct disorder:
longitudinal evidence for a familial subtype. Psychol. Med.
27:291ÔÇô300.
Faraone, S. V., J. Sergeant, C. Gillberg, and J. Biederman.
2007. The worldwide prevalence of ADHD: is it an
American condition? World Psychiatry 2:104ÔÇô113.
Fillmore, M. T., T. H. Kelly, and C. A. Martin. 2005. Effects
of d-amphetamine in human models of information
processing and inhibitory control. Drug Alcohol Dep.
77:151ÔÇô159.
Fitzpatrick, P., R. Klorman, J. T. Brumaghim, and R. W.
Keefover. 1988. Effects of methylphenidate on stimulus
evaluation and response processes: evidence from
performance and event-related potentials. Psychophysiology
25:292ÔÇô304.
Fleming, K., L. B. Bigelow, D. R. Weinberger, and T. E.
Goldberg. 1995. Neuropsychological effects of amphetamine
may correlate with personality characteristics.
Psychopharmacol. Bull. 31:357ÔÇô362.
Gandhi, P. J., G. U. Ezeala, T. T. Luyen, T. C. Tu, and M. T.
Tran. 2005. Myocardial infarction in an adolescent taking
Adderall. Am. J. Health Syst. Pharm. 62:1494ÔÇô1497.
Greydanus, D. E., and V. C. Strasburger. 2006. Adolescent
medicine. Prim. Care 33:xiiiÔÇôxviii.
Gualtieri, C. T., and L. G. Johnson. 2008. Medications do not
necessarily normalize cognition in ADHD patients. J. Atten.
Disord. 11:459ÔÇô469.
Habel, L. A., W. O. Cooper, C. M. Sox, K. A. Chan, B. H.
Fireman, P. G. Arbogast, et al. 2011. ADHD medications
and risk of serious cardiovascular events in young and
middle-aged adults. JAMA 306:2673ÔÇô2683.
Harris, S.. 2009. ÔÇ£I donÔÇÖt see it as a problemÔÇØ: more medical
students taking prescription stimulants, few see cause for
concern.
Herman, L., O. Shtayermman, B. Aksnes, M. Anzalone, A.
Cormerals, and C. Liodice. 2011. The use of prescription
stimulants to enhance academic performance among college
students in health care programs. J. Physician Assist. Educ.
22:15ÔÇô22.
Hester, R., L. S. Nandam, R. G. OÔÇÖConnell, J. Wagner, M.
Strudwick, P. J. Nathan, et al. 2012. Neurochemical
enhancement of conscious error awareness. J. Neurosci.
32:2619ÔÇô2627.
Horrigan, J. P. 2001. Present and future pharacotherapeutic
options for adult attention de´¼ücit/hyperactivity disorder.
Exp. Opin. Psychopharmacol. 2:573ÔÇô586.
Hurst, P. M., R. Radlow, N. C. Chubb, and S. K. Bagley. 1969.
Effects of D-amphetamine on acquisition, persistence, and
recall. Am. J. Psychol. 82:307ÔÇô319.
Jacobs, A. 2005. The Adderall advantage. The New York Times.
Available at: http://www.nytimes.com/2005/07/31/education/
edlife/jacobs31.html
Jensen, P. S., L. E. Arnold, J. M. Swanson, B. Vitiello, H. B.
Abikoff, L. L. Greenhill, et al. 2007. 3-year follow-up of the
NIMH MTA study. J. Am. Acad. Child Adolesc. Psychiatry
46:989ÔÇô1002.
Jiao, X., S. Velez, J. Ringstad, V. Eyma, D. Miller, and M.
Bleiberg. 2009. Myocardial infarction associated with
Adderall XR and alcohol use in a young man. J. Am. Board
Fam. Med. 22:197ÔÇô201.
Johnston, L. D., P. M. OÔÇÖMalley, J. G. Bachman, and J. E.
Schulenberg. 2004. Monitoring the future: national survey
results on drug use, 1975ÔÇô2003. Pp. 10ÔÇô12 in NIoD, ed.
Abuse. National Institutes of Health, U.S. Department of
Health and Human Services, Bethesda, MD.
Kadison, R. 2005. Getting an edge ÔÇô use of stimulants and
antidepressants in college. N. Engl. J. Med. 353:1089ÔÇô1091.
Kennedy, R. S., R. C. Odenheimer, D. R. Baltzley, W. P. Dunlap,
and C. D. Wood. 1990. Differential effects of scopolamine
and amphetamine on microcomputer-based performance
tests. Aviat. Space Environ. Med. 61:615ÔÇô621.
Kessler, R. C., L. Adler, R. Barkley, J. Biederman, C. K.
Conners, O. Demler, et al. 2006. The prevalence and
correlates of adult ADHD in the United Stated: results from
the national comorbidity survey replication. Am. J.
Psychiatry 163:716ÔÇô723.
Klorman, R., L. O. Bauer, H. W. Coons, J. L. Lewis, J.
Peloquin, R. A. Perlmutter, et al. 1984. Enhancing effects of
674 ?¬ 2012 The Authors. Published by Wiley Periodicals, Inc.
Stimulants in Individuals With and Without ADHD S. E. Lakhan & A. Kirchgessnermethylphenidate on normal young adultsÔÇÖ cognitive
processes. Psychopharmacol. Bull. 20:3ÔÇô9.
Koelega, H. S. 1993. Stimulant drugs and vigilance
performance: a review. Psychopharmacology 111:1ÔÇô16.
Kollins, S. H. 2003. Comparing the abuse potential of
methylphenidate versus other stimulants: a review of
available evidence and relevance to the ADHD patient.
J. Clin. Psychol. 64:14ÔÇô18.
Kollins, S. H. 2008. ADHD, substance use disorder, and
psychostimulant treatment current literature and treatment
guidelines. J. Atten. Disord. 12:115ÔÇô125.
Kollins, S. H., F. J. McClernon, and B. F. Fuemmeler. 2005.
Association between smoking and attention-de´¼ücit/
hyperactivity disorder symptoms in a population-based
sample of children aged 9 through 16 years. J. Am. Acad.
Child Adolesc. Psychiatry 62:1142ÔÇô1431.
Kuczenski, R., and D. S. Segal. 1997. Effects of
methylphenidate on extracellular dopamine, serotonin, and
norepinephrine: comparison with amphetamine.
J. Neurochem. 68:2032ÔÇô2037.
Kumari, V., P. J. Corr, O. F. Mulligan, P. A. Cotter, S. A.
Checkley, and I. A. Gray. 1997. Effects of acute
administration of d-amphetamine and haloperidol on
procedural learning in man: a preliminary study.
Psychopharmacology 129:271ÔÇô276.
Kutcher, J. S. 2011. Treatment of attention-de´¼ücit hyperactivity
disorder in athletes. Curr. Sports Med. Rep. 10:32ÔÇô36.
Looby, A., and M. Earleywine. 2011. Expectation to receive
methylphenidate enhances subjective arousal but not
cognitive performance. Exp. Clin. Psychopharmacol. 19:433ÔÇô
444.
Lord, S., G. Downs, P. Furlaw, A. Chaudhurl, A. Silverstein, A.
Gammaitoni, et al. 2003. Nonmedical use of prescription
opiods and stimulants among student pharmacists. J. Am.
Pharm. Assoc. 49:519ÔÇô528.
Low, K. G., and A. E. Gendaszek. 2002. Illicit use of
psychostimulants among college students: a preliminary
study. Psychol. Health Med. 7:283ÔÇô287.
Makris, A. P., C. R. Rush, R. C. Frederich, A. C. Taylor, and
T. H. Kelly. 2007. Behavioral and subjective effects of d-
ampetamine and moda´¼ünil in healthy adults. Exp. Clin.
Psychopharmacol. 15:123ÔÇô133.
Masand, P., P. Pickett, and G. B. Murray. 1991.
Psychostimulants for secondary depression in medical
illness. Psychosomatics 32:203ÔÇô208.
Mattay, V. S., K. F. Berman, J. L. Ostrem, G. Esposito, J. D. Van
Horn, and L. B. Bigelow. 1996. Dextroamphetamine enhances
ÔÇ£neural network-speci´¼ücÔÇØ physiological signals: a positron
emission tomography rCBF study. J. Neurosci. 16:
4816ÔÇô4822.
Mattay, V. S., J. H. Callicott, A. Bertolino, I. Heaton, J. A.
Frank, R. Coppola, et al. 2000. Effects of
dextroamphetamine on cognitive performance and cortical
activation. NeuroImage 12:268ÔÇô275.
Mattay, V. S., T. E. Goldberg, F. Fera, A. R. Hariri, A.
Tessitore, M. F. Egan, et al. 2003. Catechol O-
methyltransferase val158-met genotype and individual
variation in the brain response to amphetamine. Proc. Natl.
Am. Sci. USA 100:6186ÔÇô6191.
McCabe, S. E., and C. J. Boyd. 2005. Sources of prescription
drugs for illicit use. Addict. Behav. 30:1342ÔÇô1350.
McCabe, S. E., C. J. Teter, and C. J. Boyd. 2004. The use,
misuse and diversion of prescription stimulants among
middle and high school students. Subst. Use Misuse
39:1095ÔÇô1116.
McCabe, S. E., J. R. Knight, C. J. Teter, and H. Wechsler.
2005. Nonmedical use of prescription stimulants among US
college students: prevalence and correlates from a
nationwide survey. Addiction 100:96ÔÇô106.
McLaughlin, L. 2011. Adderall: the whole story. Available at:
http://reesenews.org/2011/10/26/adderall-the-whole-story/
19843/
McNiel, A. D., K. B. Muzzin, J. P. DeWald, A. L. McCann, E.
D. Schneiderman, J. Sco´¼üeld, et al. 2011. The nonmedical
use of prescription stimulants among dental and dental
hygiene students. J. Dental Edu. 75:365ÔÇô376.
Mehta, M. A., A. M. Owen, B. J. Sahakian, N. Mavaddat, J. D.
Pickard, and T. W. Robbins. 2000. Methylphenidate enhances
working memory by modulating discrete frontal and parietal
lobe regions in the human brain. J. Neurosci. 20:RC65.
Mintzer, M. Z., and R. R. Grif´¼üths. 2007. A triazolam/
amphetamine dose-effect interaction study: dissociation of
effects on memory versus arousal. Psychopharmacology
192:425ÔÇô440.
Misener, V. L., P. Luca, O. Azeke, J. Crosbie, I. Waldman, R.
Tannock, et al. 2004. Linkage of the dopamine receptor D1
gene to attention-de´¼ücit/hyperactivity disorder. Mol.
Psychiatry 9:500ÔÇô509.
Mitchell, H.. 2012. Faking ADHD Gets you into Harvard. The
Daily Beast. Available at: http://www.thedailybeast.com/
articles/2012/01/25/faking-adhd-gets-you-into-harvard.html
Molina, B. S. G., S. P. Hinshaw, J. M. Swanson, L. E. Arnold,
B. Vitiello, P. S. Jensen, et al. 2009. The MTA at 8 years:
prospective follow-up of children treated for combined type
ADHD in the multisite study. J. Am. Acad. Child Adolesc.
Psychiatry. 48:484ÔÇô500.
Murray, J. B. 1998. Psychophysiological aspects of amphetamine-
methamphetamine abuse. J. Psychol. 132:227ÔÇô237.
Musser, C. J., P. A. Ahmann, F. W. Theye, P. Mundt, S. K.
Broste, and N. Mueller-Rizner. 1998. Stimulant use and the
potential for abuse in Wisconsin as reported by school
administrators and longitudinally followed children. J. Dev.
Behav. Pediatr. 19:187ÔÇô192.
Oken, B. S., S. S. Kishiyama, and M. C. Salinsky. 1995.
Pharmacologically induced changes in arousal: effects on
behavioral and electrophysiologic measures of alertness
and attention. Electroenceph Clin. Neurophysiol. 95:
359ÔÇô371.
?¬ 2012 The Authors. Published by Wiley Periodicals, Inc. 675
S. E. Lakhan & A. Kirchgessner Stimulants in Individuals With and Without ADHDPartridge, B. J., S. K. Bell, J. C. Lucke, S. Yeates, and W. D.
Hall. 2011. Smart drugs ÔÇ£as common as coffeeÔÇØ: media hype
about neuroenhancement. PLoS One 6:e28416.
Pelham W. E., Jr, K. McBurnett, G. W. Harper, R. Milich, D.
A. Murphy, J. Clinton, et al. 1990. Methylphenidate and
baseball playing in ADHD children: whoÔÇÖs on ´¼ürst?
J. Consult. Clin. Psychol. 58:130ÔÇô133.
Piper, B. J., J. B. Fraiman, and J. S. Meyer. 2005. Repeated
MDMA (ÔÇ£EcstasyÔÇØ) exposure in adolescent male rats alters
temperature regulation, spontaneous motor activity,
attention, and serotonin transporter binding. Dev.
Psychobiol. 47:145ÔÇô157.
Polanczyk, G., M. S. de Lima, B. L. Horta, J. Biederman, and
L. A. Rohde. 2007. The worldwide prevalence of ADHD: a
systematic review and metaregression analysis. Am. J.
Psychiatry 164:942ÔÇô948.
Polchert, S. E., and R. M. Morse. 1985. Pemoline abuse. JAMA
254:946ÔÇô947.
Putukian, M., J. B. Kreher, D. B. Coppell, J. L. Glazer, D. B.
McKeag, and R. D. White. 2011. Attention de´¼ücit
hyperactivity disorder and the athlete: an American Medical
Society for Sports Medicine position statement. Clin. J.
Sport Med. 21:392ÔÇô401.
Rabiner, D. L., A. D. Anastopoulos, E. J. Costello, R. H.
Hoyle, S. E. McCabe, and H. S. Swartzweder. 2009. The
misuse and diversion of prescribed ADHD medications by
college students. J. Atten. Disord. 13:144ÔÇô153.
Rapoport, J. L., M. S. Buchsbaum, H. Weingartner, T. P.
Zahn, C. Ludlow, and E. J. Mikkelsen. 1978.
Dextroamphetamine: cognitive and behavioral effects in
normal and prepubertal boys. Science 199:560ÔÇô563.
Rasmussen, P., and C. Gillberg. 2000. Natural outcome of
ADHD with developmental coordination disorder at age
22 years: a controlled, longitudinal, community-based
study. J. Am. Acad. Child Adolesc. Psychiatry 39:1424ÔÇô
1431.
Rogers, R. D., A. J. Blackshaw, H. C. Middleton, K. Matthews,
K. Hawtin, C. Crowley, et al. 1999. Tryptophan depletion
impairs stimulus-reward learning while methylphenidate
disrupts attentional control in healthy young adults:
implications for the monoaminergic basis of impulsive
behavior. Psychopharmacology 146:482ÔÇô491.
Rosa-Neto, P., H. C. Lou, P. Cumming, O. Pryds, H.
Karrebaek, J. Lunding, et al. 2005. Methylphenidate-evoked
changes in striatal dopamine correlate with inattention and
impulsivity in adolescents with attention de´¼ücit
hyperactivity/disorder. Neuroimage 25:868ÔÇô876.
Rosenthal, E. 2012. Not acute myocardial infarction in a
teenager due to Adderall XR. Pediatr. Cardiol. 33:679.
Sahakian, B. J., and A. M. Owen. 1992. Computerized
assessment in neuropsychiatry using CANTAB: discussion
paper. J. Royal Soc. Med. 85:399ÔÇô402.
Schelleman, H., W. B. Bilker, S. E. Kimmel, G. W. Daniel, C.
Newcomb, J. P. Guevara, et al. 2012. Methylphenidate and
risk of serious cardiovascular events in adults. Am. J.
Psychiatry 169:178ÔÇô185.
Schmedje, J. F., C. M. Oman, R. Letz, and E. L. Baker. 1988.
Effects of scopolamine and dextroamphetamine on human
performance. Aviation Space Environ. Med. 59:407ÔÇô410.
Schroeder, S. R., K. Mann-Koepke, C. T. Gualtieri, D. A.
Eckerman, and G. R. Breese. 1987. Methylphenidate affects
strategic choice behavior in normal adult humans.
Pharmacol. Biochem. Behav. 28:213ÔÇô217.
Schweitzer, J. B., D. O. Lee, R. B. Hanford, C. F. Zink, T. D.
Ely, M. A. Tagamets, et al. 2004. Effect of methylphenidate
on executive functioning in adults with attention de´¼ücit/
hyperactivity disorder: normalization of behavior but not
related brain activity. Biol. Psychiatry 56:597ÔÇô606.
Sciutto, M. J., C. J. Nol´¼ü, and C. Bluhm. 2004. Effects of child
gender and symptom type on referrals for ADHD by
elementary school teachers. J. Emotion Behav. Disord.
12:247ÔÇô253.
Servan-Schreiber, D., C. S. Carter, R. M. Bruno, and J. D.
Cohen. 1998. Dopamine and the mechanisms of cognition:
Part II. D-amphetamine effects in human subjects
performing a selective attention task. Biol. Psychiatry
43:723ÔÇô729.
Silber, B. Y., R. J. Croft, K. Papafotiou, and C. Stough. 2006.
The acute effects of d-amphetamine and methamphtetamine
on attention and psychomotor performance.
Psychopharmacology 187:154ÔÇô169.
Smith, M. E., and M. J. Farah. 2011. Are prescription
stimulants ÔÇ£smart pillsÔÇØ? The epidemiology and cognitive
neuroscience of prescription stimulant use by normal
healthy individuals. Psychol. Bull. 137:717ÔÇô741.
Soetens, E., R. Dhooge, and J. Hueting. 1993. Amphetamine
enhances human-memory consolidation. Neurosci. Lett.
161:9ÔÇô12.
Soetens, E., S. Casaer, R. Dhooge, and J. Hueting. 1995. Effect
of amphetamine on long-term retention of verbal material.
Psychopharmacology 119:155ÔÇô162.
Sroufe, L. A. 2012. Ritalin gone wrong. New York Times, 29
January 2012.
Strauss, J., J. L. Lewis, R. Klorman, L. J. Peloquin, R. A.
Perlmatter, and L. F. Salzman. 1984. Effects of
methylphenidate on young adults performance and event-
related potentials in a vigilance and a paired-associates
learning test. Psychophysiology 21:609ÔÇô621.
Surles, L. K., H. J. May, and J. P. Garry. 2002. Adderall-
induced psychosis in an adolescent. J. Am. Board Fam.
Pract. 15:498ÔÇô500.
Sylvester, A. L., and B. Agarwala. 2012. Acute myocardial
infarction in a teenager due to Adderall XR. Pediatr.
Cardiol. 33:155ÔÇô157.
Teter, C. J., S. E. McCabe, J. A. Cranford, C. J. Boyd, and S.
K. Guthrie. 2005. Prevalence and motivations for the illicit
use of prescription stimulants in an undergraduate student
sample. J. Am. Coll. Health 53:253ÔÇô262.
676 ?¬ 2012 The Authors. Published by Wiley Periodicals, Inc.
Stimulants in Individuals With and Without ADHD S. E. Lakhan & A. KirchgessnerThe MTA Cooperative Group. 1999. A 14-month randomized
clinical trial of treatment strategies for attention-de´¼ücit/
hyperactivity disorder. Arch. Gen. Psychiatry 56:1073ÔÇô1086.
Tuttle, J. P., N. E. Scheurich, and J. Ranseen. 2010. Prevalence
of ADHD diagnosis and nonmedical prescription stimulant
use in medical students. Acad. Psychiatry 34:220ÔÇô223.
Unrug, A., A. Coenen, and G. van Luijtelaar. 1997. Effects of
the tranquilizer diazepam and the stimulant
methylphenidate on alertness and memory.
Neuropsychobiology 36:42ÔÇô48.
Upadhyaya, H. P., K. Rose, W. Wang, K. OÔÇÖRourke, B.
Sullivan, D. Deas, et al. 2005. Attention-de´¼ücit/hyperactivity
disorder, medication treatment, and substance use patterns
among adolescents and young adults. J. Child Adolesc.
Psychopharmacol. 15:799ÔÇô809.
Visser, S. N., C. A. Lesesne, and R. Perou. 2012. National
estimates and factors associated with medication treatment
for childhood attention-de´¼ücit/hyperactivity disorder.
Pediatrics 119:S99ÔÇôS107.
Vitiello, B., G. R. Elliott, J. M. Swanson, L. E. Arnold, L.
Hechtman, H. Abikoff, et al. 2011. Blood pressure and heart
rate in the mulimodal treatment of attention de´¼ücit/
hyperactivity disorder study over 10 years. Am. J.
Psychiatry. 169:167ÔÇô177.
Volkow, N. D., Y. S. Ding, J. S. Fowler, G. J. Wang, J. Logan,
J. S. Gatley, et al. 1995. Is methylphenidate like cocaine?
Studies on their pharmacokinetics and distribution in the
human brain. Arch. Gen. Psychiatry 52:456ÔÇô463.
Volkow, N. D., G. J. Wang, J. Newcorn, F. Telang, M. V.
Solanto, J. S. Fowler, et al. 2007. Depressed dopamine
activity in caudate and preliminary evidence of limbic
involvement in adults with attention-de´¼ücit/hyperactivity
disorder. Arch. Gen. Psychiatry 64:932ÔÇô940.
Volkow, N. D., G. J. Wang, D. Tomasi, S. H. Kollins, T. L.
Wigal, J. H. Newcorn, et al. 2012. Methylphenidate-
elicited dopamine increases in ventral striatum are
associated with long-term symptom improvement in
adults with attention de´¼ücit hyperactivity disorder.
J. Neurosci. 32:841ÔÇô849.
Ward, A. S., T. H. Kelly, R. W. Foltin, and M. W. Fischman.
1997. Effects of d-amphetamine on task performance and
social behavior of humans in a residential laboratory. Exp.
Clin. Psychopharmacol. 5:130ÔÇô136.
Weitzner, M. 1965. Manifest anxiety, amphetamine and
performance. J. Psychol. 60:71ÔÇô79.
Weyandt, L. L., and G. DuPaul. 2006. ADHD in college
students. J. Atten. Disord. 10:9ÔÇô19.
Wilens, T. E. 2003. Does the medicating ADHD increase or
decrease the risk for later substance abuse? Rev. Bras.
Psiquiatr. 25:127ÔÇô128.
Wilens, T. E., J. Biederman, and T. J. Spencer. 2002. Attention
de´¼ücit/hyperactivity disorder across the lifespan. Annu. Rev.
Med. 53:113ÔÇô131.
Wilens, T. E., S. Faraone, and J. Biederman. 2004.
Attention-de´¼ücit/hyperactivity disorder in adults. JAMA
292:619ÔÇô623.
Wilens, T. E., L. A. Adler, J. Adams, S. Sgambati, J. Rotrosen,
R. Sawtelle, et al. 2008. Misuse and diversion of stimulants
prescribed for ADHD: a systematic review of the literature.
J. Am. Acad. Child Adolesc. Psychiatry 47:21ÔÇô31.
Willett, R. A. 1962. The effect of a stimulant and a depressant
drug on the serial rote learning of nonsense syllables.
Psychopharmacologia 3:23ÔÇô34.
Wise, R. A. 2002. Brain reward circuitry: insights from
unsensed incentives. Neuron 36:229ÔÇô240.
de Wit, H., J. Crean, and J. B. Richards. 2000. Effects of
d-amphetamine and ethanol on a measure of behavioral
inhibition in humans. Behav. Neurosci. 114:830ÔÇô837.
de Wit, H., J. L. Enggasser, and J. B. Richards. 2002. Acute
administration of d-amphetamine decreases impulsivity
in healthy volunteers. Neuropsychopharmacology 27:813ÔÇô
825.
Zeeuws, I., and E. Soetens. 2007. Verbal memory performance
improved via an acute administration of D-amphetamine.
Hum. Psychopharmacol. Clin. Exp. 22:279ÔÇô287.
Zuvekas, S., and B. Vitiello. 2011. Stimulant medication use in
children: a 12-year perspective. Am. J. Psychiatry 169:160ÔÇô
166