International Journal of Neuropsychopharmacology (2014), 17, 961–977.

© CINP 2014 REVIEW

doi:10.1017/S1461145713001594

Cognitive effects of methylphenidate in healthy

volunteers: a review of single dose studies

A. M. W. Linssen, A. Sambeth, E. F. P. M. Vuurman and W. J. Riedel

Department Neuropsychology & Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, PO Box 616,
6200 MD, Maastricht, The Netherlands

Abstract
Methylphenidate (MPH), a stimulant drug with dopamine and noradrenaline reuptake inhibition properties, is
mainly prescribed in attention deficit hyperactivity disorder, is increasingly used by the general population,
intending to enhance their cognitive function. In this literature review, we aim to answer whether this is effective.
We present a novel way to determine the extent to which MPH enhances cognitive performance in a certain
domain. Namely, we quantify this by a percentage that reflects the number of studies showing performance en-
hancing effects of MPH. To evaluate whether the dose–response relationship follows an inverted-U-shaped
curve, MPH effects on cognition are also quantified for low, medium and high doses, respectively. The studies
reviewed here show that single doses of MPH improve cognitive performance in the healthy population in the
domains of working memory (65% of included studies) and speed of processing (48%), and to a lesser extent may
also improve verbal learning and memory (31%), attention and vigilance (29%) and reasoning and problem solv-
ing (18%), but does not have an effect on visual learning and memory. MPH effects are dose-dependent and the
dose–response relationship differs between cognitive domains. MPH use is associated with side effects and other
adverse consequences, such as potential abuse. Future studies should focus on MPH specifically to adequately
asses its benefits in relation to the risks specific to this drug.
Received 19 June 2013; Reviewed 13 August 2013; Revised 15 November 2013; Accepted 27 November 2013;
First published online 15 January 2014

Key words: Cognition, Dopamine, Memory, Methylphenidate.

Introduction after MPH (e.g. planning (Elliott et al., 1997)). While a

reasonable amount of studies have examined cognitive
Methylphenidate (MPH; see Table 1 for a complete list of
effects of MPH in healthy volunteers, the evidence is
abbreviations) is a stimulant drug that is mainly pre-
undeniably mixed.
scribed in attention deficit hyperactivity disorder
Cognitive effects of MPH in children with ADHD have
(ADHD, (Leonard et al., 2004)). In the past decades
been reviewed by Pietrzak et al. (2006). Their extensive re-
there has been a vast increase in the use of MPH (Diller,
view includes evidence on a broad range of cognitive
1996). Not only by patients to whom MPH is prescribed,
functions and presents it classified into several cognitive
but also by the general population, who believe that MPH
domains. An equivalent review on cognitive effects of
enhances their cognitive functions (Maher, 2008). This has
MPH in healthy volunteers is not available yet. Previous
raised ethical concern (Sahakian and Morein-Zamir, 2007;
reviews on the cognition-enhancing effects of drugs
Larriviere et al., 2009; Stix, 2009). Discussions in popular
have focused on attention, learning, memory and execu-
scientific literature consider safety, potential abuse and
tive function (Repantis et al., 2010; Smith and Farah,
side effects (Swanson and Volkow, 2008; Stix, 2009) of
2011). In the current review the full spectrum of cognitive
cognition-enhancing drugs. However, even if these issues
function is considered. The differences between studies
were no reason for concern, a critical question would
on cognitive effects of MPH – such as differences in
still be: ‘How effective are supposed cognition-enhancing
methodology, MPH dose, neuropsychological instru-
drugs actually?’. Although there are some indications that
ments employed – do not encourage conducting a
MPH may improve certain aspects of cognitive function
meta-analysis (Pietrzak et al., 2006). As we did not want
(e.g. working memory (Mehta et al., 2000b)), there are
to limit our review to one particular measure or cognitive
also reports of impaired performance on cognitive tasks
domain, we used a similar approach as Pietrzak et al.
(2006). Because the review by Pietrzak et al. (2006)
Address for correspondence: Dr A. M. W. Linssen, Department focused on studies involving children with ADHD, the
Neuropsychology & Psychopharmacology, Faculty of Psychology and reported tasks differ slightly from those in studies with
Neuroscience, Maastricht University, PO Box 616, 6200 MD Maastricht,
healthy volunteers, since both clinical status (i.e. ADHD
The Netherlands.
Tel.: 0031433881757 Fax: 0031433884560 diagnosis) and age (children vs. adults) may call for a dif-
Email: amw.linssen@alumni.maastrichtuniversity.nl ferent selection of tasks. Inspection of the range of tasks
962 A. M. W. Linssen et al.
used in studies with MPH in healthy volunteers, and the
fact that the classification applied by Pietrzak et al. (2006)
is not based on factor analysis or any other established
way of classifying cognitive tasks (or this is not reported),
we looked for a classification that was more appropriate
for the available data (Pietrzak et al., 2006).
The categorization described by Nuechterlein et al.
(2004) is based on factor analytic studies and fine-tuned
by a committee of field experts. Although the identification
considered cognitive function in schizophrenia patients, it
is generally accepted that cognitive domains are broadly
the same in healthy controls (Dickinson et al., 2006;
Genderson et al., 2007). The cognitive domains (i.e. speed
of processing, attention/vigilance, working memory,
verbal learning and memory, visual learning memory
and reasoning and problem solving) fit well with the litera-
ture on healthy volunteers (Riedel et al., 2006) and are
employed in this review (Nuechterlein et al., 2004).
Considering the mixed nature of the literature, a de-
scriptive statistic quantifying the evidence would facili-
tate its interpretation. Pietrzak et al. (2006) summarize
the results within each domain as a percentage of studies
reporting cognition enhancing effects of MPH. In order to
also take into account factors that determine the statistical
power of the studies (number of participants and number
of tasks/measures), we established a weighed percentage
reflecting the relative contribution of the studies reviewed
to the MPH effects (Kleijnen et al., 1991).
Effects of dopamine on cognition are often described
to follow an inverted-U-shaped curve in which inter-
mediate levels of neurotransmitter activity lead to
optimal cognitive performance, but lower and higher
levels may lead to suboptimal performance (Husain
and Mehta, 2011). Since MPH blocks the dopamine and
noradrenaline transporters, thereby blocking reuptake of
these neurotransmitters, MPH leads to increased levels
of dopamine and noradrenaline availability (Volkow
et al., 1998; Hannestad et al., 2010) and may demonstrate
inverted-U properties. Moreover, dose–response relation-
ships may vary between cognitive domains. Therefore,
we report a weighed percentage reflecting MPH effects,
equivalent to the one described above for low, medium
and high doses, respectively.
The aim of this review is to answer the question whether
MPH can enhance cognitive function in healthy indivi-
duals. This review specifically looks at the acute effects
of MPH on healthy adults (i.e. excluding effects of other
medications, effects on children, effects after sleep depri-
vation and long term effects). Effects on the elderly are dis-
cussed in a separate paragraph, as well as imaging data.
Method
Literature search
A literature search was performed in PubMed and
Psychinfo using the search term Methylphenidate
combined with the terms cognition, neuropsychology, execu-
tive, working memory, vigilance and inhibition in separate
searches. Reference lists of extracted articles were
screened for omissions in our search. Studies that were in-
cluded fulfilled the following criteria: used immediate re-
lease formulation of MPH; assessed the effects of acute
doses of MPH; assessed healthy human adults 18 yr and
older; assessed the effects using cognitive tasks; were
written in English; published in a peer-reviewed journal.
Both studies employing a within- and between-subjects
design were included. Studies assessing chronic or sub-
chronic effects of MPH were not included. The earliest
study included was published March 1978 and the last in-
cluded study was published May 2013.
Categorization
The neuropsychological tests were categorized into six
different cognitive domains: speed of processing, atten-
tion/vigilance, working memory, verbal learning and
memory, visual learning and memory and reasoning
and problem solving (Nuechterlein et al., 2004). Tasks
employed in the included articles were categorized fol-
lowing the classification by Nuechterlein et al. (2004). If
more than one cognitive domain was applicable, tasks
were still classified as measuring one domain only (i.e.
the most salient domain). Tasks that could not be categor-
ized in any of these six cognitive domains were not in-
cluded in the analysis (for instance ‘spatial bias’ in
(Dodds et al., 2008a)).
Outcome measure
For each domain a weighed percentage was calculated
reflecting to what extent MPH affects task performance
in that specific domain. It was calculated as follows:


( (number of participants × outcome
significance testing × relative
contribution))
Outcome measure =

( (number of participants × relative
contribution)) × 100%
in which number of participants was used as reported
for within-subjects designs, while for between-subjects
designs, the number of participants that received MPH
was used in the calculation. Outcome significance testing
was defined as: 1 = significantly improved task perform-
ance; −1 = significantly impaired task performance; 0 =
no significant effect; 0.5 = trend towards improved task
performance; −0.5 = trend towards impaired task per-
formance, and the factor to correct for multiple compari-
sons (relative contribution) was defined as: 1/number of
tasks or measures within the study that are reported in
Table 2 (i.e. if three measures were reported in the article,
but only two were listed in Table 2., the factor was 1/2 =
0.5). Only data of participants aged between 18 and 60
were included in the calculation. Data on elderly partici-
pants are discussed in a separate paragraph.
 Review on methylphenidate and cognition 963

Table 1. Abbreviations Working memory

Working memory involves the temporary storage and
ADHD Attention deficit hyperactivity disorder
A/V Attention/vigilance manipulation of information (Baddeley, 1992). For the
CNV Contingent negative variation purpose of this review, no distinction was made between
CPT Continuous performance test short term memory and working memory tasks. A com-
DSST Digit symbol substitution mon working memory task is the digit span, requiring
ID/ED Intra-/extradimensional shift task subjects to repeat a sequence of digits either in the exact
MPH Methylphenidate same or reversed order. More complex tasks include
PAL Paired associates learning memory scanning tasks and N-back tasks. Memory
PASAT Paced auditory serial addition test scanning tasks present participants with probes that they
RPS Reasoning and problem solving
have to compare to a memory set that may vary in size,
RT Response time
and hence, memory load (Sternberg, 1966). N-back tasks re-
RVIP Rapid visual information processing
quire a response to stimuli that are the same as the stimulus
SERS Stimulus evaluation/response selection task
SMS Sternberg memory scanning task that was presented N-trials before. Other tasks specifically
SoP Speed of processing assess spatial working memory, which is often associated
TMT Trail making test with dopaminergic activity (Mehta and Riedel, 2006).
TOVA Test of variables of attention Although the number of MPH studies including a test
VEM Verbal learning and memory of working memory was not very high, the proportion
VSM Visual learning and memory that shows enhancing effects in this cognitive domain
WLT Word learning test was the highest of all reported domains, namely 65%.
WM Working memory The proportion of the effect of MPH was similar across
different types of tasks. The highest proportion of signifi-
cant effects was observed with the medium dose. This
Another frequently considered evaluation parameter is was also reflected by a subset of tests, namely the spatial
effect size, and it would be interesting to compare this to working memory tests. It is possible that the MPH-effect
our study evaluation measure. However, due to the fact follows an inverted-U-shaped curve as a function of dose,
that most of the reported studies did not convey all essen- since a high dose (60 mg) exerted no effect on a spatial
tial information necessary to calculate it, effect sizes were working memory task that was affected by lower doses
not reported. in other studies ((Elliott et al., 1997; Mehta et al., 2000b;
Clatworthy et al., 2009), but note that Elliott et al. (1997)
found no main effects).
Dose effects

The outcome measure as detailed above was also calcu-
lated for low, medium and high doses separately. A
low, medium or high dose was defined as follows: low:
410 mg or 40.15 mg/kg; medium: >10 mg, 420 mg or
>0.15 mg/kg, 40.3 mg/kg; high: >20 mg or >0.3 mg/kg. If
it was not clearly stated which dose(s) led to significant
effects, it was assumed that the reported effect was appli-
cable to every administered dose.
Results and discussion
In total 60 studies met the inclusion criteria. Of these, 56
included healthy volunteers between 18 and 60 yr old. All
studies are listed in Table 2. The extent to which MPH
enhances cognitive performance (quantified by a weighed
percentage) is reported in Table 3. The results show that
MPH most effectively enhances performance in the do-
main of working memory. Second most affected were
tasks measuring speed of processing, followed by verbal
learning and memory, attention/vigilance, reasoning
and problem solving, and visual learning and memory.
In the next few paragraphs, the results per domain are
discussed in more detail.
Speed of processing
Tasks that are classified as a measure of speed of processing
are relatively simple, involving fundamental processes
such as perception and motor action. This category
includes, for example, digit symbol substitution tests
(DSST) and trail making tests (TMT); version A and B
The speed of processing domain was, with 48%, the se-
cond most affected domain in terms of performance en-
hancing effects of MPH. This is consistent with the
notion that MPH speeds up response time in healthy
volunteers (Elliott et al., 1997), reflecting response-readi-
ness enhancing effects (Linssen et al., 2011).
A striking observation is that the low dose exerted the
highest proportion of effects on cognitive performance in
this domain, followed by the medium dose, with the
highest dose showing the lowest proportion of effects.
This suggests that within this domain the optimal dose
is rather low and the higher the dose, the less healthy
volunteers benefit from it.
Verbal learning and memory
Whereas MPH affected the former two domains in 48% or
more of the reported measurements, the domain of verbal
Table 2. Summary of studies on cognitive effects of MPH in healthy volunteers

964
A. M. W. Linssen et al.
Study No. of pp M, F (age) design Dose Task/measure Domain Effect

(Agay et al., 2010) [1] 8M, 8F (32.9) placebo controlled between groups 15 mg1 CPT (omission errors) A/V ns
CPT (commission errors) A/V ns
Digit span WM sig
(Aman et al., 1984) [2] 5M, 7F(28.3) placebo controlled crossover 0.3 mg/kg CPT (omission errors) A/V ns
CPT (commission errors) A/V sig
CPT (RT) A/V ns
(Anderer et al., 2002) [3] 10M, 10F (23–34) placebo controlled crossover 20 mg Oddball (error rate) A/V ns
(Ben-Itzhak et al., 2008) [4] 9M, 17F (73.8) Placebo-controlled crossover 20 mg Go-NoGo A/V sig2
nonverbal memory VSM ns
(Bernard et al., 2011) [5] 9M, 9F (26.7) placebo controlled crossover 40 mg Choice reaction time (recognition reaction time) SoP sig
Choice reaction time (total reaction time) SoP ns
Choice reaction time (motor reaction time) SoP ns
(Bishop et al., 1997) [6] 6M, 3F (21–35) placebo controlled crossover 10 mg (2x/day) Divided attention A/V ns
Auditory vigilance A/V ns
(Brignell and Curran, 2006) [7] 6M, 10F (18–35) placebo controlled between groups 40 mg Fear conditioning VSM ns
(Brignell et al., 2007) [8] 16 HV (18–35) placebo controlled between groups 40 mg Story task VEM Trend3
(Brumaghim and Klorman, 1998) [9] 12M, 20F (20.9) placebo controlled crossover 0.3 mg/kg PAL (CVC pairs) VEM ns
(Brumaghim et al., 1987) study 1 [10] 19M (19.4) placebo controlled crossover 0.3 mg/kg SMS WM sig
(Brumaghim et al., 1987) study 2 6M, 8F (20.0) placebo controlled crossover 0.3 mg/kg SMS WM sig
(Callaway, 1984) [11] 8F (30–40) 5/10/20 mg SERS SoP sig
8F (60–75) 5/10/20 mg SERS SoP ns
placebo controlled crossover
(Camp-Bruno and Herting, 1994) [12] 7M, 8F(19–33) placebo controlled between groups 20 mg CPT (RT) A/V sig
CPT (sensitivity) A/V ns
CPT (ln beta) A/V ns
Word learning VEM ns
Buschke selective reminding VEM sig
(Campbell-Meiklejohn et al., 2012). [13] 19F (23) placebo controlled between groups 20 mg N-back WM ns
(Clark et al., 1986a) [14] 12M (18–30) placebo controlled crossover 0.65 mg/kg Dichotic monitoring task (target detection) A/V ns
Dichotic monitoring task (error rate) A/V ns
Dichotic monitoring task (RT) A/V ns
Dichotic monitoring task (signal detection) A/V ns
(Clark et al., 1986b) [15] 10M (18–30) placebo controlled crossover 0.65 mg/kg Dichotic monitoring task (target detection) A/V ns
Dichotic monitoring task (error rate) A/V sig
Dichotic monitoring task (RT) A/V ns
Dichotic monitoring task (signal detection) A/V ns
(Clatworthy et al., 2009) [16] 10M (22–32) placebo controlled crossover 60 mg Reversal learning VSM ns
Spatial WM WM ns
(Coons et al., 1981) study 1 [17] 13M (23.84) placebo controlled crossover 20 mg CPT X (omission errors) A/V ns
CPT X (commission errors) A/V ns
CPT BX (omission errors) A/V ns
CPT BX (commission errors) A/V ns
(Coons et al., 1981) study 2 23M (19.7) placebo controlled crossover 20 mg CPT X (omission errors) A/V ns
CPT X (commission errors) A/V ns
CPT BX (omission errors) A/V sig
CPT BX (commission errors) A/V ns
CPT Double (omission errors) A/V sig
CPT Double (commission errors) A/V ns
Oddball (omission errors) A/V ns
Oddball (commission errors) A/V ns
Choice RT (omission errors) SoP sig
Choice RT (commission errors) SoP ns
Choice RT (response time) SoP ns
(Cooper et al., 2005) [18] 32M (22.3) placebo controlled crossover 5/15/45 mg CPT (omission errors) A/V sig
CPT (commission errors) A/V ns
CPT (RT)/N back A/V sig
(Costa et al., 2013) [19] 54M(23.7) placebo controlled crossover 40 mg Go/No-go Task A/V ns
Stop signal task A/V ns
(Dodds et al., 2008b) [20] 14M, 6F (22.2) placebo controlled crossover 60 mg Probabilistic reversal learning VSM ns
(Drijgers et al., 2012) 21 21M, 2F (65.4) Placebo crossover 10 mg Letter digit substitution SoP ns
Simple reaction time task SoP ns
Choice reaction time task SoP ns
(Elliott et al., 1997) [22] 28M (21.3) placebo controlled crossover 20/40 mg Spatial WM WM sig4
Tower of London (old) RPS sig5
Tower of London (new) RPS sig6
Verbal fluency test SoP ns
sig4

Review on methylphenidate and cognition 965

Spatial span WM
ID/ED shift task A/V ns
Sequence generation RPS sig
RVIP (response latency) A/V sig
RVIP (performance) A/V ns
(Finke et al., 2010) [23] 9M, 9F (20–35) placebo controlled crossover 40 mg Visual perceptual processing speed SoP sig
Visual short-term memory storage capacity VSM ns
(Fitzpatrick et al., 1988) [24] 20M (19.7) placebo controlled crossover 0.3 mg/kg Memory scanning task WM sig
(Halliday et al., 1986) exp 1 [25] 8F (30–40) placebo controlled crossover 5/10/20 mg SERS SoP sig
SMS WM ns
(Halliday et al., 1986) exp 2 12M (26) placebo controlled crossover 10 mg SERS SoP sig
CPT (commission errors) A/V sig
motor task SoP sig
Table 2. (Cont.)

966
A. M. W. Linssen et al.
Study No. of pp M, F (age) design Dose Task/measure Domain Effect

(Hermens et al., 2007) [26] 32M (22.3) placebo controlled crossover 5/15/45 mg Oddball A/V sig
CPT (RT) A/V sig
CPT (omission errors) A/V sig
CPT (commission errors) A/V ns
CPT (total errors) A/V sig
Maze RPS ns
Mackworth clock (RT variability) A/V sig
Mackworth clock (false negatives) A/V sig
Mackworth clock (false positives) A/V ns
Mackworth clock (total errors) A/V sig
Verbal memory recall VEM ns
Choice reaction time SoP ns
Switching of attention (TMT A) SoP ns
Switching of attention (TMT B) SoP ns
PASAT (RT) A/V sig
PAL (word pairs) VEM ns
(Hester et al., 2012) [27] 27M (22) placebo controlled crossover 30 mg Go/No-go task (accuracy) A/V sig
Go/No-go task (Go RT) A/V ns
Go/No-go task (No-go error RT) A/V ns
(Hink et al., 1978) [28] 12M (19–28) placebo controlled crossover 10 mg Target detection task A/V ns
(Izquierdo et al., 2008) [29] 7M, 5F (40–74) placebo controlled crossover 10 mg Incidental memory task VEM sig
(Izquierdo et al., 2008) 11M, 9F (35–74) placebo controlled crossover 10 mg Formal memory task VEM Sig/ns7
(Kollins et al., 1998) [30] 5M, 5F (30.7) placebo controlled crossover 20/40 mg DSST SoP ns
circular lights task SoP sig
(Kratz et al., 2009) [31] 8M, 6F (20–40) placebo controlled crossover 20 mg Go/No-go task (hit rate) A/V ns
Go/No-go task (RT) A/V sig
Impulsivity errors A/V ns
(Kupietz et al., 1980) [32] 5M, 4F (28.7) placebo controlled crossover 5/10 mg Learning beginning reading vocabulary task
(simultaneous method) VEM sig
(progressive method) VEM ns
(Kuypers and Ramaekers, 2005) [33] 9M, 9F (26.2) placebo controlled crossover 20 mg WLT VEM ns
Syntactic resasoning task WM ns
DSST SoP ns
(Kuypers and Ramaekers, 2007) [34] 9M, 9F (26.2) placebo controlled crossover 20 mg Spatial memory task VSM ns
Change blindness task VSM ns
(Linssen et al., 2011) [35] 19M (23.4) placebo controlled crossover 10/20/40 mg CNV Lines SoP sig
CNV Stoplight SoP sig
(Linssen et al., 2012) [36] 19M (23.4) placebo controlled crossover 10/20/40 mg WLT VEM sig
Spatial WM WM ns
Set shifting A/V sig
Stop signal task A/V sig
Tower of London RPS ns
(Marquand et al., 2011) [37] 15M (20–39) placebo controlled crossover 30 mg Spatial WM WM ns
(Mehta et al., 2000a) [38] 10M (34.8) placebo controlled crossover 40 mg Spatial WM WM sig
(Moeller et al., 2012) [39] 14M, 1F (38.9) 20 mg Stroop SoP ns
(Muller et al., 2005) [40] 4M, 8F (69.8) placebo controlled crossover 20 mg 4 choice motor reaction task A/V Sig8
(Nandam et al., 2011) [41] 24M (23) placebo controlled crossover 30 mg Stop signal task A/V sig
(Naylor et al., 1985) [42] 8F (30–39) placebo controlled crossover 5/10/20 mg SERS SoP sig
(Oken et al., 1995) [43] 11M, 12F (25) placebo controlled Crossover 0.2 mg/kg Covert orienting of spatial attention task (RT) A/V sig
Covert orienting of spatial attention task (Errors) A/V ns
Parallel visual search task (RT) A/V ns
Parallel visual search task (Errors) A/V ns
Serial visual search task (RT) A/V ns
Serial visual search task (Errors) A/V ns
Digit span WM ns
(Pauls et al., 2012) [44] 16M (23.6) placebo controlled crossover 40 mg Stop signal task (original version) A/V ns
Stop signal task (adapted version) A/V sig
(Ramasubbu et al., 2012) [45] 5M, 8F (28) placebo controlled crossover 20 mg 2-back task (correct responses) WM sig
2-back task (incorrect responses) WM ns
2-back task (missed responses) WM sig
2-back task (reaction time) WM ns
0-back task (correct responses) A/V ns
0-back task (incorrect responses) A/V ns
0-back task (missed responses) A/V ns
0-back task (reaction time) A/V sig

Review on methylphenidate and cognition 967

(Roehrs et al., 1999) [46] 2M, 4F (21–30) placebo controlled crossover 10 mg Divided-attention task (central RT) A/V sig
Divided-attention task (peripheral RT) A/V ns
Divided-attention task (tracking deviations) A/V ns
auditory vigilance task (mean RT) A/V ns
auditory vigilance task (Errors) A/V ns
(Rogers et al., 1999) [47] 16M (20.4) placebo controlled between groups 40 mg ID/ED shift task A/V sig
(decreased
performance)
(Rush et al., 2001) [48] 4M, 4F (28) placebo controlled crossover 20/40 mg DSST SoP ns
(Rush et al., 1998) [49] 2M, 3F (36) placebo controlled crossover 5/10/20/40 mg DSST SoP ns
Table 2. (Cont.)

968
A. M. W. Linssen et al.
Study No. of pp M, F (age) design Dose Task/measure Domain Effect

(Schroeder et al., 1987) [50] 10M (18–40) No placebo between groups 0.15/0.30 mg/kg Concurrent probability matching
Concurrent probability matching (hit rate) RPS ns
Concurrent probability matching (changeover) RPS sig
(decreased
performance)
Concurrent probability matching (strategy) RPS sig
(decreased
performance)
(Stoops et al., 2005) [51] 2M, 5F (24) placebo controlled crossover 10/20/40 mg Arithmetic problems RPS sig
(Strauss et al., 1984) [52] 22M (19.2) placebo controlled crossover crossover 20 mg CPT Double (omission errors) A/V sig
CPT Double (commission errors) A/V trend
CPT Double (sensitivity) A/V sig
CPT Double (RT) A/V sig
PAL (CVC pairs) VEM ns
(Studer et al., 2010) [53] 5M, 6F (29.7) placebo controlled crossover 20 mg Serial visual WM task WM ns
(Theunissen et al., 2009) [54] 5M, 11F (21.8) placebo controlled crossover 20 mg Critical tracking task SoP ns
Divided attention task A/V sig
Mackworth Clock task A/V ns
Stop signal task A/V ns
(Tomasi et al., 2011) [55] 16M (33) placebo controlled between groups 20 mg N-back task (RT) WM sig
N-back task (accuracy) WM ns
visual attention task A/V ns
(Turner et al., 2003) [56] 60M (61.4) placebo controlled between groups 20–40 mg Digit span WM ns
PAL (nonverbal) VSM ns
Spatial WM WM ns
Spatial span task WM ns
Tower of London RPS ns
RVIP A/V ns
ID/ED shift task A/V Sig9
Stop signal task A/V ns
(Unrug et al., 1997) [57] 6M, 6F placebo controlled crossover 20 mg WLT VEM ns
(Volkow et al., 2008) [58] 12M, 11F (32) placebo controlled crossover 20 mg Numerical problems RPS ns
(Wetzel et al., 1981) exp 1 [59] 6M, 6F (27.5) placebo controlled crossover 0.5 mg/kg PAL (word pairs) VEM sig
(decreased
performance)
Picture recognition VSM ns
Story recall VEM sig
(decreased
performance)
 Review on methylphenidate and cognition 969

learning and memory was somewhat less affected. A pro-

portion of 31% of the studies showed enhanced perform-
ance in this domain after administration of MPH. The
cognitive domain of verbal learning and memory typi-
ns
ns
ns
ns
cally refers to declarative memory tasks such as word
learning tests, verbal paired associates learning (PAL)
and story recall. Verbal PAL tasks involve learning
VEM
VEM
VSM

A/V

pairs of stimuli (words or letters) and recalling the corre-

sponding member of the pair upon presentation of probe
stimuli.
Positive effects of MPH on declarative memory fit
well with accounts of related stimulant drugs affecting
word list learning (Soetens et al., 1993, 1995; Zeeuws and
Soetens, 2007). The relationship between MPH dose
and its effect on word list learning seems to be a positive
and linear one. This contrasts with the striking finding
that a high MPH dose can decrease performance on a
PAL task and story recall. Across the domain of verbal
Picture recognition
PAL (word pairs)

learning and memory the low and medium doses exert

MPH lessens effect of emotionally arousing material on memory, higher performance on neutral material compared to placebo.

more cognition enhancing effects than high doses.

Story recall

Participants received 15 mg MPH unless high or low in body weight in which case they received 20 or 10 mg respectively.
Go/No-go

Hence, even within one domain, different dose–response

relationships may be observed for different tasks.

Attention/vigilance
Enhanced performance when MPH was taken on the first session, but impaired when taken on second session.

As William James stated in 1890, ‘everyone knows what

0.1/0.25 mg/kg

attention is’ (James, 1890). It is, however, difficult to

give a clear and inclusive definition. It involves filtering
20 mg

information, focusing on certain aspects of what is per-

ceived, while disregarding others. Many different forms
of attention are distinguished (e.g. sustained attention, fo-
cused attention, divided attention). In this review, how-
MPH impaired performance of easy task, but enhanced performance of difficult task.

ever, a collective domain ‘attention and vigilance’ is

employed.
6M, 6F (26.6) placebo controlled crossover

18M (19–24) placebo controlled crossover

Based on previous literature, associating attention

MPH improved performance of young volunteers but not old volunteers.

with dopaminergic activity (Nieoullon, 2002; Nieoullon

and Coquerel, 2003; Cools and Robbins, 2004), it was
expected that the domain of attention/vigilance would
Enhanced performance when MPH was taken on the first session.

be one of the most affected by MPH. However, with

29%, this domain was only the fourth most affected.
MPH increased accuracy but did not affect response time.

MPH causing impairment when taken on second session.

A possibly confounding factor might be that tasks from

the attention/vigilance domain are often included in
MPH slowed response but not improve accuracy.

MPH studies as control measures because they are

thought to be sensitive to MPH effects. Indeed, this
domain was assessed most frequently of all domains
(87 measures across 27 studies). Furthermore, the tasks
within this domain were often split into multiple mea-
sures, which may affect the final outcome.

Reasoning and problem solving

(Wetzel et al., 1981) exp 2

The next cognitive domain involves planning and

(Zhu et al., 2013) [60]

decision making, aspects of cognition that are usually

referred to as executive functioning. However, in order
to allow a separate category on working memory,
which is often included in executive functioning, this do-
main is named reasoning and problem solving. A typical
task in this domain is the Tower of London, in which balls
1

9
970 A. M. W. Linssen et al.

Table 3. Percentages of studies showing cognition enhancing effects of methylphenidate in each of six cognitive domains (Total) and per
dose level (Low, Medium, High). Study reference numbers refer to studies described in Table 2

No. of measures
Total Low Medium High (No. of studies) Study references

Working memory 65 0 74 41 21 (15) 1,9,12,16,22,24,25,33,36,37,38,43,45,53,55

Speed of processing 48 79 46 44 25 (15) 5,11,17,22,23,25,26,30,33,35,39,42,48,49,54
Verbal learning and memory 31 64 75 12 18 (11) 8,10,13,26,29,32,33,36,52,57,59
Attention and vigilance 29 37 32 38 87 (27) 1,2,3,6,13,14,15,17,18,19,22,25,26,27,28,31,36,
41,43,44,45,46,47,52,54,55,60
Reasoning and Problem solving 18 1 18 74 10 (6) 22,26,36,50,51,58
Visual learning and memory 0 0 0 0 8 (6) 7,16,20,23,34,59

Table 4. Summary of EEG studies on cognitive effects of MPH in healthy volunteers

Study Dependent variables Task* Domain Main finding

(Anderer et al., 2002) N1, P2, N2 and P3 Oddball A/V Increased P300 source strength
(Brumaghim et al., 1998) P3b, P2, late slow waves PAL (CVC pairs) VEM Increased parietal P3b amplitude
(Brumaghim et al., 1987) P3b SMS WM Shorter P3b latency
(Callaway, 1984) P3b SERS SoP No effect
(Coons et al., 1981) LPC, CNV CPT, Oddball, Choice RT A/V, SoP Increased LPC in CPT, increased
CNV in choice RT
(Cooper et al., 2005) N1, P2, N2 and P3 CPT A/V Shorter P3b latency, increased P3b
amplitude
(Fitzpatrick et al., 1988) P3b Memory scanning task WM No effect
(Hermens et al., 2007) N1, P2, N2 and P3 Oddball, CPT A/V No effect
(Hink et al., 1978) N1, P2 and P3 Target detection task A/V No effect
Linssen et al. (2011) CNV CNV task SoP Increased CNV amplitude
(Naylor et al., 1985) P3 SERS SoP No effect
(Oken et al., 1995) Event-related Visual search tasks A/V No effect
desynchronization
(Strauss et al., 1984) P2, P3a, P3b CPT, PAL A/V Shorter P3b latency, increased P3b
amplitude for CPT
(Studer et al., 2010) P3, slow waves Serial visual WM task WM No effect

* Task during which the imaging data were acquired.

have to be arranged on pegs according to a predefined
pattern in as few steps as possible.
Overall, 18% of the results reflected improved perform-
ance within this domain after MPH. The reported results
suggested that improvement of performance occurs more
frequently with a higher dose.
Visual learning and memory
The last cognitive domain to discuss is visual learning
and memory. Tasks classified as assessing performance
in this cognitive domain are, for example, picture recog-
nition tests and other learning and memory tasks involv-
ing visual stimuli. None of the studies found an effect of
MPH on visual learning and memory (Wetzel et al., 1981;
Bullmore et al., 2003; Brignell and Curran, 2006; Kuypers
and Ramaekers, 2007; Dodds et al., 2008b; Clatworthy
et al., 2009; Finke et al., 2010). It is, however, important
to note that the data reported within this domain only
comprises eight measures across six studies. This gives
the conclusion regarding the absence of an MPH effect
on visual learning and memory somewhat less weight.
Imaging studies on cognitive performance under the
influence of MPH
Of the studies included in this review, 26 studies obtained
imaging data during cognitive testing. In 14 of these
studies electroencephalography (EEG) measures were
taken. Furthermore, there were seven studies with func-
tional magnetic resonance imaging (fMRI) data, three
with positron emission tomography (PET) data, one with
transcranial magnetic stimulation (TMS) data and one
with functional near-infrared spectroscopy (fNIRS) data.
The EEG data are summarized in Table 4. Components
often assessed during attention, working memory or

speed of processing tasks include N1, P2, N2 and P3 ERP
components. While the former two components, N1 and
P2, are thought to reflect perceptual processes such as
orienting and directing of attention, the N2 and P3 are
cognitive components reflecting allocation of attentional
resources and stimulus evaluation (Anderer et al., 2002).
The studies reviewed found no effects of MPH on the ear-
lier components, while increased P3 source strength,
increased P3b amplitude and shorter P3b latency were
observed in several studies (Coons et al., 1981; Strauss
et al., 1984; Anderer et al., 2002; Cooper et al., 2005).
This is thought to reflect an MPH-induced enhancement
of attentional processes or increased recruitment of atten-
tional resources. Other studies did not report an effect of
MPH on P3 (Hink et al., 1978; Callaway, 1984; Naylor
et al., 1985; Fitzpatrick et al., 1988; Hermens et al., 2007;
Studer et al., 2010). An explanation offered for these
findings is that MPH affects response processing, as
reflected by faster responses, but that MPH does not
speed stimulus evaluation processing.
Another component assessed in the studies listed in
Table 4 was the Contingent Negative Variation (CNV).
MPH was observed to enhance CNV amplitude, reflect-
ing increased response readiness (Coons et al., 1981;
Linssen et al., 2011). Event-related desynchronization,
measured during a visual search task, was not affected
by MPH (Oken et al., 1995).
Of the seven studies in this review that acquired
fMRI data, three studies assessed brain activity during
response inhibition tasks, i.e. Go/No-go and stop signal
(Hester et al., 2012; Pauls et al., 2012; Costa et al., 2013).
Hester et al. (2012) observed that activation of the dorsal
anterior cingulated cortex and the inferior parietal lobe
differed between errors of which the participants were
aware vs. unaware in a Go/No-go task. MPH increased
these differences in activation of the dorsal anterior cingu-
late cortex and the inferior parietal lobe. This is suggestive
of the underlying mechanism leading to improved re-
sponse inhibition with MPH. Pauls et al. (2012) suggest
that inhibition effects are mediated through MPH effects
on the attentional mechanisms. Pauls et al. (2012)
reported reduced activation of different regions that are
associated with the ventral attention system, i.e. the
right inferior frontal gyrus and insula, during various
types of infrequent stimuli. Costa et al. (2013) showed
that MPH increased activity in the putamen during
error of inhibition but not during successful inhibition
in the Go/No-go task, while no such effect was observed
in the stop signal task. This effect may be due to saliency
of errors in the Go/No-go task, suggesting that MPH
interacts with saliency.
Two fMRI studies on working memory showed
increased activation of the dorsal attention network and
altered default mode network activation with MPH
(Marquand et al., 2011; Tomasi et al., 2011), suggesting
that MPH may exert its effects on cognition partly by
modulating the default mode network.
Review on methylphenidate and cognition 971
During a probabilistic reversal learning task MPH
decreased activation in the ventral striatum during re-
sponse switching, while activation changed in the pre-
frontal cortex if there was no switching of response.
MPH reduced dorsal anterior cingulate cortex activation
during errors on a stroop task (Moeller et al., 2012).
Among the imaging studies were three PET studies.
One PET study revealed that MPH reduced the amount
of glucose used by the brain during cognitive task
performance (Dodds et al., 2008b). This is thought to
reflect focusing of attention. MPH was also shown to
reduce regional cerebral blood flow in the dorsolateral
prefrontal cortex and posterior parietal cortex during
MPH-induced improved performance of a working mem-
ory task (Mehta et al., 2000b). Finally, MPH-induced en-
hancement of cognitive performance could be predicted
by its effect on dopamine receptor availability, as mea-
sured with PET (Clatworthy et al., 2009).
Using TMS, MPH was shown to alter motor system ex-
citability in a response inhibition task (Kratz et al., 2009),
suggesting MPH can fine-tune the motor system. Finally,
a study employing fNIRS reported decreased oxyhemo-
globin concentration with MPH compared to placebo in
the right frontal lobe, consistent with the PET finding
by Mehta et al. (2000) described above.
In sum, the imaging studies on cognitive performance
under the influence of MPH show that MPH enhances
attentional processing and modulates activity in brain
areas associated with inhibition and attention. How-
ever, more studies are needed to draw more exact con-
clusions, as existing studies vary widely with respect to
task, method and peak/area of interest.
Cognitive effects of MPH in the elderly
A limited number of studies investigated the effects of
MPH on cognition in the elderly (Callaway, 1984;
Turner et al., 2003; Muller et al., 2005; Ben-Itzhak et al.,
2008; Izquierdo et al., 2008; Drijgers et al., 2012). The ef-
fect of MPH on working memory performance was tested
in an extensive study by Turner et al. (2003) by means of a
digit span task, a spatial working memory task and a spa-
tial span task. None of the tasks was significantly affected
by MPH.
Speed of processing was also not affected as
measured with a SERS task in the study of Callaway
(1984) and letter digit substitution and simple and choice
reaction time tasks in the study by Drijgers et al. (2012).
The four-choice motor reaction task employed by
Muller et al. (2005), showed a performance enhancing ef-
fect of MPH on a difficult version of the task. In this
uncued version, participants were asked to move a joy-
stick towards a stimulus that was presented in an uncued
location. Performance on the cued version of the task was
impaired by MPH.
Effects of MPH on verbal learning and memory was
assessed by Izquierdo (2008) with tests of formal and
972 A. M. W. Linssen et al.
incidental memory in which memory of, respectively,
unintentionally remembered an intentionally remem-
bered information was tested. MPH was shown to
reverse age-related decline of persistence of incidental
memory. No such effect was observed for formal
memory.
Reasoning and problem solving, as measured with a
Tower of London task, did not reveal any effects of
MPH on older adults’ performance.
Effects of MPH on older adults’ attention and vigilance
task performance was tested in four different tasks i.e.
RVIP task; ID/ED shift task; stop signal task (Turner
et al., 2003); Go/No-go task (Ben-Itzhak et al., 2008).
Performance of the RVIP and stop signal tasks was not af-
fected by MPH. In the ID/ED task a significant slowing of
responses similar to that in young volunteers was
observed. However, this was not accompanied by an im-
provement in accuracy, as is the case in young volunteers.
In the Go/No-go task, on the other hand, accuracy
improved under the influence of MPH, while response
time was not affected.
Within the domain of visual learning and memory,
two tests were administered, i.e. a non-verbal PAL test
and a test of nonverbal memory in which memory of
the spatial orientation of geometric objects is tested with
a recognition test (Ben-Itzhak et al., 2008). Performance
of neither of these tasks by older adults was affected by
MPH.
In sum, MPH does not improve working memory,
reasoning and problem solving and visual learning and
memory in older adults. Some effects were observed
within the domains of speed of processing, verbal learn-
ing and memory and attention and vigilance. These
results only partly parallel those in younger volunteers,
with the main difference being the lack of effects on work-
ing memory in older adults. However, the limited num-
ber of studies in older adults limits the conclusions that
can be drawn from these data.
Adverse effects and ethical issues
While we cannot speak of a global cognition enhancing
effect of MPH, the research reviewed in this paper
shows that MPH can improve working memory and
speed of processing and, to a lesser extent, verbal learning
and memory, reasoning and problem solving and atten-
tion and vigilance in healthy volunteers. Reports of cog-
nition enhancing effects of MPH might encourage such
use. We would, therefore, like to put our findings in per-
spective and discuss adverse effects of MPH and related
ethical issues.
The effectiveness of MPH as cognitive enhancer
should not be overestimated (Ragan et al., 2013). All ex-
perimental studies reviewed here reflect effects in rela-
tively homogeneous groups assessed in controlled
environments using sensitive tests. In daily life, circum-
stances are much more diverse and complex, which
makes it hard to verify the enhancing effects of MPH on
performance in authentic situations. Any such effect is
likely to be relatively small in comparison to the effects
of adequate sleep, education and work–life balance, and
will be subject to individual differences.
Even if MPH substantially improved real-life
performances, the question remains whether the
benefits outweigh the risks. Common adverse effects of
chronic MPH use include insomnia, nervousness, irrita-
bility, anxiety, jitteriness, increased heart rate, dizziness,
drowsiness, headache, stomach ache, anorexia and
appetite suppression (Diller, 1996; Klein-Schwartz,
2002; Repantis et al., 2010). Large doses of MPH can
lead to psychosis, seizures and cardiovascular events
(Lakhan and Kirchgessner, 2012). Cardiovascular
effects associated with ADHD stimulant medications
include hypertension and tachycardia (Lakhan and
Kirchgessner, 2012).
Another risk related to MPH use is the potential
abuse of the drug. When MPH is used appropriately
for ADHD there is little evidence of addiction and/or
abuse of MPH (Diller, 1996). However, MPH can have
reinforcing effects through its effects on dopamine in
the brain (Volkow et al., 1999). Reinforcing effects depend
on the rate of uptake of the drug (Volkow et al., 2002;
Leonard et al., 2004), which explains why people who
use MPH to induce a high administer it intravenously
or intranasally, while people who merely take it to stay
awake, take it orally (Klein-Schwartz, 2002; Volkow
and Swanson, 2003). Self-administration of MPH is likely
limited by the low rate of clearance of MPH from the
brain, in which it differs from cocaine (Volkow et al.,
1995).
MPH use without prescription could be dangerous for
various reasons. Individual risks of which users may not
be aware, such as interaction with other medicinal drugs
or abnormalities in the cardiovascular system, cannot be
monitored by a physician if MPH is obtained otherwise
(Sahakian and Morein-Zamir, 2007). If users purchase
the pills online it might not actually be MPH, which
may create additional unknown risks (Ragan et al.,
2013). This may be a motive to regulate off-label stimulant
use (Sahakian and Morein-Zamir, 2007). However, mak-
ing MPH or other medications easily and legally available
can lead to other problems with coercion to take such
drugs (for example, in specific military or medical pro-
fessions or in children) and fairness (if only rich people
can afford to buy such drugs).
Attitudes towards cognitive enhancement vary be-
tween authors: while some are generally positive and op-
timistic and mainly call for guidelines (Sahakian and
Morein-Zamir, 2007; Greely et al., 2008), others are
more conservative (Ragan et al., 2013) or even consider
the current debate to be a ‘bubble’ (Lucke et al., 2011)
or ‘media hype’ (Partridge et al., 2011) and merely stress
that the evidence for increased stimulant use is weak.
However, everyone agrees that more research is needed,

whether it is to obtain accurate prevalence rates or to
increase our knowledge about the benefits and harm of
cognition enhancing drug use in healthy individuals.
We would like to add one recommendation to the existing
abundance of recommendations: research and reviews of
research on cognition-enhancing drugs should preferably
address one single drug at a time. ‘Cognition-enhancing
drugs’ are often described as if there were a group of
virtually identical drugs with similar effectiveness and
side effect profiles. It is very important to study specific,
individual features of a drug, as it is essential to study
a drug’s effectiveness in relation to its side effects and
other potential risks. Any description of a group of
drugs is likely to be a generalization and may lead to
over- or under-estimation of risks and benefits.
Conclusions
In this review the performance enhancing effect of MPH
within various cognitive domains was quantified by a
percentage (weighed on the basis of specified criteria
such as number of subjects). This is a major improvement
compared to earlier reviews in which only some domains
of cognition were considered, the categorization in
domains was less well specified (Repantis et al., 2010;
Smith and Farah, 2011) and/or the quality was either
not taken into account or based on criteria that hardly dif-
ferentiate between studies (e.g. double blind design, ran-
domization (Jadad et al., 1996)). Furthermore, this review
compares 59 studies, which is considerably more than in
previous reviews. The studies reviewed show that MPH
improves cognitive performance in the healthy popu-
lation in the domains of working memory and speed of
processing, and to a lesser extent may also improve verbal
learning and memory, attention and vigilance and
reasoning and problem solving, but not visual learning
and memory (see Table 3).
There were quite large differences between the
domains with respect to the cognition enhancing effect
of MPH, the lowest percentage being 0% and the highest
65%. These differences confirm that in studying cognitive
performance it is important to distinguish between differ-
ent domains of cognitive function. MPH may not globally
improve cognitive performance, but it has potential to en-
hance certain aspects of cognitive performance at certain
doses.
The dose–response relationship of the cognition modu-
lating effect of MPH differs across different cognitive
domains. In some domains, low doses are more effective
than high doses. An explanation for this may be that, in
healthy volunteers, dopamine availability is already
close to the optimal level. Enhancing dopamine activity
may push the level of dopamine beyond the optimum
without improving performance, or even leading to sub-
optimal performance.
Factors limiting the conclusions in this review relate
to the decisions that were made on how to categorize,
Review on methylphenidate and cognition 973
list and present the data. Tasks not described by
Nuechterlein et al. (2004) were categorized by the
authors. Other decisions that were well thought through,
but might still be somewhat arbitrary include: (1) some
tasks were split into several measures whereas others
were not; (2) a statistical trend was given a weight of
0.5; (3) if it was not clear which of the reported doses
led to significant effects, it was assumed that the reported
effect was applicable to every dose; (4) sometimes two
low doses are reported, but they are only weighed once;
(5) there was no correction for multiple comparisons
for multiple dosing. Finally a major limitation of any
review is that studies that did not show significant
effects are generally underreported (i.e. publication
bias). Therefore, any review is likely to present an over-
estimation of the reported effects.
In sum, MPH improves working memory and speed of
processing and, to a lesser extent, verbal learning and
memory, attention and vigilance and reasoning and prob-
lem solving in healthy young volunteers. MPH effects are
dose-dependent and the dose–response relationship dif-
fers between the different cognitive domains. Imaging
studies show enhanced attention processing and altered
attention- and inhibition-related brain activation. MPH
improves cognitive performance in the elderly on tasks
of speed of processing, verbal learning and memory
and attention and vigilance. MPH effects are, however,
considered to be relatively small and MPH use is asso-
ciated with side effects and other adverse consequences,
such as potential abuse. Future studies should focus on
MPH specifically to adequately asses the benefit–risk
ratio of this specific drug.
Statement of Interest
Anke Linssen and Anke Sambeth have no financial inter-
ests to disclose. Eric FPM Vuurman is employed full time
by Maastricht University. He was involved in conducting
clinical trials for several pharmaceutical companies
over the last three years: MSD, GSK and Transcept phar-
maceuticals. Financial compensation for his work was
only to Maastricht University and raises no conflict of
interest. There were no other commercial or financial rela-
tionships that could be construed as a potential conflict of
interest. Wim J. Riedel is honorary Professor at Maastricht
University. He was an employee of F.Hoffmann-La Roche
Ltd, Basel, Switzerland until December 2011 and since
then has been an employee of Cambridge Cognition
Ltd, Cambridge, United Kingdom.
References
Agay N, Yechiam E, Carmel Z, Levkovitz Y (2010) Non-specific
effects of methylphenidate (Ritalin) on cognitive ability and
decision-making of ADHD and healthy adults.
Psychopharmacology (Berl) 210:511–519.
974 A. M. W. Linssen et al.
Aman MG, Vamos M, Werry JS (1984) Effects of methylpheni-
date in normal adults with reference to drug action in
hyperactivity. Aust N Z J Psychiatry 18:86–88.
Anderer P, Saletu B, Semlitsch HV, Pascual-Marqui RD (2002)
Perceptual and cognitive event-related potentials in neuro-
psychopharmacology: methodological aspects and clinical
applications (pharmaco-ERP topography and tomography).
Methods Find Exp Clin Pharmacol 24 (Suppl. C):121–137.
Baddeley A (1992) Working memory. Science 255:556–559.
Ben-Itzhak R, Giladi N, Gruendlinger L, Hausdorff JM (2008)
Can methylphenidate reduce fall risk in community-living
older adults? A double-blind, single-dose cross-over study.
J Am Geriatr Soc 56:695–700.
Bernard K, Penelaud PF, Mocaer E, Donazzolo Y (2011) Absence
of psychostimulant effects of a supratherapeutic dose of
tianeptine: a placebo-controlled study vs. methylphenidate in
young healthy volunteers. J Clin Psychopharmacol 31:441–448.
Bishop C, Roehrs T, Rosenthal L, Roth T (1997) Alerting effects of
methylphenidate under basal and sleep-deprived conditions.
Exp Clin Psychopharmacol 5:344–352.
Brignell CM, Curran HV (2006) Drugs, sweat, and fears: a
comparison of the effects of diazepam and methylphenidate
on fear conditioning. Psychopharmacol (Berl) 186:504–516.
Brignell CM, Rosenthal J, Curran HV (2007) Pharmacological
manipulations of arousal and memory for emotional material:
effects of a single dose of methylphenidate or lorazepam.
J Psychopharmacol 21:673–683.
Brumaghim JT, Klorman R (1998) Methylphenidate’s effects on
paired-associate learning and event-related potentials of young
adults. Psychophysiol 35:73–85.
Brumaghim JT, Klorman R, Strauss J, Lewine JD, Goldstein MG
(1987) Does methylphenidate affect information processing?
Findings from two studies on performance and P3b latency.
Psychophysiol 24:361–373.
Bullmore E, Suckling J, Zelaya F, Long C, Honey G, Reed L,
Routledge C, Ng V, Fletcher P, Brown J, Williams SC (2003)
Practice and difficulty evoke anatomically and pharmacologi-
cally dissociable brain activation dynamics. Cereb Cortex
13:144–154.
Callaway E (1984) Human information-processing: some effects
of methylphenidate, age, and scopolamine. Biol Psychiatry
19:649–662.
Campbell-Meiklejohn D, Simonsen A, Scheel-Kruger J,
Wohlert V, Gjerloff T, Frith CD, Rogers RD, Roepstorff A,
Moller A (2012) In for a penny, in for a pound: methylpheni-
date reduces the inhibitory effect of high stakes on persistent
risky choice. J Neurosci 32:13032–13038.
Camp-Bruno JA, Herting RL (1994) Cognitive effects of
milacemide and methylphenidate in healthy young adults.
Psychopharmacol (Berl) 115:46–52.
Clark CR, Geffen GM, Geffen LB (1986a) Role of monoamine
pathways in the control of attention: effects of droperidol and
methylphenidate in normal adult humans. Psychopharmacolo
(Berl) 90:28–34.
Clark CR, Geffen GM, Geffen LB (1986b) Role of monoamine
pathways in attention and effort: effects of clonidine and
methylphenidate in normal adult humans. Psychopharmacol
(Berl) 90:35–39.
Clatworthy PL, Lewis SJ, Brichard L, Hong YT, Izquierdo D,
Clark L, Cools R, Aigbirhio FI, Baron JC, Fryer TD,
Robbins TW (2009) Dopamine release in dissociable
striatal subregions predicts the different effects of oral
methylphenidate on reversal learning and spatial working
memory. J Neurosci 29:4690–4696.
Cools R, Robbins TW (2004) Chemistry of the adaptive mind.
Philos Transact A Math Phys Eng Sci 362:2871–2888.
Coons HW, Peloquin LJ, Klorman R, Bauer LO, Ryan RM,
Perlmutter RA, Salzman LF (1981) Effect of methylphenidate
on young adult’s vigilance and event-related potentials.
Electroencephalogr Clin Neurophysiol 51:373–387.
Cooper NJ, Keage H, Hermens D, Williams LM, Debrota D,
Clark CR, Gordon E (2005) The dose-dependent effect of
methylphenidate on performance, cognition and psychophy-
siology. J Integr Neurosci 4:123–144.
Costa A, Riedel M, Pogarell O, Menzel-Zelnitschek F,
Schwarz M, Reiser M, Moller HJ, Rubia K, Meindl T,
Ettinger U (2013) Methylphenidate effects on neural activity
during response inhibition in healthy humans. Cereb Cortex
23:1179–1189.
Dickinson D, Ragland JD, Calkins ME, Gold JM, Gur RC (2006)
A comparison of cognitive structure in schizophrenia patients
and healthy controls using confirmatory factor analysis.
Schizophr Res 85:20–29.
Diller LH (1996) The run on Ritalin. Attention deficit disorder
and stimulant treatment in the 1990s. Hastings Cent Rep
26:12–18.
Dodds C, Muller U, Manly T (2008a) Effects of psychostimulants
on alertness and spatial bias in healthy participants. J Cogn
Neurosci 21:529–537.
Dodds CM, Muller U, Clark L, van Loon A, Cools R,
Robbins TW (2008b) Methylphenidate has differential effects
on blood oxygenation level-dependent signal related to
cognitive subprocesses of reversal learning. J Neurosci
28:5976–5982.
Drijgers RL, Verhey FR, Tissingh G, van Domburg PH, Aalten P,
Leentjens AF (2012) The role of the dopaminergic system in
mood, motivation and cognition in Parkinson’s disease: a
double blind randomized placebo-controlled experimental
challenge with pramipexole and methylphenidate. J Neurol Sci
320:121–126.
Elliott R, Sahakian BJ, Matthews K, Bannerjea A, Rimmer J,
Robbins TW (1997) Effects of methylphenidate on spatial
working memory and planning in healthy young adults.
Psychopharmacol (Berl) 131:196–206.
Finke K, Dodds CM, Bublak P, Regenthal R, Baumann F,
Manly T, Muller U (2010) Effects of modafinil and
methylphenidate on visual attention capacity: a TVA-based
study. Psychopharmacol (Berl) 210:317–329.
Fitzpatrick P, Klorman R, Brumaghim JT, Keefover RW (1988)
Effects of methylphenidate on stimulus evaluation and
response processes: evidence from performance and
event-related potentials. Psychophysiol 25:292–304.
Genderson MR, Dickinson D, Diaz-Asper CM, Egan MF,
Weinberger DR, Goldberg TE (2007) Factor analysis of
neurocognitive tests in a large sample of schizophrenic
probands, their siblings, and healthy controls. Schizophr Res
94:231–239.
Greely H, Sahakian B, Harris J, Kessler RC, Gazzaniga M,
Campbell P, Farah MJ (2008) Towards responsible use
of cognitive-enhancing drugs by the healthy. Nature
456:702–705.
Halliday R, Callaway E, Naylor H, Gratzinger P, Prael R (1986)
The effects of stimulant drugs on information processing in
elderly adults. J Gerontol 41:748–757.

Hannestad J, Gallezot JD, Planeta-Wilson B, Lin SF,
Williams WA, van Dyck CH, Malison RT, Carson RE, Ding YS
(2010) Clinically relevant doses of methylphenidate signifi-
cantly occupy norepinephrine transporters in humans in vivo.
Biol Psychiatry 68:854–860.
Hermens DF, Cooper NJ, Clark CR, Debrota D, Clarke SD,
Williams LM (2007) An integrative approach to determine the
best behavioral and biological markers of methylphenidate.
J Integr Neurosci 6:105–140.
Hester R, Nandam LS, O’Connell RG, Wagner J, Strudwick M,
Nathan PJ, Mattingley JB, Bellgrove MA (2012) Neurochemical
enhancement of conscious error awareness. J Neurosci
32:2619–2627.
Hink RF, Fenton WH Jr., Tinklenberg JR, Pfefferbaum A,
Kopell BS (1978) Vigilance and human attention under
conditions of methylphenidate and secobarbital intoxication:
an assessment using brain potentials. Psychophysiol
15:116–125.
Husain M, Mehta MA (2011) Cognitive enhancement by drugs
in health and disease. Trends Cogn Sci 15:28–36.
Izquierdo I, Bevilaqua LR, Rossato JI, Lima RH, Medina JH,
Cammarota M (2008) Age-dependent and age-independent
human memory persistence is enhanced by delayed post-
training methylphenidate administration. Proc Natl Acad
Sci USA 105:19504–19507.
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ,
Gavaghan DJ, McQuay HJ (1996) Assessing the quality of
reports of randomized clinical trials: is blinding necessary?
Control Clin Trials 17:1–12.
James W (1890) The principles of psychology. New York:
Henry Holt.
Kleijnen J, Knipschild P, Riet ter G (1991) Clinical trials of
homeopathy. BMJ 302:316–323.
Klein-Schwartz W (2002) Abuse and toxicity of methylphenidate.
Curr Opin Pediatr 14:219–223.
Kollins SH, Rush CR, Pazzaglia PJ, Ali JA (1998) Comparison
of acute behavioral effects of sustained-release and
immediate-release methylphenidate. Exp Clin
Psychopharmacol 6:367–374.
Kratz O, Diruf MS, Studer P, Gierow W, Buchmann J, Moll GH,
Heinrich H (2009) Effects of methylphenidate on motor system
excitability in a response inhibition task. Behav Brain Funct
5:12.
Kupietz SS, Richardson E, Gadow KD, Winsberg BG (1980)
Effects of methylphenidate on learning a ‘beginning reading
vocabulary’ by normal adults. Psychopharmacol (Berl)
69:69–72.
Kuypers KP, Ramaekers JG (2005) Transient memory
impairment after acute dose of 75 mg 3.4-Methylene-
dioxymethamphetamine. J Psychopharmacol 19:633–639.
Kuypers KP, Ramaekers JG (2007) Acute dose of MDMA (75 mg)
impairs spatial memory for location but leaves contextual
processing of visuospatial information unaffected.
Psychopharmacol (Berl) 189:557–563.
Lakhan SE, Kirchgessner A (2012) Prescription stimulants in
individuals with and without attention deficit hyperactivity
disorder: misuse, cognitive impact, and adverse effects. Brain
Behav 2:661–677.
Larriviere D, Williams MA, Rizzo M, Bonnie RJ (2009)
Responding to requests from adult patients for
neuroenhancements: guidance of the Ethics, Law and
Humanities Committee. Neurology 73:1406–1412.
Review on methylphenidate and cognition 975
Leonard BE, McCartan D, White J, King DJ (2004)
Methylphenidate: a review of its neuropharmacological,
neuropsychological and adverse clinical effects. Hum
Psychopharmacol 19:151–180.
Linssen AM, Vuurman EF, Sambeth A, Nave S, Spooren W,
Vargas G, Santarelli L, Riedel WJ (2011) Contingent negative
variation as a dopaminergic biomarker: evidence from
dose-related effects of methylphenidate. Psychopharmacol
(Berl) 218:533–542.
Linssen AM, Vuurman EF, Sambeth A, Riedel WJ (2012)
Methylphenidate produces selective enhancement of
declarative memory consolidation in healthy volunteers.
Psychopharmacol (Berl) 221:611–619.
Lucke JC, Bell S, Partridge B, Hall WD (2011) Deflating the
neuroenhancement bubble. AJOB Neurosci 2:38–43.
Maher B (2008) Poll results: look who’s doping. Nature
452:674–675.
Marquand AF, De Simoni S, O’Daly OG, Williams SC,
Mourao-Miranda J, Mehta MA (2011) Pattern
classification of working memory networks reveals
differential effects of methylphenidate, atomoxetine, and
placebo in healthy volunteers. Neuropsychopharmacol
36:1237–1247.
Mehta MA, Riedel WJ (2006) Dopaminergic enhancement of
cognitive function. Curr Pharm Des 12:2487–2500.
Mehta MA, Calloway P, Sahakian BJ (2000a) Amelioration of
specific working memory deficits by methylphenidate in a case
of adult attention deficit/hyperactivity disorder. J
Psychopharmacol 14:299–302.
Mehta MA, Owen AM, Sahakian BJ, Mavaddat N, Pickard JD,
Robbins TW (2000b) Methylphenidate enhances working
memory by modulating discrete frontal and parietal lobe
regions in the human brain. J Neurosci 20:RC65.
Moeller SJ, Honorio J, Tomasi D, Parvaz MA, Woicik PA,
Volkow ND, Goldstein RZ (2012) Methylphenidate enhances
executive function and optimizes prefrontal function in both
health and cocaine addiction. Cereb Cortex Epub ahead of
print.
Muller U, Suckling J, Zelaya F, Honey G, Faessel H,
Williams SC, Routledge C, Brown J, Robbins TW,
Bullmore ET (2005) Plasma level-dependent effects of
methylphenidate on task-related functional magnetic
resonance imaging signal changes. Psychopharmacol (Berl)
180:624–633.
Nandam LS, Hester R, Wagner J, Cummins TD, Garner K,
Dean AJ, Kim BN, Nathan PJ, Mattingley JB, Bellgrove MA
(2011) Methylphenidate but not atomoxetine or citalopram
modulates inhibitory control and response time variability.
Biol Psychiatry 69:902–904.
Naylor H, Halliday R, Callaway E (1985) The effect of
methylphenidate on information processing. Psychopharmacol
(Berl) 86:90–95.
Nieoullon A (2002) Dopamine and the regulation of cognition
and attention. Prog Neurobiol 67:53–83.
Nieoullon A, Coquerel A (2003) Dopamine: a key regulator to
adapt action, emotion, motivation and cognition. Curr Opin
Neurol 16 (Suppl. 2):S3–S9.
Nuechterlein KH, Barch DM, Gold JM, Goldberg TE, Green MF,
Heaton RK (2004) Identification of separable cognitive factors
in schizophrenia. Schizophr Res 72:29–39.
Oken BS, Kishiyama SS, Salinsky MC (1995) Pharmacologically
induced changes in arousal: effects on behavioral and
976 A. M. W. Linssen et al.
electrophysiologic measures of alertness and attention.
Electroencephalogr Clin Neurophysiol 95:359–371.
Partridge BJ, Bell SK, Lucke JC, Yeates S, Hall WD (2011) Smart
drugs “as common as coffee”: media hype about neuroen-
hancement. PloS ONE 6:e28416. doi:10.1371/journal.
pone.0028416.
Pauls AM, O’Daly OG, Rubia K, Riedel WJ, Williams SC,
Mehta MA (2012) Methylphenidate effects on prefrontal
functioning during attentional-capture and response inhi-
bition. Biol Psychiatry 72:142–149.
Pietrzak RH, Mollica CM, Maruff P, Snyder PJ (2006) Cognitive
effects of immediate-release methylphenidate in children with
attention-deficit/hyperactivity disorder. Neurosci Biobehav
Rev 30:1225–1245.
Ragan CI, Bard I, Singh I (2013) What should we do about
student use of cognitive enhancers? An analysis of current
evidence. Neuropharmacol 64:588–595.
Ramasubbu R, Singh H, Zhu H, Dunn JF (2012)
Methylphenidate-mediated reduction in prefrontal
hemodynamic responses to working memory task: a functional
near-infrared spectroscopy study. Hum Psychopharmacol
27:615–621.
Repantis D, Schlattmann P, Laisney O, Heuser I (2010)
Modafinil and methylphenidate for neuroenhancement in
healthy individuals: a systematic review. Pharmacol Res
62:187–206.
Riedel WJ, Mehta MA, Unema PJ (2006) Human cognition
assessment in drug research. Curr Pharm Des 12:2525–2539.
Roehrs T, Papineau K, Rosenthal L, Roth T (1999) Sleepiness and
the reinforcing and subjective effects of methylphenidate. Exp
Clin Psychopharmacol 7:145–150.
Rogers RD, Blackshaw AJ, Middleton HC, Matthews K,
Hawtin K, Crowley C, Hopwood A, Wallace C, Deakin JF,
Sahakian BJ, Robbins TW (1999) Tryptophan depletion impairs
stimulus-reward learning while methylphenidate disrupts
attentional control in healthy young adults: implications for
the monoaminergic basis of impulsive behaviour.
Psychopharmacol (Berl) 146:482–491.
Rush CR, Kollins SH, Pazzaglia PJ (1998)
Discriminative-stimulus and participant-rated effects
of methylphenidate, bupropion, and triazolam in
d-amphetamine-trained humans. Exp Clin Psychopharmacol
6:32–44.
Rush CR, Essman WD, Simpson CA, Baker RW (2001)
Reinforcing and subject-rated effects of methylphenidate
and d-amphetamine in non-drug-abusing humans. J Clin
Psychopharmacol 21:273–286.
Sahakian B, Morein-Zamir S (2007) Professor’s little helper.
Nature 450:1157–1159.
Schroeder SR, Mann-Koepke K, Gualtieri CT, Eckerman DA,
Breese GR (1987) Methylphenidate affects strategic choice
behavior in normal adult humans. Pharmacol Biochem Behav
28:213–217.
Smith ME, Farah MJ (2011) Are prescription stimulants
‘smart pills’? The epidemiology and cognitive neuroscience
of prescription stimulant use by normal healthy individuals.
Psychol Bull 137:717–741.
Soetens E, D’Hooge R, Hueting JE (1993) Amphetamine enhances
human-memory consolidation. Neurosci Lett 161:9–12.
Soetens E, Casaer S, D’Hooge R, Hueting JE (1995) Effect of
amphetamine on long-term retention of verbal material.
Psychopharmacol (Berl) 119:155–162.
Sternberg S (1966) High-speed scanning in human memory.
Science 153:652–654.
Stix G (2009) Turbocharging the brain. Scientific American
Mind 301:46–49, 52–55.
Stoops WW, Lile JA, Fillmore MT, Glaser PE, Rush CR
(2005) Reinforcing effects of methylphenidate: influence of
dose and behavioral demands following drug administration.
Psychopharmacol (Berl) 177:349–355.
Strauss J, Lewis JL, Klorman R, Peloquin LJ, Perlmutter RA,
Salzman LF (1984) Effects of methylphenidate on young
adults’ performance and event-related potentials in a
vigilance and a paired-associates learning test. Psychophysiol
21:609–621.
Studer P, Wangler S, Diruf MS, Kratz O, Moll GH, Heinrich H
(2010) ERP effects of methylphenidate and working memory
load in healthy adults during a serial visual working memory
task. Neurosci Lett 482:172–176.
Swanson JM, Volkow ND (2008) Increasing use of stimulants
warns of potential abuse. Nature 453:586.
Theunissen EL, Elvira Jde L, van den Bergh D, Ramaekers JG
(2009) Comparing the stimulant effects of the
H1-antagonist fexofenadine with 2 psychostimulants,
modafinil and methylphenidate. J Clin Psychopharmacol
29:439–443.
Tomasi D, Volkow ND, Wang GJ, Wang R, Telang F,
Caparelli EC, Wong C, Jayne M, Fowler JS (2011)
Methylphenidate enhances brain activation and deactivation
responses to visual attention and working memory tasks in
healthy controls. Neuroimage 54:3101–3110.
Turner DC, Robbins TW, Clark L, Aron AR, Dowson J,
Sahakian BJ (2003) Relative lack of cognitive effects of
methylphenidate in elderly male volunteers. Psychopharmacol
(Berl) 168:455–464.
Unrug A, Coenen A, van Luijtelaar G (1997) Effects of
the tranquillizer diazepam and the stimulant
methylphenidate on alertness and memory.
Neuropsychobiol 36:42–48.
Volkow ND, Swanson JM (2003) Variables that affect the clinical
use and abuse of methylphenidate in the treatment of ADHD.
AJ Psychiatry 160:1909–1918.
Volkow ND, Ding YS, Fowler JS, Wang GJ, Logan J, Gatley JS,
Dewey S, Ashby C, Liebermann J, Hitzemann R, et al.
(1995) Is methylphenidate like cocaine? Studies on their
pharmacokinetics and distribution in the human brain. Arch
Gen Psychiatry 52:456–463.
Volkow ND, Wang GJ, Fowler JS, Gatley SJ, Logan J, Ding YS,
Hitzemann R, Pappas N (1998) Dopamine transporter
occupancies in the human brain induced by
therapeutic doses of oral methylphenidate. AJ Psychiatry
155:1325–1331.
Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Wong C,
Hitzemann R, Pappas NR (1999) Reinforcing effects of
psychostimulants in humans are associated with increases in
brain dopamine and occupancy of D(2) receptors. J Pharmacol
Exp Ther 291:409–415.
Volkow ND, Fowler JS, Wang GJ, Ding YS, Gatley SJ
(2002) Role of dopamine in the therapeutic and
reinforcing effects of methylphenidate in humans:
results from imaging studies. Eur Neuropsychopharmacol
12:557–566.
Volkow ND, Fowler JS, Wang GJ, Telang F, Logan J, Wong C,
Ma J, Pradhan K, Benveniste H, Swanson JM (2008)

Methylphenidate decreased the amount of glucose needed
by the brain to perform a cognitive task. PLoS ONE 3:e2017.
doi: 10.1371/journal.pone.0002017.
Wetzel CD, Squire LR, Janowsky DS (1981) Methylphenidate
impairs learning and memory in normal adults. Behav Neural
Biol 31:413–424.
Review on methylphenidate and cognition 977
Zeeuws I, Soetens E (2007) Verbal memory performance
improved via an acute administration of D-amphetamine.
Hum Psychopharmacol 22:279–287.
Zhu Y, Gao B, Hua J, Liu W, Deng Y, Zhang L, Jiang B, Zang Y
(2013) Effects of methylphenidate on resting-state brain ac-
tivity in normal adults: an fMRI study. Neurosci Bull 29:16–27.