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 fi mainly prescribed in attention de cit hyperactivity disorder, is increasingly used by the general population, Downloaded from https://academic.oup.com/ijnp/article/17/6/961/692761 by guest on 29 September 2021 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: [email protected] 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 combined with the terms cognition, neuropsychology, execu- fact that the classification applied by Pietrzak et al. (2006) tive, working memory, vigilance and inhibition in separate is not based on factor analysis or any other established searches. Reference lists of extracted articles were way of classifying cognitive tasks (or this is not reported), screened for omissions in our search. Studies that were in- we looked for a classification that was more appropriate cluded fulfilled the following criteria: used immediate re- for the available data (Pietrzak et al., 2006). lease formulation of MPH; assessed the effects of acute The categorization described by Nuechterlein et al. doses of MPH; assessed healthy human adults 18 yr and (2004) is based on factor analytic studies and fine-tuned older; assessed the effects using cognitive tasks; were by a committee of field experts. Although the identification written in English; published in a peer-reviewed journal. considered cognitive function in schizophrenia patients, it Both studies employing a within- and between-subjects is generally accepted that cognitive domains are broadly design were included. Studies assessing chronic or sub- the same in healthy controls (Dickinson et al., 2006; chronic effects of MPH were not included. The earliest Genderson et al., 2007). The cognitive domains (i.e. speed study included was published March 1978 and the last in- Downloaded from https://academic.oup.com/ijnp/article/17/6/961/692761 by guest on 29 September 2021 of processing, attention/vigilance, working memory, cluded study was published May 2013. verbal learning and memory, visual learning memory fi and reasoning and problem solving) t well with the litera- Categorization ture on healthy volunteers (Riedel et al., 2006) and are employed in this review (Nuechterlein et al., 2004). The neuropsychological tests were categorized into six Considering the mixed nature of the literature, a de- different cognitive domains: speed of processing, atten- scriptive statistic quantifying the evidence would facili- tion/vigilance, working memory, verbal learning and tate its interpretation. Pietrzak et al. (2006) summarize memory, visual learning and memory and reasoning the results within each domain as a percentage of studies and problem solving (Nuechterlein et al., 2004). Tasks reporting cognition enhancing effects of MPH. In order to employed in the included articles were categorized fol- also take into account factors that determine the statistical lowing the classification by Nuechterlein et al. (2004). If power of the studies (number of participants and number more than one cognitive domain was applicable, tasks of tasks/measures), we established a weighed percentage were still classified as measuring one domain only (i.e. reflecting the relative contribution of the studies reviewed the most salient domain). Tasks that could not be categor- to the MPH effects (Kleijnen et al., 1991). ized in any of these six cognitive domains were not in- Effects of dopamine on cognition are often described cluded in the analysis (for instance ‘spatial bias’ in to follow an inverted-U-shaped curve in which inter- (Dodds et al., 2008a)). mediate levels of neurotransmitter activity lead to optimal cognitive performance, but lower and higher Outcome measure levels may lead to suboptimal performance (Husain and Mehta, 2011). Since MPH blocks the dopamine and For each domain a weighed percentage was calculated fl noradrenaline transporters, thereby blocking reuptake of re ecting to what extent MPH affects task performance in that specific domain. It was calculated as follows: these neurotransmitters, MPH leads to increased levels
of dopamine and noradrenaline availability (Volkow ( (number of participants × outcome et al., 1998; Hannestad et al., 2010) and may demonstrate significance testing × relative )) inverted-U properties. Moreover, dose–response relation- = contribution
Outcome measure ( ( × ships may vary between cognitive domains. Therefore, number of participants relative contribution)) × 100% we report a weighed percentage reflecting MPH effects, equivalent to the one described above for low, medium in which number of participants was used as reported and high doses, respectively. for within-subjects designs, while for between-subjects The aim of this review is to answer the question whether designs, the number of participants that received MPH MPH can enhance cognitive function in healthy indivi- was used in the calculation. Outcome significance testing duals. This review specifically looks at the acute effects was defined as: 1=significantly improved task perform- of MPH on healthy adults (i.e. excluding effects of other ance; −1=significantly impaired task performance; 0= medications, effects on children, effects after sleep depri- no significant effect; 0.5=trend towards improved task vation and long term effects). Effects on the elderly are dis- performance; −0.5=trend towards impaired task per- cussed in a separate paragraph, as well as imaging data. 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 Method 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= Literature search 0.5). Only data of participants aged between 18 and 60 A literature search was performed in PubMed and were included in the calculation. Data on elderly partici- Psychinfo using the search term Methylphenidate 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 Downloaded from https://academic.oup.com/ijnp/article/17/6/961/692761 by guest on 29 September 2021 SERS Stimulus evaluation/response selection task fi SMS Sternberg memory scanning task that was presented N-trials before. Other tasks speci cally 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- Speed of processing lated for low, medium and high doses separately. A Tasks that are classified as a measure of speed of processing fi low, medium or high dose was de ned as follows: low: are relatively simple, involving fundamental processes 4 4 4 10 mg or 0.15 mg/kg; medium: >10 mg, 20 mg or such as perception and motor action. This category 4 >0.15 mg/kg, 0.3 mg/kg; high: >20 mg or >0.3 mg/kg. If includes, for example, digit symbol substitution tests fi it was not clearly stated which dose(s) led to signi cant (DSST) and trail making tests (TMT); version A and B effects, it was assumed that the reported effect was appli- The speed of processing domain was, with 48%, the se- cable to every administered dose. 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 fl Results and discussion volunteers (Elliott et al., 1997), re ecting response-readi- ness enhancing effects (Linssen et al., 2011). In total 60 studies met the inclusion criteria. Of these, 56 A striking observation is that the low dose exerted the included healthy volunteers between 18 and 60 yr old. All highest proportion of effects on cognitive performance in studies are listed in Table 2. The extent to which MPH this domain, followed by the medium dose, with the fi enhances cognitive performance (quanti ed by a weighed highest dose showing the lowest proportion of effects. percentage) is reported in Table 3. The results show that This suggests that within this domain the optimal dose MPH most effectively enhances performance in the do- is rather low and the higher the dose, the less healthy main of working memory. Second most affected were volunteers benefit from it. tasks measuring speed of processing, followed by verbal learning and memory, attention/vigilance, reasoning Verbal learning and memory and problem solving, and visual learning and memory. In the next few paragraphs, the results per domain are Whereas MPH affected the former two domains in 48% or discussed in more detail. more of the reported measurements, the domain of verbal Table 2. Summary of studies on cognitive effects of MPH in healthy volunteers 964 .M .Lnsne al. et Linssen W. M. A. 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 Downloaded fromhttps://academic.oup.com/ijnp/article/17/6/961/692761bygueston29September2021 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 Downloaded fromhttps://academic.oup.com/ijnp/article/17/6/961/692761bygueston29September2021 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 eiwo ehlhndt n cognition and methylphenidate on Review Spatial span WM sig4 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 965 Table 2. (Cont.) 966 .M .Lnsne al. et Linssen W. M. A. 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 Downloaded fromhttps://academic.oup.com/ijnp/article/17/6/961/692761bygueston29September2021 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 Downloaded fromhttps://academic.oup.com/ijnp/article/17/6/961/692761bygueston29September2021 (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 eiwo ehlhndt n cognition and methylphenidate on Review (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 967 Table 2. (Cont.) 968 .M .Lnsne al. et Linssen W. M. A. 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 Downloaded fromhttps://academic.oup.com/ijnp/article/17/6/961/692761bygueston29September2021 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- cally refers to declarative memory tasks such as word learning tests, verbal paired associates learning (PAL) and story recall. Verbal PAL tasks involve learning 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 Downloaded from https://academic.oup.com/ijnp/article/17/6/961/692761 by guest on 29 September 2021 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 learning and memory the low and medium doses exert more cognition enhancing effects than high doses. Hence, even within one domain, different dose–response relationships may be observed for different tasks. Picture recognitionStory recall VSM ns VEM ns Attention/vigilance

As William James stated in 1890, ‘everyone knows what attention is’ (James, 1890). It is, however, difficult to give a clear and inclusive definition. It involves filtering 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- ever, a collective domain ‘attention and vigilance’ is employed. cult task.

fi Based on previous literature, associating attention with dopaminergic activity (Nieoullon, 2002; Nieoullon and Coquerel, 2003; Cools and Robbins, 2004), it was expected that the domain of attention/vigilance would be one of the most affected by MPH. However, with 29%, this domain was only the fourth most affected. rst session. rst session, but impaired when taken on second session.

fi fi A possibly confounding factor might be that tasks from the attention/vigilance domain are often included in 24) placebo controlled crossover 20 mg Go/No-go A/V ns – 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 The next cognitive domain involves planning and

) exp 2 6M, 6F (26.6) placebo controlled crossover 0.1/0.25 mg/kg PAL (word pairs)decision making, VEM ns aspects of cognition that are usually ) [60] 18M (19

1981 referred to as executive functioning. However, in order

2013 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 Participants received 15 mg MPHMPH unless increased high accuracy or but low didMPH in not lessens body affect effect weight response of in time. emotionally whichEnhanced arousing case performance material they when on received MPH memory, 20 wasMPH higher or taken causing performance 10 on impairment mg on the when respectively. neutral takenEnhanced material on performance compared second when to session. MPH placebo. wasMPH taken improved on performance the of youngMPH volunteers impaired but performance not of old easyMPH volunteers. task, slowed but response enhanced but performance not of improve dif accuracy. (Zhu et al., (Wetzel et al., 1 2 3 4 5 6 7 8 9 task in this domain is the Tower of London, in which balls 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 Downloaded from https://academic.oup.com/ijnp/article/17/6/961/692761 by guest on 29 September 2021

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 to note that the data reported within this domain only pattern in as few steps as possible. comprises eight measures across six studies. This gives Overall, 18% of the results reflected improved perform- the conclusion regarding the absence of an MPH effect ance within this domain after MPH. The reported results on visual learning and memory somewhat less weight. suggested that improvement of performance occurs more frequently with a higher dose. Imaging studies on cognitive performance under the influence of MPH Visual learning and memory Of the studies included in this review, 26 studies obtained The last cognitive domain to discuss is visual learning imaging data during cognitive testing. In 14 of these and memory. Tasks classified as assessing performance studies electroencephalography (EEG) measures were in this cognitive domain are, for example, picture recog- taken. Furthermore, there were seven studies with func- nition tests and other learning and memory tasks involv- tional magnetic resonance imaging (fMRI) data, three ing visual stimuli. None of the studies found an effect of with positron emission tomography (PET) data, one with MPH on visual learning and memory (Wetzel et al., 1981; transcranial magnetic stimulation (TMS) data and one Bullmore et al., 2003; Brignell and Curran, 2006; Kuypers with functional near-infrared spectroscopy (fNIRS) data. and Ramaekers, 2007; Dodds et al., 2008b; Clatworthy The EEG data are summarized in Table 4. Components et al., 2009; Finke et al., 2010). It is, however, important often assessed during attention, working memory or Review on methylphenidate and cognition 971 speed of processing tasks include N1, P2, N2 and P3 ERP During a probabilistic reversal learning task MPH components. While the former two components, N1 and decreased activation in the ventral striatum during re- P2, are thought to reflect perceptual processes such as sponse switching, while activation changed in the pre- orienting and directing of attention, the N2 and P3 are frontal cortex if there was no switching of response. cognitive components reflecting allocation of attentional MPH reduced dorsal anterior cingulate cortex activation resources and stimulus evaluation (Anderer et al., 2002). during errors on a stroop task (Moeller et al., 2012). The studies reviewed found no effects of MPH on the ear- Among the imaging studies were three PET studies. lier components, while increased P3 source strength, One PET study revealed that MPH reduced the amount increased P3b amplitude and shorter P3b latency were of glucose used by the brain during cognitive task observed in several studies (Coons et al., 1981; Strauss performance (Dodds et al., 2008b). This is thought to et al., 1984; Anderer et al., 2002; Cooper et al., 2005). reflect focusing of attention. MPH was also shown to This is thought to reflect an MPH-induced enhancement reduce regional cerebral blood flow in the dorsolateral of attentional processes or increased recruitment of atten- prefrontal cortex and posterior parietal cortex during Downloaded from https://academic.oup.com/ijnp/article/17/6/961/692761 by guest on 29 September 2021 tional resources. Other studies did not report an effect of MPH-induced improved performance of a working mem- MPH on P3 (Hink et al., 1978; Callaway, 1984; Naylor ory task (Mehta et al., 2000b). Finally, MPH-induced en- et al., 1985; Fitzpatrick et al., 1988; Hermens et al., 2007; hancement of cognitive performance could be predicted Studer et al., 2010). An explanation offered for these by its effect on dopamine receptor availability, as mea- findings is that MPH affects response processing, as sured with PET (Clatworthy et al., 2009). reflected by faster responses, but that MPH does not Using TMS, MPH was shown to alter motor system ex- speed stimulus evaluation processing. citability in a response inhibition task (Kratz et al., 2009), Another component assessed in the studies listed in suggesting MPH can fine-tune the motor system. Finally, Table 4 was the Contingent Negative Variation (CNV). a study employing fNIRS reported decreased oxyhemo- MPH was observed to enhance CNV amplitude, reflect- globin concentration with MPH compared to placebo in ing increased response readiness (Coons et al., 1981; the right frontal lobe, consistent with the PET finding Linssen et al., 2011). Event-related desynchronization, by Mehta et al. (2000) described above. measured during a visual search task, was not affected In sum, the imaging studies on cognitive performance by MPH (Oken et al., 1995). under the influence of MPH show that MPH enhances Of the seven studies in this review that acquired attentional processing and modulates activity in brain fMRI data, three studies assessed brain activity during areas associated with inhibition and attention. How- response inhibition tasks, i.e. Go/No-go and stop signal ever, more studies are needed to draw more exact con- (Hester et al., 2012; Pauls et al., 2012; Costa et al., 2013). clusions, as existing studies vary widely with respect to Hester et al. (2012) observed that activation of the dorsal task, method and peak/area of interest. anterior cingulated cortex and the inferior parietal lobe differed between errors of which the participants were Cognitive effects of MPH in the elderly aware vs. unaware in a Go/No-go task. MPH increased these differences in activation of the dorsal anterior cingu- A limited number of studies investigated the effects of late cortex and the inferior parietal lobe. This is suggestive MPH on cognition in the elderly (Callaway, 1984; of the underlying mechanism leading to improved re- Turner et al., 2003; Muller et al., 2005; Ben-Itzhak et al., sponse inhibition with MPH. Pauls et al. (2012) suggest 2008; Izquierdo et al., 2008; Drijgers et al., 2012). The ef- that inhibition effects are mediated through MPH effects fect of MPH on working memory performance was tested on the attentional mechanisms. Pauls et al. (2012) in an extensive study by Turner et al. (2003) by means of a reported reduced activation of different regions that are digit span task, a spatial working memory task and a spa- associated with the ventral attention system, i.e. the tial span task. None of the tasks was significantly affected right inferior frontal gyrus and insula, during various by MPH. types of infrequent stimuli. Costa et al. (2013) showed Speed of processing was also not affected as that MPH increased activity in the putamen during measured with a SERS task in the study of Callaway error of inhibition but not during successful inhibition (1984) and letter digit substitution and simple and choice in the Go/No-go task, while no such effect was observed reaction time tasks in the study by Drijgers et al. (2012). in the stop signal task. This effect may be due to saliency The four-choice motor reaction task employed by of errors in the Go/No-go task, suggesting that MPH Muller et al. (2005), showed a performance enhancing ef- interacts with saliency. fect of MPH on a difficult version of the task. In this Two fMRI studies on working memory showed uncued version, participants were asked to move a joy- increased activation of the dorsal attention network and stick towards a stimulus that was presented in an uncued altered default mode network activation with MPH location. Performance on the cued version of the task was (Marquand et al., 2011; Tomasi et al., 2011), suggesting impaired by MPH. that MPH may exert its effects on cognition partly by Effects of MPH on verbal learning and memory was modulating the default mode network. assessed by Izquierdo (2008) with tests of formal and 972 A. M. W. Linssen et al. incidental memory in which memory of, respectively, makes it hard to verify the enhancing effects of MPH on unintentionally remembered an intentionally remem- performance in authentic situations. Any such effect is bered information was tested. MPH was shown to likely to be relatively small in comparison to the effects reverse age-related decline of persistence of incidental of adequate sleep, education and work–life balance, and memory. No such effect was observed for formal will be subject to individual differences. memory. Even if MPH substantially improved real-life Reasoning and problem solving, as measured with a performances, the question remains whether the Tower of London task, did not reveal any effects of benefits outweigh the risks. Common adverse effects of MPH on older adults’ performance. chronic MPH use include insomnia, nervousness, irrita- Effects of MPH on older adults’ attention and vigilance bility, anxiety, jitteriness, increased heart rate, dizziness, task performance was tested in four different tasks i.e. drowsiness, headache, stomach ache, anorexia and RVIP task; ID/ED shift task; stop signal task (Turner appetite suppression (Diller, 1996; Klein-Schwartz, et al., 2003); Go/No-go task (Ben-Itzhak et al., 2008). 2002; Repantis et al., 2010). Large doses of MPH can Downloaded from https://academic.oup.com/ijnp/article/17/6/961/692761 by guest on 29 September 2021 Performance of the RVIP and stop signal tasks was not af- lead to psychosis, seizures and cardiovascular events fected by MPH. In the ID/ED task a significant slowing of (Lakhan and Kirchgessner, 2012). Cardiovascular responses similar to that in young volunteers was effects associated with ADHD stimulant medications observed. However, this was not accompanied by an im- include hypertension and tachycardia (Lakhan and provement in accuracy, as is the case in young volunteers. Kirchgessner, 2012). In the Go/No-go task, on the other hand, accuracy Another risk related to MPH use is the potential improved under the influence of MPH, while response abuse of the drug. When MPH is used appropriately time was not affected. for ADHD there is little evidence of addiction and/or Within the domain of visual learning and memory, abuse of MPH (Diller, 1996). However, MPH can have two tests were administered, i.e. a non-verbal PAL test reinforcing effects through its effects on dopamine in and a test of nonverbal memory in which memory of the brain (Volkow et al., 1999). Reinforcing effects depend the spatial orientation of geometric objects is tested with on the rate of uptake of the drug (Volkow et al., 2002; a recognition test (Ben-Itzhak et al., 2008). Performance Leonard et al., 2004), which explains why people who of neither of these tasks by older adults was affected by use MPH to induce a high administer it intravenously MPH. or intranasally, while people who merely take it to stay In sum, MPH does not improve working memory, awake, take it orally (Klein-Schwartz, 2002; Volkow reasoning and problem solving and visual learning and and Swanson, 2003). Self-administration of MPH is likely memory in older adults. Some effects were observed limited by the low rate of clearance of MPH from the within the domains of speed of processing, verbal learn- brain, in which it differs from cocaine (Volkow et al., ing and memory and attention and vigilance. These 1995). results only partly parallel those in younger volunteers, MPH use without prescription could be dangerous for with the main difference being the lack of effects on work- various reasons. Individual risks of which users may not ing memory in older adults. However, the limited num- be aware, such as interaction with other medicinal drugs ber of studies in older adults limits the conclusions that or abnormalities in the cardiovascular system, cannot be can be drawn from these data. 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 Adverse effects and ethical issues may create additional unknown risks (Ragan et al., While we cannot speak of a global cognition enhancing 2013). This may be a motive to regulate off-label stimulant effect of MPH, the research reviewed in this paper use (Sahakian and Morein-Zamir, 2007). However, mak- shows that MPH can improve working memory and ing MPH or other medications easily and legally available speed of processing and, to a lesser extent, verbal learning can lead to other problems with coercion to take such and memory, reasoning and problem solving and atten- drugs (for example, in specific military or medical pro- tion and vigilance in healthy volunteers. Reports of cog- fessions or in children) and fairness (if only rich people nition enhancing effects of MPH might encourage such can afford to buy such drugs). use. We would, therefore, like to put our findings in per- Attitudes towards cognitive enhancement vary be- spective and discuss adverse effects of MPH and related tween authors: while some are generally positive and op- ethical issues. timistic and mainly call for guidelines (Sahakian and The effectiveness of MPH as cognitive enhancer Morein-Zamir, 2007; Greely et al., 2008), others are should not be overestimated (Ragan et al., 2013). All ex- more conservative (Ragan et al., 2013) or even consider perimental studies reviewed here reflect effects in rela- the current debate to be a ‘bubble’ (Lucke et al., 2011) tively homogeneous groups assessed in controlled or ‘media hype’ (Partridge et al., 2011) and merely stress environments using sensitive tests. In daily life, circum- that the evidence for increased stimulant use is weak. stances are much more diverse and complex, which However, everyone agrees that more research is needed, Review on methylphenidate and cognition 973 whether it is to obtain accurate prevalence rates or to list and present the data. Tasks not described by increase our knowledge about the benefits and harm of Nuechterlein et al. (2004) were categorized by the cognition enhancing drug use in healthy individuals. authors. Other decisions that were well thought through, We would like to add one recommendation to the existing but might still be somewhat arbitrary include: (1) some abundance of recommendations: research and reviews of tasks were split into several measures whereas others research on cognition-enhancing drugs should preferably were not; (2) a statistical trend was given a weight of address one single drug at a time. ‘Cognition-enhancing 0.5; (3) if it was not clear which of the reported doses drugs’ are often described as if there were a group of led to significant effects, it was assumed that the reported virtually identical drugs with similar effectiveness and effect was applicable to every dose; (4) sometimes two side effect profiles. It is very important to study specific, low doses are reported, but they are only weighed once; individual features of a drug, as it is essential to study (5) there was no correction for multiple comparisons a drug’s effectiveness in relation to its side effects and for multiple dosing. Finally a major limitation of any other potential risks. Any description of a group of review is that studies that did not show significant Downloaded from https://academic.oup.com/ijnp/article/17/6/961/692761 by guest on 29 September 2021 drugs is likely to be a generalization and may lead to effects are generally underreported (i.e. publication over- or under-estimation of risks and benefits. bias). Therefore, any review is likely to present an over- estimation of the reported effects. In sum, MPH improves working memory and speed of Conclusions processing and, to a lesser extent, verbal learning and In this review the performance enhancing effect of MPH memory, attention and vigilance and reasoning and prob- within various cognitive domains was quantified by a lem solving in healthy young volunteers. MPH effects are percentage (weighed on the basis of specified criteria dose-dependent and the dose–response relationship dif- such as number of subjects). This is a major improvement fers between the different cognitive domains. Imaging compared to earlier reviews in which only some domains studies show enhanced attention processing and altered of cognition were considered, the categorization in attention- and inhibition-related brain activation. MPH domains was less well specified (Repantis et al., 2010; improves cognitive performance in the elderly on tasks Smith and Farah, 2011) and/or the quality was either of speed of processing, verbal learning and memory not taken into account or based on criteria that hardly dif- and attention and vigilance. MPH effects are, however, ferentiate between studies (e.g. double blind design, ran- considered to be relatively small and MPH use is asso- domization (Jadad et al., 1996)). Furthermore, this review ciated with side effects and other adverse consequences, compares 59 studies, which is considerably more than in such as potential abuse. Future studies should focus on previous reviews. The studies reviewed show that MPH MPH specifically to adequately asses the benefit–risk improves cognitive performance in the healthy popu- ratio of this specific drug. 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 Statement of Interest reasoning and problem solving, but not visual learning fi and memory (see Table 3). Anke Linssen and Anke Sambeth have no nancial inter- There were quite large differences between the ests to disclose. Eric FPM Vuurman is employed full time domains with respect to the cognition enhancing effect by Maastricht University. He was involved in conducting of MPH, the lowest percentage being 0% and the highest clinical trials for several pharmaceutical companies 65%. These differences confirm that in studying cognitive over the last three years: MSD, GSK and Transcept phar- performance it is important to distinguish between differ- maceuticals. Financial compensation for his work was fl ent domains of cognitive function. MPH may not globally only to Maastricht University and raises no con ict of fi improve cognitive performance, but it has potential to en- interest. There were no other commercial or nancial rela- fl hance certain aspects of cognitive performance at certain tionships that could be construed as a potential con ict of doses. interest. Wim J. Riedel is honorary Professor at Maastricht The dose–response relationship of the cognition modu- University. He was an employee of F.Hoffmann-La Roche lating effect of MPH differs across different cognitive Ltd, Basel, Switzerland until December 2011 and since domains. In some domains, low doses are more effective then has been an employee of Cambridge Cognition than high doses. An explanation for this may be that, in Ltd, Cambridge, United Kingdom. healthy volunteers, dopamine availability is already close to the optimal level. Enhancing dopamine activity may push the level of dopamine beyond the optimum References without improving performance, or even leading to sub- Agay N, Yechiam E, Carmel Z, Levkovitz Y (2010) Non-specific optimal performance. effects of methylphenidate (Ritalin) on cognitive ability and Factors limiting the conclusions in this review relate decision-making of ADHD and healthy adults. to the decisions that were made on how to categorize, Psychopharmacology (Berl) 210:511–519. 974 A. M. W. Linssen et al.

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