The Use and Impact of Cognitive Enhancers among University Students: A Systematic Review

Abstract

Introduction:
Cognitive enhancers (CEs), also known as "smart drugs", "study aids" or "nootropics" are a cause of concern. Recent research studies investigated the use of CEs being taken as study aids by university students. This manuscript provides an overview of popular CEs, focusing on a range of drugs/substances (e.g., prescription CEs including amphetamine salt mixtures, methylphenidate, modafinil and piracetam; and non-prescription CEs including caffeine, cobalamin (vitamin B12), guarana, pyridoxine (vitamin B6) and vinpocetine) that have emerged as being misused. The diverted non-prescription use of these molecules and the related potential for dependence and/or addiction is being reported. It has been demonstrated that healthy students (i.e., those without any diagnosed mental disorders) are increasingly using drugs such as methylphenidate, a mixture of dextroamphetamine/amphetamine, and modafinil, for the purpose of increasing their alertness, concentration or memory.

Aim:
To investigate the level of knowledge, perception and impact of the use of a range of CEs within Higher Education Institutions.

Methodology:
A systematic review was conducted in adherence with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Whilst 1400 studies were identified within this study through a variety of electronic databases (e.g., 520 through PubMed, 490 through Science Direct and 390 through Scopus), 48 papers were deemed relevant and were included in this review.

Results:
The most popular molecules identified here included the stimulant CEs, e.g., methylphenidate, modafinil, amphetamine salt mixtures and caffeine-related compounds; stimulant CEs' intake was more prevalent among males than females; drugs were largely obtained from friends and family, as well as via the Internet. It is therefore suggested that CEs are increasingly being used among healthy individuals, mainly students without any diagnosed cognitive disorders, to increase their alertness, concentration, or memory, in the belief that these CEs will improve their performance during examinations or when studying. The impact of stimulant CEs may include tolerance, dependence and/or somatic (e.g., cardiovascular; neurological) complications.

Discussion:
The availability of CEs for non-medical indications in different countries is influenced by a range of factors including legal, social and ethical factors. Considering the risk factors and motivations that encourage university students to use CE drugs, it is essential to raise awareness about CE-related harms, counteract myths regarding "safe" CE use and address cognitive enhancement in an early stage during education as a preventative public health measure.

Full text

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BrainSci.2021,11,355.https://doi.org/10.3390/brainsci11030355www.mdpi.com/journal/brainsci
SystematicReview
TheUseandImpactofCognitiveEnhancersamongUniversity
Students:ASystematicReview
SafiaSharif
1
,AmiraGuirguis
1,2,
*,SuzanneFergus
1,
*andFabrizioSchifano
1

1
Psychopharmacology,SubstanceMisuseandNovelPsychoactiveSubstancesResearchUnit,
SchoolofLifeandMedicalSciences,UniversityofHertfordshire,HatfieldAL109AB,UK;
s.sharif2@herts.ac.uk(S.S.);f.schifano@herts.ac.uk(F.S.)
2
InstituteofLifeSciences2,SwanseaUniversity,SwanseaSA28PP,Wales,UK
*Correspondence:amira.guirguis@swansea.ac.uk(A.G.);S.Fergus@herts.ac.uk(S.F.)
Abstract:Introduction:Cognitiveenhancers(CEs),alsoknownas“smartdrugs”,“studyaids”or
“nootropics”areacauseofconcern.RecentresearchstudiesinvestigatedtheuseofCEsbeingtaken
asstudyaidsbyuniversitystudents.ThismanuscriptprovidesanoverviewofpopularCEs,focusingon
arangeofdrugs/substances(e.g.,prescriptionCEsincludingamphetaminesaltmixtures,methylpheni‐
date,modafinilandpiracetam;andnon‐prescriptionCEsincludingcaffeine,cobalamin(vitamin
B12),guarana,pyridoxine(vitaminB6)andvinpocetine)thathaveemergedasbeingmisused.Thedi‐
vertednon‐prescriptionuseofthesemoleculesandtherelatedpotentialfordependenceand/orad‐
dictionisbeingreported.Ithasbeendemonstratedthathealthystudents(i.e.,thosewithoutany
diagnosedmentaldisorders)areincreasinglyusingdrugssuchasmethylphenidate,amixtureof
dextroamphetamine/amphetamine,andmodafinil,forthepurposeofincreasingtheiralertness,
concentrationormemory.Aim:Toinvestigatethelevelofknowledge,perceptionandimpactofthe
useofarangeofCEswithinHigherEducationInstitutions.Methodology:Asystematicreviewwas
conductedinadherencewiththePreferredReportingItemsforSystematicReviewsandMeta‐Anal‐
yses(PRISMA)guidelines.Whilst1400studieswereidentifiedwithinthisstudythroughavariety
ofelectronicdatabases(e.g.,520throughPubMed,490throughScienceDirectand390throughSco‐
pus),48papersweredeemedrelevantandwereincludedinthisreview.Results:Themostpopular
moleculesidentifiedhereincludedthestimulantCEs,e.g.,methylphenidate,modafinil,ampheta‐
minesaltmixturesandcaffeine‐relatedcompounds;stimulantCEs’intakewasmoreprevalent
amongmalesthanfemales;drugswerelargelyobtainedfromfriendsandfamily,aswellasviathe
Internet.ItisthereforesuggestedthatCEsareincreasinglybeingusedamonghealthyindividuals,
mainlystudentswithoutanydiagnosedcognitivedisorders,toincreasetheiralertness,concentra‐
tion,ormemory,inthebeliefthattheseCEswillimprovetheirperformanceduringexaminations
orwhenstudying.TheimpactofstimulantCEsmayincludetolerance,dependenceand/orsomatic
(e.g.,cardiovascular;neurological)complications.Discussion:TheavailabilityofCEsfornon‐med‐
icalindicationsindifferentcountriesisinfluencedbyarangeoffactorsincludinglegal,socialand
ethicalfactors.Consideringtheriskfactorsandmotivationsthatencourageuniversitystudentsto
useCEdrugs,itisessentialtoraiseawarenessaboutCE‐relatedharms,counteractmythsregarding
“safe”CEuseandaddresscognitiveenhancementinanearlystageduringeducationasapreven‐
tativepublichealthmeasure.
Keywords:neuroenhancement;cognitiveenhancement;drugabuse;universitystudents;study
drugs;non‐medicaldruguse;smartdrugs

1.Introduction
Cognitiveenhancementisdefinedasan“amplificationorextensionofcorecapacity
ofthemindbyimprovingtheinternalandexternalinformationprocessingsystems”[1].
Cognitiveenhancementcanbeachievedintwoways,e.g.,“pharmacologically”,bytaking
Citation:Sharif,S.;Guirguis,A.;
Fergus,S.;Schifano,F.TheUseand
ImpactofCognitiveEnhancers
amongUniversityStudents:A
SystematicReview.BrainSci.2021,
11,355.https://doi.org/10.3390/
b
rainsci11030355
AcademicEditor:BasavarajS.
Balapal
Received:16February2021
Accepted:3March2021
Published:10March2021
Publisher’sNote:MDPIstaysneu‐
tralwithregardtojurisdictional
claimsinpublishedmapsandinsti‐
tutionalaffiliations.

Copyright:©2021bytheauthors.
LicenseeMDPI,Basel,Switzerland.
Thisarticleisanopenaccessarticle
distributedunderthetermsand
conditionsoftheCreativeCommons
Attribution(CCBY)license
(http://creativecommons.org/licenses
/by/4.0/).

BrainSci.2021,11,3552of38
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cognitiveenhancer(CE)drugs/substances;or“non‐pharmacologically”,bymaintaininga
healthylifestyle,whichincludesbeingphysically,mentallyandsociallyactive;eatinga
healthy,balanceddiet;drinkingalcoholonlyinmoderation;andmaintaininggoodsleep
habits[2].CEs,alsoknownas“smartdrugs”or“nootropics”,areaheterogeneousgroup
ofchemicalsubstancesthatareusedtoimprovecognitivefunction[3],particularly
memory,alertness,attention,learningperformance,creativityandmotivation[4].CEsare
typicallybeingobtained,andattimesbyhealthyindividuals[5,6],onprescription,over‐
the‐counter,online,orthroughothersourcessuchasfamilyorfriends[7].Theclinical
impactofCEs’ingestioncanbesignificant,withthesemoleculesbeingabletoaffectvari‐
ousneurotransmitterpathwaysinthebrain,includingthecholinergic,dopaminergic,nor‐
adrenergicandserotonergicpathways[8].Whilsttheirmechanismofactionisnotfully
understood[3],mostpopularCEs(e.g.,methylphenidate,modafinilandamphetamine
saltmixtures)arestimulants[9].Methylphenidateincreasesthelevelsofnoradrenaline
(NA)anddopamine(DA)inboththeprefrontalcortexandthecortical/subcorticalre‐
gions,andthiseffectmaybeassociatedwithlevelsofimprovedattentioninAttention
DeficitHyperactivityDisorder(ADHD)[10].Conversely,withmodafinil—amedicinebe‐
ingusedtotreatnarcolepsy—stimulantactionsareassociatedwithanimpactonNA,glu‐
tamate(NMDAorN‐methyl‐D‐aspartate)andDA[11].Inparticular,modafinilincreases
DAlevelsinthecaudateandnucleusaccumbens(Nac),whilstblockingDAtransporters
inahealthyindividual’sbrain[12].Outofthesemolecules,modafinilmaybebettertoler‐
ated,inducinglessadversedrugreactions,whilstnotbeingassociatedwithahighriskof
dependence[13].Theamphetaminesaltmixtures(e.g.,inthebrandedproductAdderall)
blockthere‐uptakeofbothNAandDAintothepre‐synapticneuron,andincreasetheir
releaseaswellfromthepre‐synapticneuron,henceincreasingtheirconcentrationsinthe
synapticcleft[14].
Indeed,sincethe1940s,bothmodafinilandamphetamine(e.g.,“gopills”)CEcate‐
gorieshavebeenthesubjectofmilitaryresearch,tohelpsoldiersstayalertwhilstattenu‐
atingtheeffectsofsleepdeprivation[15,16].However,thesedrugsareincreasinglybeing
usedbyhealthyindividuals,includingstudentsandnightshiftworkers,toimprovetheir
cognitiveandmotivationalfunctions[17].AssociationsbetweenCEsanddrugsinsports
havebeeninvestigated[18].CEsanddrugsinsportssharemanyaspectswithrespectto
“enhancement”and“doping”.Theformermaybemoresociallyacceptable,whilstthe
latterisconsideredillegalandisheavilymonitoredbyorganisationssuchasTheWorld
Anti‐DopingAgency(WADA).TheuseoffreelyavailableCEs,suchascaffeinatedprod‐
uctsandvitamins,havebeeninvestigatedinathletesas“gateway”and“predictor”of
physicalenhancersuse.Thenon‐monitoredCEswerefoundtobehighlyusedamongathletes
withorwithoutphysicalenhanceruse[19].Studiesalsoshowedthatusersoferogonomicaids
suchascaffeinemayfavourdopingdueto“biasedreasoningpatterns”[19].
ItisimportanttonotethatstudentsusingCEsdonotonlyaimtoachieveacognitive
enhancement,butalsoamotivationalenhancementandanoverflowofenergy.Theymay
useacombinationofCEsaswellasalcohol,and/orrecreationalsedatives,inanattempt
toachieveagoodqualitysleep,reducenervousnessandimproveoverallperformancein
examsandstudy‐relatedassessments[20,21].
ThelifetimeprevalencerateofprescribedCEs’intakefornon‐medicalreasons,asa
self‐attempttoincreasecognitiveperformances,amonguniversitystudentsintheUKand
Irelandhasbeenestimatedtobearound10%[22].However,theselevelsofintakemaybe
underestimated[23]andthetrendhasattractedaconsiderableinterest[22],relatingtoits
social,ethicalandlegalimplications[24–26].Whilstmoststudieshavefocusedonthe
prevalenceofalimitedrangeofafewCEs(e.g.,amphetaminesaltmixtures,methylpheni‐
dateandmodafinil),focusingonintakebystudentsinHigherEducationInstitutions
(HEIs),astudybyNapoletanoetal.(2020)identifiedatotalof142uniqueCEs.These
moleculeswerethensub‐groupedinto10categories,accordingtorecentlyproposedclas‐
sifications[27]including:prescribeddrugs,plants/herbs/products,psychostimulants;im‐
age‐ andperformance‐enhancingdrugs(IPEDs),miscellaneous,GABAergic(gamma‐

BrainSci.2021,11,3553of38

aminobutyricacid‐ergic)drugs,phenethylamines,cannabimimetics,tryptaminederiva‐
tives,andpiperazinederivatives.Inparallelwiththecontinuousemergenceofnew/novel
psychoactivesubstances(NPS),whichhasenrichedtherepertoireofillicitdruguse[28],
thismanuscriptaimstoprovideanupdatedoverviewoftheuseofCEsamonguniversity
students.
2.Methods
ThecurrentsystematicliteraturereviewwasperformedinadherencewiththePre‐
ferredReportingItemsforSystematicReviewsandMeta‐Analyses(PRISMA)guidelines
[29],toestimateCEs’prevalenceofintake;andassessknowledge,awarenessandimpact
ofCEs’useamonguniversitystudents.
2.1.LiteratureSearch(InclusionandExclusionCriteria)
ThefocusherewasonquantitativeandqualitativestudiesrelatingtoCEs’useamong
Universitystudents:Theliteraturesearchwasperformedusingarangeofkeyword
strings,e.g.,cognitiveenhancersANDneuroenhancement,prescriptiondrugmisuseOR
prescriptiondrugabuseamonghealthyindividualsANDenhancement.Inparticular,the
searchstrategywasconductedfromthreedatabasesScopus,PubMedandSciencedirect.
Finally,amanualsearchwasalsocarriedoutusingGoogleScholarinordertoensurenone
ofthekeyarticlesandstudiesweremissed.
Inclusioncriteriawerequantitative(surveys)andqualitative(interviews)studies
havingbeencarriedoutamonghealthystudentsaged18yearsandolderinHEIs.Articles
wereincludediftheyrelatedtoarangeofnineCEs(prescriptionCEsincludingamphet‐
aminesaltmixtures,methylphenidate,modafinilandpiracetam;andnon‐prescription
CEsincludingcaffeine,cobalamin(vitaminB12),guarana,pyridoxine(vitaminB6)and
vinpocetine),whichwereselectedherebecauseoftheirpopularityamonguniversitystu‐
dents[4,7,22,26,30].StudieswritteninEnglish,fromtheyear2000(i.e.,fromaroundthe
timewhenNPSstartedtoemergeindrugscenarios)to2020wereincludedinthestudy
search.Regional/worlddrugreports(e.g.,fromtheEuropeanMonitoringCentrefor
DrugsandDrugAddiction/EMCDDAandtheUnitedNationsOfficeforDrugand
Crime/UNODC)wereincludedhereaswell.Conversely,studiesfocussingonunderage
children,onpreclinicalexperimentsorstudentswithmedicaldiagnosesusingtheselected
drugs/substancesformedicalreasonswereexcludedfromthestudy.Non‐Englisharticles
werealsoexcluded.
2.2.QualityAssessment
Basedontheinclusioncriteria,theselectedarticleswereappraisedforqualityusing
PRISMAchecklists[29].SearchresultswereexportedtoMendeley,afreereferenceman‐
agerandacademicsocialnetwork.Thistoolwasusedtodeterminethestructureofthe
indexstudymethodology[29].
3.Results
3.1.SummaryoftheLiteratureSearch
Theliteraturesearchidentifiedatotalof1400studieshere(e.g.,520throughPubMed,
490throughScienceDirectand390throughScopus)(Figure1).Forty‐eightstudieswere
excludedastheywereduplicates,1294studieswerescreenedandwereexcludedbased
ontheirtitleandabstract,10didnotmeettheinclusioncriteria,and48weredeemedrel‐
evantandwereincludedinthisreview(Table1).

BrainSci.2021,11,35524of38

Table1.SummaryoftheliteraturereviewfocusingonCognitiveEnhancer(CE)drug(s)/substance(s)beingconsideredforthestudy(e.g.,methylphenidate,am‐
phetamine,modafinilandpiracetam,caffeinepills,guarana,cobalamin(vitaminB12),vinpocetineandpyridoxine(vitaminB6).
ReferenceCountryPrescription
CE
Non‐Pre‐
scription
CE
StudySampleMethodology
Used
Results/LifetimePrevalenceof
CENotes/Limitations
[30]UK
Ritalin,Dex‐
troampheta‐
mine/am‐
phetamine,
Modafinil
andAr‐
modafinil
‐
Survey=506partici‐
pants.
Interview=15partic‐
ipants
Onlinesurvey
andInterview.
Outof506participants,45.5%
(n=230)reportedthattheyhad
usedarangeofCEdrugsinthe
previous12monthsforthe
purposeofstudy.Maleusage
wasreportedasbeingmore
thantwoandahalftimes
higherthanfemaleusage.
ThemotivationalfactorsbehindCEuse
wereinvestigatedwithgreaterunder‐
standingofthefactorsinfluencingtheir
use.Universitiesneedtodevelopa
greaterawarenessoftheprevalenceof
CEuseamongsttheirstudentsandcon‐
sidertakinganactiveapproachinreduc‐
ingtheiruse.
[7]Brazil
Modafinil
Methylpheni‐
date
Piracetam
‐ 1865participants.Onlinesurvey.
Outof1865respondents,4.2%
hadusedCEsintheprevious
12 months,andtheprevalence
amongLawstudentsreached
14.3%.Themostcommonly
usedsmartdrugwas
methylphenidate.Thedrug
wasmostlyobtainedthrougha
friend.
Thelimitationwasthequestionnaireit‐
self.Itispossiblethattherewasa
memorybiasandomissionofresponse,
underestimatingtheprevalencefound.
However,thelimitationwasreducedas
thequestionnairewasself‐administered
andanonymous.

BrainSci.2021,11,35525of38

[31]UK
Modafinil
Ampheta‐
mine
Methylpheni‐
date
BetaBlockers
‐
612participantsfrom
RussellGroupuni‐
versities.
Onlinesurvey.17%reportedhavingused
smartdrugspreviously.
Thelimitationofthisstudywasthatit
wasopentoallUKfull‐timeundergrad‐
uatestudents,althoughthemajorityof
theparticipantswerefromRussell
Groupuniversities.However,theydid
notcollectadditionaldataondiscipline
oruniversityand,therefore,cannotbe
surehowrepresentativethesampleis
fortheUKuniversitypopulationasa
wholeorthepopulationatthehostuni‐
versity.Thismeansthatfactorssuchas
competitivenesscannotbeextracted
fromthedata.
[32]UKModafinil‐
15undergraduate
studentsatRussell
Groupuniversities.
Interview.
AlluserstookModafinil,with
somealsohavingtriedDextro‐
amphetamine/amphetamine
andRitalinforthepurposeof
study.Byrecruitingbothusers
andnon‐users,allnon‐users
werefoundtobefemale.
Allintervieweesreportedimprovingac‐
ademicstudyastheprimarypurposesof
druguse,particularlyvaluingimproved
focus,increasedefficiencyandreduced
procrastination.Theseeffectswere
judgedtobehighlydesirableinthecon‐
textoftimeconstraintsandfatiguewhen
approachingexamsanddeadlines.

BrainSci.2021,11,35526of38

[33]Iran
Modafinil,
Methylpheni‐
date,Am‐
phetamine,
Piracetam
Vinpocetine
Vinpoce‐
tine.
Cross‐sectional
studywasper‐
formedbyanalysing
atotalsampleof579
studentsintheone
UniversityofMedi‐
calSciencesstudents
from1stto5thyear.
Papersurvey.
Some44(17.6%)ofthere‐
spondentsansweredthatthey
hadusedCEsatleastoncein
theirlife,toincreaseconcentra‐
tion.
Therewasasignificantrela‐
tionshipbetweenCEuseand
theageofrespondents(p<
0.05).Accordingtologisticre‐
gressionanalysis,therewasa
significantrelationshipbe‐
tweenknowingsomeonewho
hadused,stresslevelandCE
use(p<0.05).
Samplecollectionwasoneofthemain
limitations.Forexample,thefemale
samplewaslargerthanthemalesam‐
ple.Studentsenteredthestudywithout
priornoticeofit,whichmeansthata
factormayplayarole,aswellas
memorybias,especiallywhenstudents
arebeingaskedtorecordnon‐pharma‐
ceuticaluse.Finally,itisrecommended
thatastudyshouldbeconductedinall
universitiesofIranandtheirresults
compared.Therefore,althoughitisob‐
viousthattheuseofthesedrugsforin‐
creasingcognitionwasinvestigated
moreamongstudentpopulations,itis
notpossibletogeneralisetootherpopu‐
lations.
[34]Pakistan Methylpheni‐
date ‐
Across‐sectional
studywascon‐
ductedinMedical
collegesinPakistan,
usingaself‐con‐
structed,validated
questionnaire.The
samplesize(400)
wascalculatedusing
open‐sourceStatis‐
ticsforEpidemio‐
logical
Healthsoftware.
Papersurvey.
Some27participantsadmitted
theuseofMethylphenidateto
improveconcentration.Peer
pressurewasfoundtobeama‐
jorfactorinitsmisuse.
Thestudydeterminedtheprevalenceof
non‐therapeuticuseofmethylphenidate
aswellasascertaininganybenefits,side
effects,andotherfactorsassociatedwith
thisuse.Thisisacross‐sectionalstudy
and,apartfromachi‐squaretest,no
otherstatisticalanalysiscouldbeper‐
formed.Thestudyonlyincludestwocit‐
iesinPakistanandmustbeexpandedto
includeotherregionsaswell,especially
theregionslabelledashighriskfordrug
misuse.Thisstudydoesnotextensively
explorethereasonsforaparticipantopt‐
ingfordrugabuse,regardlessofaca‐
demicperformanceorenvironment.

BrainSci.2021,11,35527of38

[35]BrazilMethylpheni‐
date ‐
Simplerandomsam‐
pleofstudentsofthe
UniversidadFederal
deMinasGerais(n=
438),invitedtoan‐
sweranonlineques‐
tionnaireaboutthe
useofmethylpheni‐
date
Onlinesurvey.
Outof378studentsincluded,
5.8%(n=22)reportedusing
methylphenidateforCE;of
them,41%(9/22)inthe4weeks
priortothesurvey.
Thestudyestimatestheprevalenceof,
andfactorsassociatedwith,theuseof
methylphenidateforcognitiveenhance‐
mentamongundergraduatestudents.
[36]Belgium
Methylpheni‐
date,Am‐
phetamine,
Modafinil
‐
Across‐sectional
studyof3159Medi‐
calstudents.
Papersurvey
andonlinesur‐
vey.
Approximately8.7%ofthestu‐
dentsreportedthattheyused
CEtoimprovetheiracademic
performanceduringexamtime.
Thestudyinvestigatedtheprevalenceof
thenon‐medicaluseofmethylphenidate
andknowledgeofthisdrugamongUn‐
dergraduateMedicalstudentsofthe
UniversityoftheFreeState.
[37]Canada
Methylpheni‐
date,Am‐
phetamine,
Modafinil

Caffeine
11focusgroups,3–7
participantsper
group.
Focusgroupin‐
terview.
Approximately5%to30%of
studentsreportedtheuseof
CE.
Thestudyhascertainlimitations.Firstly,
forconfidentialityreasons,theydidnot
askparticipantsabouttheirownhistory
ofusingCEs.Thisprecludedthemfrom
knowingwhenparticipantsweretruly
referringtoafriendintheirnarratives,
orwhentheywerefollowingtheinter‐
viewer’sinstructionstomasktheirown
illicitactivities.Second,theydidnotdi‐
rectlyquestionparticipantsonhowthey
knewabouttheeffectsofCEs,asthis
wasanunexpectedlineofinquiry.
[38]Italy
Coffee,
Ginkgo‐bi‐
loba,Caf‐
feine,Am‐
phetamine,
Modafinil,
Methylpheni‐
date
Ginkgobi‐
loba,Caf‐
feine,En‐
ergydrinks
433medicalstu‐
dents.Papersurvey.
Approximately74.7%ofthe
studentssaidtheyhaveused
CEtoimprovecognitivefunc‐
tions.Theremainingstudents
wereawareofconcernsabout
safetyandsideeffects.
Thestudyexploredtheuseandattitudes
towardtheuseofCEinItalianMedical
students.Onlyoneuniversitywasin‐
volved;therefore,thegeneralizabilityof
theirfindingstothewholeItalianstu‐
dentpopulationislimited.

BrainSci.2021,11,35528of38

[39]Iran
Ampheta‐
mine,
Methylpheni‐
date
‐
Cross‐sectionalstudy
wasconducted
among560Medical
studentsandclinical
residentsofBabol
UniversityofMedi‐
calSciencesduring
theacademicyear
2014–2015.
Papersurvey.
Some444students(79.3%)
filledoutthequestionnaires.49
(11%)individualsreportedam‐
phetamineandmethylpheni‐
date(Ritalin)use.Themean
ageofthestimulantdrugusers
was24.6±4.8years.Themain
initiatingfactorwastoimprove
concentration(29persons;
59.2%).
Thestudywastoevaluatethecurrent
situationofstimulantuseamongMedi‐
calstudentsandresidentsofBabolUni‐
versityofMedicalSciences.
Thesurveywasconductedinclassbe‐
forethelecturestarted,sothestudents
mayhavebeeninarushtofinishthe
questionnaires.
[40]
UK,
France,
Austria,
Belgium,
Brazil,
Canada,
German,
Hungary,
Ireland,
NewZea‐
land,Aus‐
tralia,
USA,
Portugal,
Switzer‐
landand
theNeth‐
erlands
Methylpheni‐
date,
Modafinil,
Ampheta‐
mine,Canna‐
bis
‐ (2015)n=79,640
(2017)n=29.758
Onlinesurvey.
Non‐probability
sample.
TheGlobal
DrugSurveyis
anannuallycon‐
ductedanony‐
mouswebsur‐
veyonsubstance
use.Twodata
setsfromthe
maleandfemale
GlobalDrug
Survey(GDS).
TheGlobalDrugSurvey(GDS)
isthelargeststudyonCEs
drugsthathaseverbeencon‐
ducted.Acrossbothyears,
thereweremoremalethanfe‐
malerespondents.
Accordingtoresponsesfrom
bothyears,themainsourceof
supplyforCEdrugspartici‐
pantswasthecircleoffriends
(47.8%).Oneintenindicated
thattheInternetwastheirmain
source(11.8%).
Familymemberswithapre‐
scription(6.1%)andphysicians
(3.8%)werelesscommon
sourcesforstimulantdrugs
usedforCEs.Overall,4.9%and
13.7%oftheglobalsamplere‐
portedtheuseofCEdrugsto
improveperformanceatwork
orwhilestudying.
Severallimitationswereconsidered:The
firsttwoandmostimportantlimitations
ofthestudyaretheself‐selectionofGDS
surveyparticipantsandtheuseofself‐
reporteddata.Sincethesampleisself‐
selectedandthesubstanceuseforCE
drugsconsistsofself‐reporteddata,the
actualextentofCEdrugsinthepartici‐
patingcountriesisnotaccurately
known.
Thesampleshouldnotbeconsidered
representativeofanycountry’sgeneral
population.
Athirdlimitationisthattheimpactof
recallbiasordeliberatemisreportingon
resultsmustbeconsidered.
Finally,duetotheanonymouswebsur‐
veyinstrument,thesameindividual
mighthavecompletedtheGDS2015
multipletimes.However,<1%ofthe
sampleprovidedidenticalresponsesets
acrossdemographicsandkeyvariables
usedintheseanalyses.

BrainSci.2021,11,35529of38

[41]Australia
Methylpheni‐
date,
Modafinil,
Ampheta‐
mine
‐ 1136Australianstu‐
dents.Onlinesurvey.
6.5%reportedthattheyused
CEtoimproveacademicper‐
formance.
Thestudyfoundthattheprevalenceof
non‐medicalprescriptionstimulantuse,
toimproveacademicperformance,is
lowamonguniversitystudentsinAus‐
tralia.Thecross‐sectionaldesignmeans
thatitisnotpossibletoinfercausalrela‐
tionshipsbetweentheuseofprescrip‐
tionstimulantsandotherfactors.The
useofself‐reportingmeasuresmayhave
introducedrecallandsocialdesirability
biases.
[42]Austria ‐ Caffeine
pills2284students.Papersurvey.14.9%ofparticipantsreported
theuseofCaffeinepills.
(I)Toinvestigatewhetherincludingcaf‐
feinetabletsinthedefinitionofpharma‐
cologicalneuroenhancement(PN)
withinaquestionnaireincreasesthePN
prevalenceestimate(framingeffect),
(II)Toinvestigatewhetherthehealth‐re‐
latedriskattitudeisincreasedinstu‐
dentswhousePN.

BrainSci.2021,11,35530of38

[43]Australia
Methylpheni‐
date,
Modafinil,
Ampheta‐
mine
‐ 642students.Onlinesurvey.
6.32%ofindividualsreported
lifetimeuseofoneormorepre‐
scriptionCEdrugs,listedfor
thepurposesofstudy‐related
enhancement.
Eventhoughthisstudyprovidessome
insightsintotheCEdrugusethatoccurs
atAustralianuniversities,therearesome
limitationstoconsider.Resultsshould
beinterpretedinthelightoftheconven‐
ienceandcross‐sectionalsamplingmeth‐
odsused.ParticipantsstudyingScience
degrees,womenandundergraduates
werealsooversampled.Asaresult,the
distributionofthestudentsinthecur‐
rentstudymaynotbeanaccuraterepre‐
sentationoftheentirestudentpopula‐
tionatAustralianuniversities.Thenum‐
berofillicitCEsdruguserswasalsoso
lowthatstatisticalanalyseswere
deemedinappropriateforthisgroup.
Therefore,cautionshouldbeexercised
ininterpretingtheresults,giventhecon‐
straintsofthesample.Asperprevious
work,futurestudiesmayconsiderexam‐
iningtheacademicoutcomesofAustral‐
ianstudentsthatuseCEdrugs,particu‐
larlycontextualisedregardingcoping.

BrainSci.2021,11,35531of38

[44]UK
Methylpheni‐
date,Dextro‐
ampheta‐
mine/am‐
phetamine,
Modafinil
CaffeineAllLevel1andLevel
4M.Pharm.
Papersurvey.
Convenience
sample.
Theresponserateswere89.3%
(Level1)and89.0%(Level4)
with48.0%ofrespondentsre‐
portingtheywereCEusers
(largelycaffeine).Additionally,
42.4%thoughtusingpharma‐
ceuticalCEsforimprovingaca‐
demicgradesbreachedtheir
CodeofConduct.
Thestudycouldbedoneforother
Schools,suchasotherhealthcaredisci‐
plines.However,theopinionswerecap‐
turedatonepointintime,datawere
self‐reported,andthefindingsarenot
generalisable.Perhaps,ifthestudyhad
beenconductedimmediatelybeforethe
writtenexaminations,prevalenceofCE
usewouldhavebeenhigher.Manually
distributingpaper‐basedquestionnaires
tostudentsinacompulsoryclassandan
onlinedistributionwouldenhancethe
responserate.Otherwaystomaximise
theresponserateincludedhavingarela‐
tivelyshortquestionnairewithquestions
largelyasclosedquestions.Educational
workshopscouldfurtherexploreethical
issues.
[45]Greece
Ampheta‐
mine,
methylpheni‐
date,
Cannabis
‐ 591Medicalstu‐
dents.Onlinesurvey.
About1in10medicalstudents
misusedprescriptiondrugs,
mostlyforself‐treatment
purposesandabout1in4used
illicitdrugs,mostlyfor
recreationalpurposes,with
cannabisbeingthemost
frequentlyused.
Toanalysetheprevalenceoflifetimeand
currentuseofillicitdrugsamong
Medicalstudentsworldwide.
ConsideringthatCEuseduringmedical
schoolaffectsstudents’personaland
professionallives,furtherinternational
studiesareneededtoelucidatethe
prevalenceandthemotivationofthat
useamongmedicalstudents.

BrainSci.2021,11,35532of38

[46]NewZea‐
land
Methylpheni‐
date,amphet‐
amine,
Modafinil
‐
449Pharmacy,Medi‐
cine,Nursingand
LawStudents.
Papersurvey.
Responseratewas88.6%
(442/499).
PrevalencerateofCEwas6.6%
intheuniversityenvironment
sampledTherewerenosignifi‐
cantdifferencesinstudentmo‐
tivationandlearningstrategies
betweenusersofCEandnon‐
users.
Toinvestigatewhatfactorsexplainthe
decisiontouseCEsamongtertiarystu‐
dentsinNewZealand,usingtheTheory
ofPlanedBehaviour.
Thisresearchsupportsthenotionthat
thedecisiontouseCEsisnotjustanau‐
tonomouschoicethatoccursinisolation.
Attitudesontheethicalandsocialac‐
ceptabilityofCEuseweremorelikelyto
drivethedecisiontouseCEs.
[47]Greece
Methylpheni‐
date,
Modafinil
ginseng,
taurine,caf‐
feine,Vita‐
minBcom‐
plex
450universitystu‐
dents. Papersurvey.
Thefindingsshowthatuniver‐
sitystudentsmayengagein
pharmacologicalcognitiveen‐
hancers’(PCE)useindepend‐
entoftheirstudentexperi‐
ences.Rather,achemicallyas‐
sistedperformanceenhance‐
mentmindsetseemstodiffer‐
entiateusersfromnon‐usersof
PCEs.
Thestudydidnotaddresswhethersuch
achievementmotivationsunderliethe
decision‐makingprocessestousePCEs
amonguniversitystudents.
[48]SouthAf‐
rica
Methylpheni‐
date‐
Year5Undergradu‐
ateMedicalstudents
(541students).
Papersurvey.
Some11%reportedtheuseof
methylphenidateforstudyen‐
hancementpurposes.
Therearefewlimitationsinthisstudy.
Thesurveywasself‐administered,and
thequestionnairewasconductedinclass
beforethelecturestarted,sothestudents
mayhavebeeninarushtofinishit.The
questionnairewasnotstructuredinsuch
awaytodeterminewhetherparticipants
withAttentionDeficitHyperactivity
Disorder(ADHD)wereusing
methylphenidateasprescribedormisus‐
ingitforreasonsnotrelatedtotheir
ADHD.

BrainSci.2021,11,35533of38

[49]UK
Methylpheni‐
date,Am‐
phetamine,
Modafinil
‐
66participantsfrom
RussellGroupuni‐
versities.
Focusgroupin‐
terview.
Some58/66studentsthought
thatitisagoodchoicetouse
CEs.
Thisstudywasconductedtocompare
theacuteeffectsofmethylpheni‐
date/MPH,modafinil,and3,4‐meth‐
ylenedioxymethamphetamineonthe
neuralmechanismsunderlyingre‐
sponse.Notabletodisentangleneural
activationinresponsetosuccessfulvs.
failedinhibitionsinthepresentstudy
duetothemodestnumberofno‐gotri‐
als.Thesmallnumberofinhibitiontrials
(i.e.,no‐gotrials)alsolimitedthefunc‐
tionalrelevanceofthebehaviouralre‐
sults,albeitMPHandmodafinilsignifi‐
cantlyincreasedtheprobabilityofinhi‐
bition.
[50]Australia
Methylpheni‐
date,Am‐
phetamine,
Modafinil
‐ 38students.Interview.n=5hadusedCEs.
CEsusersreportedhigherlevelsof
stressandlowerlevelsofabilitytocope
thanthesampleaverage.
[51]
United
Arabof
Emirates
‐ Caffeine
175universitystu‐
dentsinoneuniver‐
sityonly:
Year1toyear4.
TheSchoolsof:Art
andCreativeEnter‐
prises.
BusinessSciences,
Communicationand
MediaSciences.
SchoolofEducation
andSchoolofSus‐
tainability
Sciences
Papersurvey.
Convenience
sample.
Eighty‐sixpercentofthe175
participants,bothmalesandfe‐
males,atZayedUniversity,
Dubaiconsumedcaffeinated
beverageswithanaveragein‐
takeof249.7±235.9mg.Thein‐
takeamongthe150caffeine
consumersvariedfrom4.2
mg/dayto932.2mg/day.
Thestudywastodeterminethepreva‐
lenceofcaffeinatedbeverageconsump‐
tionamonguniversitystudentsandthe
perceivedbenefits.Inadditiontothees‐
timationofdailycaffeineconsumption,
thestudywasundertakeninoneuniver‐
sityonly.
IntheUAE,thelimitedstudiesthatwere
doneregardingthisconcernshowedthe
hightendencyofuniversitystudentsto‐
wardstheconsumptionofcaffeinated
drinks,mainlyenergydrinks.

BrainSci.2021,11,35534of38

[52]Iceland
Methylpheni‐
date,Dextro‐
ampheta‐
mine/am‐
phetamine,
Modafinil
‐ n=521.Onlinesurvey.
Approximately11%usedCE
withoutprescription,42%had
aprescription.Thereasonfor
themisusewastoimprove
theiracademicperformance.
Toreviewhistoricalinformationcon‐
cerningprescriptionstimulantsandto
summarisetheliteraturewithrespectto
misuseamongadults,particularlycol‐
legestudents,includingriskfactors,me‐
diatorsandmoderators,andmotivations
forprescriptionstimulantmisuse.Lack
ofunderstandinginvariabilityaccord‐
ingtodoselevelandindividualvariabil‐
ityisaclearlimitationacrossmoststud‐
iesexaminingthepotentialforneu‐
rocognitiveenhancementfromprescrip‐
tiondrugs.
[53]France
Methylpheni‐
date,
Modafinil,
3,4‐Methyl
enedioxy
methamphet‐
amine
(MDMAor
ecstasy),pi‐
racetam,am‐
phetamine.
‐
1718Medicalstu‐
dentsandphysi‐
cians.
Onlinesurvey.
Approximately33%reported
theuseofCE,mainlytoin‐
creaseacademicperformances
andtostayawakeduringexam
preparations.
Toestimatetheprevalenceofpsychost‐
imulantuseintheFrenchmedicalcom‐
munityandtheirmotives.Lackofdirect
informationontheperiodofstimulant
use.Itwasachoicetokeepthequestion‐
naireshorttomaximizetheresponse
rate.Thislimitwaspartiallyaddressed
bytheageatthefirstpsychostimulant
use,whichwasconsideredintheanal‐
yses.

BrainSci.2021,11,35535of38

[54]Lithuania
Modafinil,
Methylpheni‐
date,Am‐
phetamine
‐
Across‐sectionalsur‐
veystudywasper‐
formedbyanalysing
aconveniencesam‐
pleofn=579inthe
twouniversitiesof‐
feringMedicaledu‐
cationinLithuania.
Papersurvey.
Approximately8.1%reported
thattheyhadusedCEintheir
lifetime.
Toanalysetheuseofcognitiveenhanc‐
ersamongmedicalstudentsinLithua‐
nia,todeterminethereasonsforusage
andevaluatethecontributingfactors,
suchassociodemographiccharacteris‐
tics,stresslevels,sleepqualityand
knowingsomebodywhohasuseda
neuro‐enhancingdrug.Studentspartici‐
patedinthestudywithoutanyprevious
knowledgeaboutit,whichmeansthata
surprisefactormayhaveplayedarole
andmemoriescouldbebiased.
[55]
Lithuania
andthe
Nether‐
lands
Racetam
groupsub‐
stancesBen‐
zodiazepines
Modafinil,
Methylpheni‐
date,Am‐
phetamine
Caffeine
pills
Interviewn=35
Surveyn=113
Onlinesurvey
andInterview
From113respondentsinthe
survey,24(21%)reportedhav‐
ingtriedCEs.
Mostofparticipantsturnedto
CEstoenhancetheirconcentra‐
tionforthepurposeofstudy
andtimemanagement.
Futureresearchneedstotakeintoac‐
countthegreatvarietyofdrugs/sub‐
stancesthatstudentsuseasCEsinreal‐
lifesettings.
[56] TheNeth‐
erlands
Methylpheni‐
date,
Modafinil,
Rivastigmine,
BetaBlockers
‐ 1572students.Onlinesurvey.
Noresponsewasreportedon
theuseofModafinilandRi‐
vastigmine.52studentsre‐
portedtheuseofmethylpheni‐
date.36%hadusedBetaBlock‐
ersatleastonceintheirlife‐
time.
Conveniencesamplingconstitutedonly
anapproximaterepresentationofthe
studentpopulationintheNetherlands.
Women,forexample,wereover‐
sampled.Inaddition,thesamplewas
notequallydistributedfordifferentuni‐
versities,aswellasnotdistributedbeing
inlinewiththeabsolutedifferencein
numberofstudentsofthe14DutchGov‐
ernmentsupporteduniversities.

BrainSci.2021,11,35536of38

[57]Iran Methylpheni‐
date Alcohol16,000medicalstu‐
dents. Papersurvey.
Theprevalenceofprescription
drugmisuse,alcoholuseinthe
previousyear,andeveryillicit
substanceusewas4.9%,6.9%,
and2.9%,respectively.
Thereislimitedinformationaboutillicit
druguseandassociatedfactorsin
hookahsmokersinIran.So,theaimof
thisstudywastoassessthestatusofil‐
licitdruguseandassociatedfactors
amonghookahsmokersofKhalilAbad
cityin2015.
[21] Switzer‐
land
Methylpheni‐
date,
Modafinil
‐
Studentsatthree
Swissuniversities
wereinvitedby
emailtoparticipate
inaweb‐basedsur‐
vey.Ofthe29,282
studentswhowere
contacted,3056par‐
ticipated.
Onlinesurvey.
Approximately22%usedCEto
improvecognitiveperfor‐
manceswhilestudying.
Investigatestudents’attitudestoward
PCE.Theresponserateforthepresent
surveywas10%.Thestudysamplemay
nothavebeennecessarilyrepresentative
ofallSwissstudents.Althoughallstu‐
dentsfromUniBasandETHZ(ETHZü‐
richUniversity)wereinvited,only5000
ofatotalof26,000studentswhowere
currentlyenrolledatUniversityofZü‐
rich(UZH),whohadpreviouslyagreed
tobecontactedforparticipationinvari‐
ousstudies,couldbeinvited.
[22]UKand
Ireland
Modafinil,
Methylpheni‐
date,Dextro‐
ampheta‐
mine/am‐
phetamine
‐ 877studentsin104
universities.
Papersurveyofa
convenience
sampleof877
studentsmeas‐
uredPCEpreva‐
lence,attitudes,
sources,pur‐
posesandethics.
Only2%reportedthatthey
haveusedCE.
Resultsfromtheconveniencesample
surveymaybebiased,duetopartici‐
pants’self‐selection.Theyonlyusedan
onlinesurvey,whichwasconsideredtoo
costlyandunfeasibleduetoaccessbarri‐
ers.

BrainSci.2021,11,35537of38

[58]
Northern
Ireland,
Wales
andEng‐
land
Cannabis,Ec‐
stasy,am‐
phetamines
‐
3706studentsfrom7
universitiesacross
NorthernIreland,
WalesandEngland.
England(Gloucester‐
shiren=908,Bath
Span=462,Oxford
Brookesn=203,
Chestern=883,
Plymouthn=167);
Wales(Swansean=
398);andtheRepub‐
licofNorthernIre‐
land(Ulstern=463).
Eachparticipating
institutionprovided
ethicalapproval.
Papersurvey.
Convenience
sample.
Some5%reportedthatthey
hadregularuseofCE,and25%
usedCEoccasionally,and70%
never.
Thestudycouldbecarriedoutatother
schools,suchasotherinhealthcaredis‐
ciplines.However,theopinionswere
capturedatonepointintime,datawere
self‐reported,andthefindingsarenot
generalisable.
Perhapsifthestudyhadbeenconducted
immediatelybeforethewrittenexamina‐
tions,prevalenceofCEusewouldhave
beenhigher.Manuallydistributingpa‐
per‐basedquestionnairestostudentsina
compulsoryclassandanonlinedistribu‐
tionwouldenhancetheresponserate.
Otherwaystomaximisetheresponse
rateincludedhavingarelativelyshort
questionnairewithquestionslargelyas
closedquestions.
[59]Switzer‐
land
Methylpheni‐
date,Dextro‐
ampheta‐
mine/am‐
phetamine,
Modafinil
‐ 1765students.Onlineandpa‐
persurvey.
4.7%hadusedCEforthepur‐
poseofstudying.
Thefindingsfromthissurveycanlead
toabetterunderstandingofwhysome
studentsarealreadyusingCEandcan
alsoaddtothediscussiononsocial
normsandvaluesinthecontextoflegal‐
izingorprohibitingsuchproducts.

BrainSci.2021,11,35538of38

[60]France
Methylpheni‐
date
Modafinil,
ampheta‐
mines,Pi‐
racetam
‐ 206students.
Onlinesurvey
senttoaFrench
sampleofMedi‐
cineandPhar‐
macologystu‐
dentsusing
email.
Among206undergraduatestu‐
dents,139students(67.4%)de‐
claredtohaveconsumedat
leastonecognitiveenhancerin
thepast12months.Twelvestu‐
dents(8.6%ofcognitiveen‐
hancersusersand5.8%ofour
totalsample)usedillicitphar‐
maceuticalneuroenhancers.
Assessprevalenceandmotivationsfor
licit(useinsidemedicalindication)and
illicitpharmaceuticalneuroenhancer
consumption(tabletform)inanon‐se‐
lectedFrenchsampleofMedicineand
Pharmacologystudents.Aprevalenceof
5.8%forsmartdrugsconsumptionin
PharmacologyandMedicalstudents,
mostlyinordertoenhanceacademic
performancesandvigilancewasrec‐
orded.Methylphenidatewasthemost
frequentlyconsumedmolecule.
[61]USA
Methylpheni‐
date,Dextro‐
ampheta‐
mine/am‐
phetamine
‐ 4yearsrepeated
study.Onlinesurvey.
1in5studentsreportedtheuse
ofCEatleastonceintheirlife‐
time.
Examinedstimulants’cognitive
enhancementeffectsandthe
psychologicalprofileofnon‐medical
stimulantusers.Adouble‐blind,
placebo‐controlledexperimentfoundno
enhancingeffectofmixedamphetamine
salts(Adderall)onhealthyparticipants’
inhibitorycontrol,workingmemory,
episodicmemory,convergentcreativity,
perceptualintelligenceanda
standardizedachievementtest.No
moderatingeffectsofbaseline
performanceorCatechol‐O‐
methyltransferase(COMT)genotype
weredetected.

BrainSci.2021,11,35539of38

[62]Germany
Ampheta‐
mine,
Methylpheni‐
date,Ecstasy,
Cocaine
‐ 18participants. Interview.
Amongallparticipants(n=18
=100%),77.8%(n=14)had
usedillicitstimulants(AMPH)
and38.9%(n=8)prescription
stimulants(MPH).22.2%(n=4)
hadusedprescriptionaswell
asillicitstimulantsforaca‐
demicperformanceenhance‐
ment.
Severallimitationswerereported.One
ofthemisthelimitednumberofinter‐
views:Only18interviewsweretaken
intoconsideration.Inspiteofthefact
thattheUniversitypopulationwas
36,000registeredstudentswhohadthe
possibilitytonoticetheadvertisingplac‐
ardsofthisinterviewstudythroughout
thecampus,only30studentscontacted
them,andonly22werewillingtopartic‐
ipate.GivenCEprevalenceratesof3–
20%,thereshouldhavebeenamuch
highernumberofpotentialparticipants
forthisstudy.Theyhypothesizethatthe
stigmatizingsubjectofthisstudyisthe
reasonforthelowparticipationrate,
notwithstandingthefactthatanonymity
wasguaranteedandthatparticipants
wereremuneratedfortheirtimeandef‐
fortwith30Euros.
[63]USA
Methylpheni‐
date,Am‐
phetamine
‐
1115medicalstu‐
dentsamulti‐institu‐
tionalcensususinga
31–48itemonline
surveyregardinguse
ofprescriptionpsy‐
chostimulants
Onlinesurvey.
Approximately18%hadre‐
portedthattheyusedCEat
leastonceintheirlifetime.
Giventhatstudents’responsesareself‐
reported,andthatnon‐medicallypre‐
scribedstimulantuseisillegal,misre‐
portingisapotentialconcerninthis
survey.However,thesurveydidnot
distinguishbetweengivingaway(ille‐
gal)orselling(criminal)thesedrugs.
Previousstudieshaveindicatedthat
anonymousself‐reportedsurveyshave
lowmisreportingrates.

BrainSci.2021,11,35540of38

[64]USA
Dextroam‐
pheta‐
mine/am‐
phetamine
(Adderall)
‐ 213,633tweets.Onlinesurvey.
Approximately12.9%tweets
concernedtheuseofAdderall
forstudyingpurposes.
First,noteveryAdderalltweetwasre‐
latedtoactualuse.Forexample,they
observedsonglyricsthatimpactthese
counts,suchasthetwooftenquoted
lines“Collegehoeslovealcoholand
poppingAdderall”and“I’vebeenup
for3days…Adderallandredbull.”In
oursample,therewere4275tweetsthat
havethewords“collegehoeslove”and
894thathavethewords“beenupfor
three3days”.Thesenumbersprobably
inflatethenumberofmatchesfor“col‐
lege”,“alcohol”,and“redbull”above
thenumberofpeopletweetingabout
usingthesesubstances.
[65]Germany
Dextroam‐
pheta‐
mine/am‐
phetamine,
Modafinil,
Methylpheni‐
date
‐ 2569students. Papersurvey.
Anestimated12‐monthpreva‐
lenceofusingcognitiveen‐
hancingdrugswas20%.Preva‐
lencevariedbysex(male
23.7%,female17.0%),fieldof
study(highestinstudentsstud‐
yingSports‐relatedfields,
25.4%),andsemester(firstse‐
mester24.3%,beyondfirstse‐
mester16.7%).
Asaresultofthestudyfindings,drug
preventionmodelsneedtobeestab‐
lishedatalluniversitiesinGermany.
[66]USA
Dextroam‐
pheta‐
mine/am‐
phetamine,
Methylpheni‐
date,
Modafinil
‐
372Medical,Phar‐
macyandRespira‐
toryTherapystu‐
dents.
Onlinesurvey.
Approximately10.9%Medi‐
cine,9.7%Pharmacyand26.3%
Respiratorythestudentsre‐
portedtheuseofCEtoenhance
alertnessandimproveaca‐
demicperformance.
Theincidenceofpsychosisorwith‐
drawalassociateddepressionisnot
knownforprescriptiondrugs.

BrainSci.2021,11,35541of38

[67]Canada
Methylpheni‐
date,
Modafinil
Caffeine
pills
647Medicalstudents
acrossallfouryears.Onlinesurvey.
Approximately8%oftheSen‐
iorsreporttheuseofCEvs.2%
ofJuniorstudentsusingCEfor
cognitiveenhancement.
Itwascarriedoutatasingleinstitution;
however,wehavenoreasontobelieve
thattheresultsarenotgeneralizableto
studentsstudyingelsewhere.Whileself‐
selectionmayhaveledtoapositivere‐
sponsebias,itisequallyplausiblethat
nonrespondentsdidnotwishtodis‐
closeuseofcognitiveenhancers.
[68]UKMethylpheni‐
date
Caffeine
pills1614students.Onlinesurvey.
Approximately33%hadused
drugswithoutprescriptionof
which0.5%usedstimulantsfor
astudyingreason.6%usedcaf‐
feinepills.
Thelimitationinthisstudyisthatthere‐
sponseratesarequitelowandalsothe
studyisexposedtothelimitationsofall
self‐reportedsurveys.
[69]Italy
Modafinil,
Methylpheni‐
date,Dextro‐
ampheta‐
mine/am‐
phetamine
‐ 77Undergraduate
students.Papersurvey.Approximately16%reported
theyhadtakenCEinthepast.
Thelimitationinthisstudyistheques‐
tiononCEusewhichdidnotspecify
whatexactlythestudentstook;theirbe‐
haviourriskisdifficulttoassessandas‐
sumesthatthetrulyproblematicbehav‐
iouristotakeCEdrugswithouthaving
aprescription.
[70]Iran Methylpheni‐
date‐ GroupofMedical
students Papersurvey.
Approximately8.7%reported
theuseofmethylphenidateat
leastonceintheirlifetime.
Thefirstlimitationisthevalidityofself‐
reportedmethylphenidateuseamong
respondentswhichdependsontheir
willingnesstoreplytruthfullytothesur‐
vey.Second,thesampleinthestudywas
fromoneuniversity,therebynecessitat‐
ingthatsimilarstudiesbeconductedin
othermedicalschoolsforcomparison.
Third,thestudydidnotexplicitlyad‐
dressdurationorfrequencyof
methylphenidateuse.Therefore,itisun‐
knownwhethernon‐prescriptionusers
tookmethylphenidateregularlyoronly
occasionally.

BrainSci.2021,11,35542of38

[71] Germany
Methylpheni‐
date,Dextro‐
ampheta‐
mine/am‐
phetamine,
Modafinil,
MDMA
‐
1035studentsofpu‐
pilsfrom(Vocational
andGrammar
Schools)and512stu‐
dentsfromMedicine,
PharmacyandEco‐
nomicsSchools.
Papersurvey.
Approximately1.55%ofpupils
fromVocationalandGrammar
Schoolvs.0.78%amongstu‐
dentsinMedical,Pharmacy
andEconomicsreportedalife‐
timeprovenanceforCEuse.
2.42%ofpupilsvs.2.93%of
studentsreportedlifetimeuse
ofCEforcognitiveenhance‐
ment.
Datasamplingwasnon‐random,partici‐
pantswerenotabletorefuseparticipa‐
tioninadiscreteway.Atleastinthestu‐
dentpopulation,inwhichapproxi‐
mately30%didnotfillinthequestion‐
naires;itcannotbeexcludedthatstimu‐
lantuseisunderreportedsinceespe‐
ciallystudentswith“negativebehav‐
iours”didnotfillinthequestionnaires,
leadingtounderreportingofstimulant
use.
[72] USA
Dextroam‐
pheta‐
mine/am‐
phetamine,
Methylpheni‐
date
‐ 4580students.Onlinesurvey.
Approximately75.8%reported
thattheyhaveusedampheta‐
mine(Adderall)inthepast
year,24.5%usedmethylpheni‐
date(Ritalin).
Sampleconsistedofstudentsfromasin‐
gleuniversity,whichmaylimitthegen‐
eralizabilityoftheresults.However,the
prevalenceratesofillicituseofprescrip‐
tionstimulantsinthissingleinstitution
studywerecomparabletothosefound
innationalsurveysofcollegestudents.
[73]USA
Dextroam‐
pheta‐
mine/am‐
phetamine,
Methylpheni‐
date
‐ 9161students.Papersurvey.
Approximately8.1%reported
lifetimeuseofCE,5.4%re‐
portedpastyearuseofCEto
increasealertnessandconcen‐
tratebetter.
The2001CollegeAlcoholSurvey(CAS)
didnotmeasurelegitimatemedicaluse
ofprescriptionstimulantsordiagnosis,
soitwasnotpossibletoassesshow
manystudentswithlegitimateprescrip‐
tionsforstimulantsmayhavemisused
theirownorsomeoneelse’sstimulant
medication.Asthedatawerecross‐sec‐
tional,inferencesaboutcausalityare
limitedandtheycouldnotassess
whethercertainfactorsprecededinitia‐
tionofnon‐medicaluseofprescription
stimulants.Longitudinaldataare
neededtofurtherexaminethedirection‐
alityoftheseassociations.

BrainSci.2021,11,35543of38

[74]USA
Methylpheni‐
date,Dextro‐
ampheta‐
mine/am‐
phetamine,
MDMA
‐ 150students.Papersurvey.
Approximately35.3%reported
theyhadmisusedAmpheta‐
mineonceintheirlifetime,10%
abuseditmonthlyand8%
weekly.
Reportsofstimulantusearehighinthe
research;itmaybethatarelativelysmall
samplewasnotrepresentativeofcollege
studentsingeneral,despiteattemptsto
avoidselectionbias.Asignificantpro‐
portionofstudentscamefromUnder‐
graduatePsychologyclassesandthese
studentsmaydifferfromthoseinother
Majors.Alternatively,itispossiblethat
small,competitivecollegesattractstu‐
dentswhohavebeenexposedtostimu‐
lantuse,orwhoarewillingtoexperi‐
mentwithAmphetaminestoenhance
academicperformance.


BrainSci.2021,11,35527of38


Figure1.Cognitiveenhancers’intakebyuniversitystudents:PreferredReportingItemsforSys‐
tematicReviewsandMeta‐Analyses(PRISMA)FlowDiagram.
Table1showsthesummaryoffindingsfromtheliteraturereviewontheprevalence
ofCEsamonguniversitystudents.
NinestudieswereconductedintheUK(i.e.,sixsurveystudies,twointerviewsand
onemixedmethodsstudy).Theremainingstudiesincludedsurveystudiesthatwerecon‐
ductedintheUSA(n=8)andIran(n=4).InAustralia,threesurveysandoneinterview,
inCanada,twosurveysandonefocusgroupinterview,inGermany,threesurveysand
oneinterviewwereconducted.Threesurveystudieswerecarriedoutineachofthefol‐
lowingcountries:Brazil,France,ItalyandSwitzerland.Twosurveystudieswerecarried
outineachofthefollowingcountries:Austria,Belgium,Greece,NewZeelandandthe
Netherlands;andonesurveystudywascarriedoutineachofthefollowingcountries:
Hungary,Iceland,Ireland,Lithuania,Pakistan,Portugal,SouthAfricaandUAE.Finally,
onemixed‐methodsstudywascarriedoutinbothLithuaniaandtheNetherlands.Partic‐
ipantswerestudentsfromarangeofdisciplines,includingMedicine,Pharmacy,Engi‐
neering,Law,ComputerScience,Business,Education,PsychologyandSocialSciences.
Thesamplesizeofthedifferentstudiesrangedbetween77and80,000participantseach.
Anoverviewofthedemographicvariables,prevalenceofuse,technicalknowledge
ofCEs,motivationsforuse,sourceofCEs’acquisitionandpositive/negativesubjective
effectsissummarisedhere.
1. Demographics’variables
MaleswerehereidentifiedasthemosttypicalCEmisusers
[7,22,30,31,41,51,52,63,66,70,71,73–75],withsomestudiesreportingamale:femaleratioof
3:1[54].Incontrastwiththis,aWelshstudyreportedthatfemalerepresentationwas
slightlymorethanmales[68].
Records identified through data
b
ase searching
(n= 1400)
Pub Med (n= 520)
Science direct (n= 490)
Scopus (n= 390)
ScreeningIncludedEligibilityIden
t
i
f
ica
t
ion
Records screening after dupl icates
removed (n= 1352)
A
r
ticles
excluded
(titles/abstract)
(n =1294)
Full-text articles assessed
for eligibility
(n =58)
Full-text a
r
ticles
excluded, with
reasons
(n = 10)
Animal study (n=7).
Participants under 18
years old (n=1).
Non-English articles
(n=2)
Studies included in
quantitative synthesis
(n = 48)
A
r
ticles
removed due
to duplicate
(n=48)

BrainSci.2021,11,35528of38

2. PrevalenceofCEs’use
AgrowthofCEs’intakeoverthepastfewyearshasbeenreported,includingfrom
bothhigh‐rankinguniversitiesandhighlycompetitivecoursessuchasMedicineand
Pharmacy[41].IntheUK,findingsshowedthat33%oftheparticipantsusedCEswhich
werenotprescribedtothemforthepurposeofstudy[68].Inasurveyconductedamong
UKandIrelanduniversitystudents,itwasfoundthatthelifetimeprevalenceoftheuse
ofmodafinil,methylphenidateandamphetaminewere,respectively,6.2%,5.9%,and2%
[22].Conversely,thelifetimeprevalenceofCEs’intakeamongUniversitystudentsinthe
USwasestimatedtorangebetween5%and43%[76].Moreprecisely,ameta‐analysisfrom
theUSestimatedthatthemisuseofCEsamonguniversitystudentswas17%[75].Com‐
paredtotheUS,mostBritishuniversitystudentsmaybemorecautiousinusingprescrip‐
tiondrugsasCEs[49].
ArecentstudyinBrazilreportedthat,outof1865studentsfromdifferentacademic
disciplines,4.2%reportedtohavinghadusedCEsinthelast12 months,withthemost
popularmoleculehavingbeenmethylphenidatewhichwasnotassociatedwithanADHD
diagnosis.Withrespecttowhatisbeingdescribedinlesscompetitivestudyfields[77],
MedicineandPharmacyhavebeenidentifiedasbeingbothstressfulandhighlycompeti‐
tiveacademiccoursesworldwide[44,45].Inthisrespect,astudythatwasconducted
amongmedicalstudentsinIran(2000–2007)showedthatmethylphenidateusers’mean
knowledgescorewashigherthanthatofnon‐users(p=0.008),withage(range18–28
years),sex(male92.5%)and26%fourthschoolyearhavingbeenpositivelycorrelated
withknowledgescore(p<0.05).Some8.7%ofparticipantshadtakenmethylphenidateat
leastonceintheirlifetime[70].Similarly,astudycarriedoutinLithuaniareportedthat
thepointprevalenceofCEs(modafinil,methylphenidateandamphetamine)amongmed‐
icalstudentswas8.1%[77].
Finally,caffeineuseasaCEhasgrowninpopularityworldwide[78].Astudyinthe
UAEassessedtheprevalenceandperceivedbenefitsofcaffeinatedbeverageconsumption
amonguniversitystudents[51].Morethan98.5%ofthestudyparticipantswereshownto
becaffeineconsumers,with31%havingreportedbeingaddictedtocaffeine;heavycaf‐
feineconsumptionwassignificantlyassociatedwithheartproblems[51].
Despitetheglobalpopularityofthenon‐prescriptioncaffeine,mostresearcharticles
reporttheuseofprescriptionCEsamonguniversitystudents.Therefore,thetruepreva‐
lenceofprescriptionvs.non‐prescriptionCEsamonguniversitystudentsisnotfullyun‐
derstoodand,hence,moreresearchisneeded.
3.2.CEs’KnowledgeandReportedPositive/NegativeEffects
Universitystudentsmaybeattractedbystimulantdrugsforseveralreasons,e.g.,to
increaseawaketime,enhancecognitiveperformance,improveprofessionalandacademic
achievement[41],butalsotohelpwithsocialisingandgettinghigh[79].Indeed,themain
motivationsformisusingmethylphenidatemayrelatetoimprovingconcentration
(65.2%),helpingwithstudying(59.8%)andincreasingwakefulness(47.5%)[73].Other
studieshaveassociatedmethylphenidatemisusewiththeneedtohelpwithconcentration,
stayalert,havemoreenergyandimproveself‐confidencelevels[17,34,70].A2019UK
qualitativestudywithBiomedicalScienceundergraduatestudentsexaminedtheirunder‐
standingoftherisksofnon‐prescribeddrugs,andparticularlymodafinil,misuse.Drivers
ofusewererelatedtouniversitypressuresanddesirestoincreaseproductivity;thecus‐
tomisationofthesleep–wakecyclewasdescribedasakeybenefitof‘studydrug’use[32].
Increasingthelevelsofcognitiveperformancemayindeedpotentiallyallowstudents
tostudyformorehours,and/orincreaseworkingmemoryperformance[80].According
toGreelyetal.(2008),modafinilmaybechosenasaCEbecauseofitshighonlineaccessi‐
bilityandavailability.Conversely,whilststudiesintheUKsuggestedthatCEdrugssuch
asmodafinilcanenhancethinkingskills[81],over‐confidencewasreportedasoneofthe
CE’ssideeffects,togetherwithahighriskofdependence[2].

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ThepopularityofcaffeineandrelatedproductsasCEsmayberelatedtotheneedto
boostenergy,stayawake,improvemood,increaseconcentrationandsocialise[51].Inthe
UAE,themeanlevelofknowledgeaboutcaffeinewasdescribedaslessthan33%.Younger
participants(p=0.008)andthosewhoworkedinhealthcareandeducation(p<0.001)were
significantlymoreknowledgeableaboutitsnegativeeffects,includinganxiety,insomnia,
tachycardia,irritabilityandmuscletremors[51].Arecentsystematicreviewfocussingon
theeffectsofthecaffeine‐containingplantPaulliniacupana(“guarana”)oncognitionin
young,healthyadultsfoundimprovedlevelsinbothreactiontimeandaccuracyperfor‐
mance[82].Guaranahasalsobeendescribedtoimprovememoryperformanceandin‐
creasealertnesslevels[83].Long‐termuseofhighdoseofguaranacan,however,resultin
aseriesofadverseeffects,includingirritability,palpitationandanxiety[2,84].
Despitethelegalrestrictionsthatcontrolthepossessionandsupplyofcontrolled
CEs,studentsoftenobtainthemduetotheirdesiredpharmacologicaleffects.Table2sum‐
marisesthedesiredeffectsofCEs,theirneuro‐modulatoryeffectsandtheirlegalclassifi‐
cation.
MixturesofCEsubstances/drugsusedbyhealthystudentstoimprovecognitionis
ontheriseandisbeingconsideredasatypeof“academicdoping”[85].Poly‐CEusehas
beendocumentedinpreviousstudies[86].InSwitzerland,usersreportedingesting
methylphenidateinadditiontootherCEs.Othersreportedusingbothmodafinilinaddi‐
tiontoAlzheimer’sdiseasedrugs.Othersingestedantidepressantsincombinationwith
Parkinson’sdiseasedrugs[86].Studieshaveshownthatmethylphenidateuserswere
morelikelytouseillicitsubstancesaswelle.g.,marijuanaandecstasy(MDMAor3,4‐
methylenedioxymethamphetamine)ascomparedtootherprescriptionCEus‐
ers[9].
Poly‐CEusewithpsychostimulantandothereffectsoffersbothsynergisticandad‐
ditiveeffectsbasedonusedsubstances,hencepotentiallycombiningcognitiveeffectswith
wakefulness;emotionaland/ormotivationaleffects;mood‐,performance‐,andexecutive
functioning‐enhancingandeuphoriceffects[87,88],withriskstohealththatmayrange
frommildtoseriousrisksincludingdependence,toleranceandneurological,psychologi‐
calandcardiovasculardisorders,withariskofoverdosepotentiallyleadingtodeath.
The2015WesternAustralianStimulantRegulatorySchemeshowedthatstudents
mayuseCEtocopewithstudy‐relatedstress[89].TheyalsofoundthatCEusersarealso
regularillicitpsychostimulantusers,yettherelationshipbetweenCEandotherpsychost‐
imulantsuchasMDMA(ecstasy)co‐use/consumptionistobedetermined[90].

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Table2.StudiessummarisingCognitiveEnhancers(CEs)’legalclassification,desiredeffectsandneuro‐modulatorymechanisms.
Drug/Sub‐
stance
Brand
Name
Misuseof
Drugs
Regulation
(2001)(UK)
Misuseof
DrugsAct
1971(UK)
CurrentlyRecommendedClinicalUseandNeuro‐ModulatoryMechanism
Ampheta‐
minesaltsAdderallSchedule2ClassB
AmphetaminesareaclassofpharmaceuticalsthatincludeAdderall,dextroamphetamine,and
lisdexapmhetamine(L‐lysine‐d‐amphetamine)[91].Thesedrugsweredevelopedtotreatatten‐
tiondeficithyperactivitydisorder(ADHD)inadultsandchildren[4].Thesemoleculesareclassi‐
fiedasScheduleIIaccordingtotheMisuseofDrugsRegulation(2001)andClassBaccordingto
theMisuseofDrugsAct1971,duetotheirhighabusepotential.Eventhoughtheriskofdevelop‐
ingdependenceonthesedrugsisbelievedtobelowforindividualstakingthemforADHD,the
ScheduleIIclassificationindicatesthatthereisahighpotentialforabuseandseveredependence
[4].Thesedrugswerealsodemonstratedtoimproveepisodicmemory,workingmemory,and
someaspectsofattentioningeneralpopulation[92].Thetherapeuticeffectofbothamphetamine
andmethylphenidateinADHDisconsistentwiththefindingoftheabnormalitiesinthecate‐
cholaminesysteminindividualswithADHD[93,94].
Caffeine Genius
Caffeine
Over‐the
counter
(OTC)
‐
Theusageofcaffeineisincreasingworldwide[95].Theunderlyingmotivationsaremainly
memoryandconcentrationenhancementandphysicalperformanceimprovement.Coffeeand
caffeine‐containingproductsaffectthecentralnervoussystem,withtheirlocomotoractivity
stimulationandanxiogenic‐likeeffects[78].Caffeinealsoimpactsonotherneurotransmitters,in‐
cludingdopamine,noradrenaline,serotonin,glutamate,acetylcholineandgamma‐aminobutyric
acid[96].CaffeineconsumptionisveryprevalentamongtheUK[97]andUAE[51]population.
Healthyconsumptionneedstobepromoted[51].Althoughcaffeineisalsoastimulant,itisnot
illegaltousewithoutaprescription[66].
Cyanocobala‐
min(vitamin
B12)
AthleteOTC‐
Itmayhelppatientsonlong‐termmedicationsandthosewithneurologicaldisorders[98].Cogni‐
tiveperformancecanbeimproved,andtheriskofbrainatrophyreduced,byVitaminB12[99].

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
Guarana
(Paullinia
cupana)
N‐R‐GOTC‐
PaulliniacupanaisaplantnativetotheAmazonbasinwhichisespeciallycommoninBrazil[100].
AreviewstudyontheeffectofGuaranaamonghealthyindividualsreportedanimprovementin
reactiontimeandaccuracyofperformanceatcognitivetasks[82].Guaranaseedsarepopular
worldwidefortheircognitive,stimulantandbehaviouraleffects[82].
Methylpheni‐
date RitalinSchedule2ClassB
ItisastimulantdrugusedtotreatADHDandnarcolepsy.IthasbeencontrolledasScheduleII
accordingtotheMisuseofDrugsRegulation(2001)andClassBaccordingtotheMisuseofDrugs
Act1971duetoitshighabusepotential.Volkowandcolleagues(2004)showedtheeffectsof
methylphenidateonmotivation,whichcanaffectacademicperformancewhilstincreasingcogni‐
tiveabilityandimprovingstudents’self‐ratedinterestinarelativelydullmathematicaltask.A
studyreportedthatmethylphenidatehasoneofthehighestprescriptionsrates,associatedwith
anabundanceofwebsitesofferingtosellandsupplythedrugwithoutaprescriptiontoUKusers
[30].Universitystudentsmightbeattractedtomethylphenidatebecauseofitsallegedincreasein
attentionandfocusinglevels[101].Amonguniversitystudents,theself‐reportedmisusingrates
werefrom1.5to31%dependingonthedifferentsurveysconsidered,withthemostnationally
(Germanwhitemales,affiliatedwithaformallyorganisedfraternity)representativestudyesti‐
matinganannualillicitmethylphenidateusageofabout4%[101].
ModafinilProvigil
Prescrip‐
tion‐only‐
medicine
(POM)
‐
Wakefulness‐promotingagentssuchasmodafinilandarmodafinilarestimulantdrugswhichare
usedinthetreatmentofnarcolepsyandshiftworkerssleepdisorders[30].Themechanismofac‐
tionofmodafinilispoorlyexplainedintheliterature.Ithasbeenreportedthatmodafinilaffects
GABAergicanddopaminergicpathwaysintheprefrontalcortexandhaseffectsonneurotrans‐
mittersystems(e.g.,noradrenalineanddopamine)[80].Modafinilispraisedforitsabilitytoim‐
provereactiontime,logicalreasoningandproblemsolving[77].
PiracetamNootropilPOM‐
Compoundsfromtheracetamfamilyincludepiracetam,oxiracetam,etc[102].Piracetambelongs
tothenootropicdrugs’groupwhichincludesthebraincellmetabolismandenergyenhancement
[103].AlthoughPiracetamisofficiallyrecognizedasanootropic,itsenhancingeffectsinthe
healthyindividual’sbrainaremoderate[104,54].Theracetammoleculesarebeingusedacrossa
rangeofbraindisorders,includingAlzheimer’sdisease,narcolepsy,ADHD,Parkinson’sdisease
andbrainaging[105,106].

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
Pyridoxine
(vitaminB6)NestrexOTC‐
Pyridoxine,oneofthemostcommonformsofVitaminB6[107],issaidtosignificantlyimprove
verbalmemoryandexecutivefunction[108].Itcanaidinthesynthesisofneurotransmittersand
aminoacids.Someoftheseneurotransmittersarenorepinephrine,serotonin,GABAanddopa‐
mine[108].ThereisnoevidencethatVitaminB6short‐termuse(e.g.,for5–12weeks)improves
cognitivefunctionormood[109].MoreevidenceisneededtodeterminewhetherVitaminB6
supplementsmightimprovecognitioninhealthypeople.
Vinpocetine
(Vincaminor)CavintonOTC‐
Isanalkaloidoftheperiwinkleplant(Vincaminor)[110]
,
whichhasbeenshowntoexertabrain
neuroprotectiveeffectbyacombinedactiononbrainmetabolism,cerebralcirculationandrheo‐
logicalpropertiesoftheblood.Thismayboostthecerebralmetabolismthusenhancingbothoxy‐
genandglucoseutilizationwhilstconsequentlyimprovingcerebralfunctionsandprovidingpro‐
tectioneveninconditionsofhypoxiaandischaemia[111].Itiscommonlyusedasanootropic
thatpromotesmemoryformation[106].


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3.3.SourcesofCEs’Acquisition
SourcesofCEacquisitionmayrelatetofriendsandfamily[7,59].Studentsdiagnosed
withADHD,butnottakingtheirmethylphenidatemedicationregularly,havebeenre‐
portedasthemainsourceforfellowstudents[4].Inanotherstudy,75.5%ofmethylpheni‐
datewasidentifiedashavingbeenpurchasedfromfriendsatauniversitycampuswhilst
64.3%ofmodafinilwasobtainedonline[22].Accessingthewebfordrugacquisitionac‐
tivitiesisareasonforconcern[30],withyoungpeople(18–25yearsold)beingathighrisk
becausethereisnowaytoknowwhattheactualingredientsofthedrugs/substancesare
inthoseproducts[30],theyareextensiveusersoftheInternet[112];itwasfoundthatover
athirdofthewebsitessellingmodafinilspecificallyrecommendeduseofthedrugtoaid
studying[30].
4.Discussion
Thecurrentsystematicreviewprovidedanin‐depthandupdatedunderstandingon
CEs’prevalenceofuse;levelsofknowledge;andtheirimpactonHEIuniversitystudents,
whichisclearlyacriticalpublichealthissue.Thepastfewyearshaveseenincreasinglev‐
elsofconcernabouttheuseofpharmaceuticalcognitiveenhancementamonguniversity
studentsworldwide,withthelifetimeprevalenceofCEsmisuseamongthesesubjects
rangingfrom6%to20%,dependingonthestudysubject[67].Ofparticularconcern,how‐
ever,isCE’suseinHealthSciences/Biomedicalstudents
[34,36,38,39,45,48,54,57,63,67,70,71].MostdatainitiallyemergedfromtheUnitedStates
[61,75,113],eventuallyfollowedbyreportsfromtheUnitedKingdom[22],Australia
[46,50];andEurope,namelyfromFrance[53,60],andItaly[38,69].
ThemostpopularprescriptionCEsamongtheselectedonesinthisstudywere
modafinil,methylphenidateandamphetaminesaltmixtures[71],withmethylphenidate
beingthemostpopularamongstudents[9].Conversely,themostpopularfreelyavailable
CEwasCaffeine[78].Althoughnotconfirmedbysomestudies[113,114],maleswereiden‐
tifiedhereasmorelikelytouseCEdrugsthanfemales[31,52,63,71,75,77].Somestudies
alsoshowedthat,despitethatthenumberoffemaleparticipantswashigherthantheir
malecounterparts,therateofCEusewasmuchhigherthaninfemalestudents[77].
Althoughnodifferencesbetweengendersinfavouringmethylphenidateasthemost
popularCEorinthepreferentialchoiceofanyCEwererecorded,thereweregenderdif‐
ferencesinmotivationforuse[33].Femalestudents’motivationforCEuseweretoin‐
creaseconcentration,memory,alertnessandacademicperformance,andbecause“friends
useit”.Incontrast,malestudents’motivationsforCEuseweremainlytoincreasestudy
timeandexperiment[33].
Ingeneral,withregardtoillicitsubstanceuse,DrAdamWinstock(CEOoftheGlobal
drugSurvey)pointedoutthegenderdifferences,explainingitaspossiblyresultingfrom
societalstigma,shameandculturalexpectationsaroundwomentakingdrugs.Additional
factorsthatinfluencewomen’sdecisionsinusingdrugsincludepregnancyandmother‐
hood.Economicstatusandthelowerrateofcriminalactivityamongstwomenalsoreduce
femaledruguseandexposuretoillicitdrugsascomparedtomales[115].
Indeed,severalsocialfactorshavebeenidentifiedheretoinfluenceCEs’usepractices
amonguniversitystudents[56].Theseincluded:peer‐pressure,competition,performance
demandsandpriordruguse[85],butalsorecreation[79].
TheavailabilityofCEsfornon‐medicalindicationsinthedifferentcountriesisaf‐
fectedbyarangeoffactors,includinglegal,social,andethicalfactors[33,40,116].Indeed,
someCEsarebeingopenlymadeavailableonline[30,117],wheretheyaremarketedas
“smartdrugs”,“studydrugs”,“plantfood”,“researchchemicals”and“designerdrugs”
aswell[30,112].Theunregulatedonlineaccess,andespeciallysoformodafiniland
methylphenidate,islikelytobeassociatedwithanincreaseinCEs’non‐medicaluseand
subsequentharm[30].Indeed,highlevelsofmodafinilmayhavereportedlybeensold
andshippedtostudentsathigh‐ranking/topUKuniversities,mostlyduringthe

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examinationperiod[118].Conversely,asCEs’legalalternativetoeitherprescribingor
illicitdrugsofabuse,guaranawasfoundheretobepopular,withaffordableonlineprices
encouragingyoungusers/studentstobuygreaterquantitiesinordertoreceivediscounts
andfreeshipping[30,119].
Sahakianetal.(2008)openedadebateonthepositiveimpactonimprovingcognitive
functions,suggestingthatbenefitsofCEsshouldbemaximised,andtheirharmmini‐
mised[25].Insomestudies,CEdrugshavebeenshowntomoderatelyenhancecognitive
performanceinhealthyindividuals[120].Accordingly,CEtoolsincludingpharmacolog‐
icalcognitiveenhancementcouldimprovethequalityoflifeofbothbusyworkersand
exhaustedstudentstoextendtheirwork/academicproductivitylevels[121],hencebene‐
fittingboththeindividualandsociety[25].Therehavebeenextensivereportsfocussing
onCEs’intaketoaidconcentrationandmemoryamonghealthyindividuals,including
students,academics,shiftworkers,andevenchessplayerstoimprovetheircognitiveper‐
formance[122].AstudybySmithandFarah(2011a)suggestedthattheeffectsofboth
methylphenidateandamphetaminesaltmixturesoncognitiveperformancesinhealthy
participantsshowedpositivelyconsistenteffectsinlearning,butespeciallysoindelayed
recallandrecognitiontesting,pointingtoaneffectonmemoryconsolidation[4].Anad‐
ditionalstudybySchelleetal.(2015)showedapositiveeffectofmethylphenidateon
memoryandplanningperformanceinhealthyindividuals.However,othershavesug‐
gestedthatevidenceregardingtheclinicalbenefitsofCEsinhealthyindividualsisstill
inconclusive[123].A2010systematicreviewandmeta‐analysisofpublishedrandomised
controlledtrialsoftheeffectofbothmodafinilandmethylphenidateinhealthyindividu‐
alsshowedthattheanticipatedeffectsofthesetwoagentsascognitiveenhancersex‐
ceededtheiractualeffect[80].Hence,ithasbeensuggestedthattheabilityofampheta‐
mine‐typesubstancemixturestoenhanceacademicperformanceamongstudentscould
beattributedtotheireffectonenergy,confidenceandmotivationlevelsratherthantoa
directeffectoncognitiveperformances[124].Infact,individualsmaybebiasedinpre‐
dictingtheirownperformance,e.g.,theyeitherunderestimateoroverestimatetheiraca‐
demiccompetence[125].Moreover,cognitiveimprovementseemstovaryconsiderably
fromoneagenttoanother,andSmithetal.(2011)reportedthatonethirdofstudiesfrom
pastliteraturereviewsshowednullresults.Onecouldthenarguethattherearemoreun‐
publishedstudiesintheliteraturewithnullresults,duetopublicationbiasfavouringpos‐
itiveresults[4].
Ontheotherhand,useofstimulantCEsmaybeassociatedwithnegativeacademic
performancesintermsoftheeuphoricstateinduced,withabnormalmoodelationpre‐
ventingthestudentfromspendingenoughtimeinpreparationforanexam[17,57].Fur‐
thermore,methylphenidateisreportedtopresentwithadependencepotential[126],and
modafinildependencecaseshavebeenidentifiedaswell[127].Itisalsoworthnotingthe
amphetamine‐typesubstance‐relateddependence;withdrawal;andpsychosisissues[28].
UntowardeffectsrelatingtotheindexCEmayindeedinfluencestudents’choices,with
thembeingkeentoconsidermodafinilasopposedtomethylphenidateandamphetamine
saltmixtures.Indeed,StewardandPickersgill(2019)foundthatalltheirCEusershad
ingestedmodafinil,withonlysomealsohavingtriedmethylphenidateandamphetamine
saltmixturesforthepurposeofstudy.Infact,studentsdescribedhowtheuseof
methylphenidateandamphetaminesaltmixturescouldresultindependenceandhence
thesewereapproachedmorecautiously[32].Overall,however,theuseofmethylpheni‐
datehassignificantlyincreased,withitsconsumption,indefineddailydoses,havingin‐
creasedtoapproximately2.4billionworldwide[35].IntheUK,bothmethylphenidateand
amphetaminecompoundsareClassBcontrolleddrugs[128].Thismeanstheycanbepro‐
videdviaprescription,butthemaximumquantityissuedshouldnotexceed30days(un‐
lessjustifiedbytheprescriber)andapersonalimport/exportlicenceisrequiredto
transportthedruginoroutoftheUKiftheamountexceedsa3‐monthsupply[30].
Modafinilisaprescription‐onlymedicineintheUK,butitisnotcontrolledunderthe
MisuseofDrugsAct1971orsubjecttoschedulingundertheMisuseofDrugsRegulations

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2001;hence,itisillegaltosupplyitwithoutaprescription,butitisnotillegaltopossess
thedrugforpersonaluse[128].Tocopewiththeserestrictions,CEs’sellingwebsitespro‐
vidediscreetpackaging;offerfreereshipmentifthepackageisseized;andencourage
third‐party,difficulttotrack,paymentmethods[30].Thisoutcomesuggestsrunningcam‐
paignsthatmitigateharmandraiseawarenessamongstudentswhouseCEdrugs.Fi‐
nally,althoughcaffeineisalsoastimulant,itsuseisnotassociatedwitheitheracquisition,
affordability,availability,orlegalityissues[42,66].However,withcaffeinehigh‐dosage
intakearangeofmedicalandpsychiatriceffectscanbeobserved,mosttypicallyincluding
anxiety,panicattacks,sleepingdisordersandcardiovascularissues[129].
ACochranereviewfoundnoevidencethatshort‐termintakeofvitaminsB6andB12
supplementsimprovecognitivefunctionormood.Thereviewdidfindsomeevidence
thatdailyvitaminB6andB12supplementscanaffectbiochemicalindicesofvitaminB6
andB12statusinhealthyindividuals,butthesechangeshadnooverallimpactoncogni‐
tion[107].
Accordingtothereviewoftheliterature,thedrugsselectedwerechosenbasedon
theirpopularityamonghealthyuniversitystudents,butthedrugsmostusedamongstu‐
dentswere(modafinil,methylphenidateandAdderall)and,intermsofsubstances,caf‐
feinewasthemostpopularamonguniversitystudents.However,astudybyCarlier,J
(2019)reportedthatmethylphenidateisoneofthemostpopularCEsandseveralana‐
loguesappearedonthedrugmarketduringthelastyears.However,littleornoscientific
dataonthesenewanaloguesareavailable.
AssportsorganisationssuchasWADAareoverviewingandprohibitingtheuseof
physicalenhancers,nosuchcontrolexistsinschoolsanduniversities.Therefore,inorder
todecreasethelong‐termdeleteriouseffectsofCEsinindividualswhousethem,govern‐
ment‐levelinterventionsareurgentlyrequired.
Aharmreductionprogrammeisalsorecommendedtoreducethenegative,legaland
societalimpactofsubstanceuse[125].Theprogrammeshouldconsidersupportingindi‐
vidualswithproblematicsubstanceuseandtheirfamilieswithcompassionandappropri‐
ateadviceandinterventions,whilstsafeguardingtheirdignity[125].Thesefindingssug‐
gesttheimportanceofraisingawarenessoftheharmsofCEuse,provideaccurate
knowledge,counteractmythsregarding“safe”CEuseandaddresscognitiveenhance‐
mentinanearlystageduringeducationasapreventativepublichealthmeasure.
5.Limitations
Thereareafewlimitationsthatwereconsideredinthismanuscript.Thefirstlimita‐
tionisrelatedheretothesolefocusonEnglishlanguagestudieshavingbeenincludedin
thesearch;futurestudiesshouldconsiderfurtherlanguages.Thesecondlimitationrelates
tothemethodsusedbythedifferentstudies,typicallyinvolvingself‐reportingsurveys
whichcouldhaveintroducedbiases.Finally,thecurrentstudyfocusedonlyonunder‐
graduatestudents;however,postgraduatestudents,academicstaff,andremainingwork‐
ersshouldbeconsideredbyfuturestudies.
6.Conclusions
AnumberofstudentsworldwidemaybewillingtoconsiderCEs’ingestiontoim‐
provetheiracademicperformances.TheattitudeofuniversitystudentsaboutCEsand
theirpossiblebenefitsis,however,basedonanecdotal,andarguablybiased,information
obtainedfromthemedia,theweb,andfriends[130].Overall,itseemsfromthisreview
thatthetopicisnotbeingsufficientlycoveredinthecurriculumofmodernuniversities.
Conversely,thisissueshouldbediscussed,asaninter‐professionalorinter‐disciplinary
learningopportunity,fromapublichealthperspective[7,44].CEs’usemayarguablybe
reducedifstudents’levelsofawarenesswereraised,emphasisingthatCEs’intakemay
posearisktosafety,andespeciallysoinvulnerableindividuals[31].Indeed,impactsof
CEdrugs’intakemayincludetolerance,dependence,withdrawal,cardiovascularand
neurologicaldisorderswitharelatedriskofdeathduetooverdose[28,117,131].The

BrainSci.2021,11,35536of38

implementationofaharmreductioncampaign,inordertobringtheoverallconsumption
down,hasbeenproposedaswell[41,91].
Finally,Shaw(2014)suggestedthatoneofthemostfascinatingissuesintheemerging
fieldofneuroethicsispharmaceuticalcognitiveenhancement.Medicaldebate[21,132]has
largelyfocusedontheCEs’potentialtohelpthosewhoarecognitivelyimpaired.Hence,
itisheresuggestedthatCEs’usebyuniversitystudents,seemstoraisetheissueof“cos‐
metic”neuropsychopharmacology[133,134].
AuthorContributions:AlltheAuthorsequallycontributedtotheinitialplanningofthedatacol‐
lection;S.S.draftedthepaperitself.A.G.,S.F.,andF.S.criticallyreviewedthefinaldraftpriorto
submission.Allauthorshavereadandagreedtothepublishedversionofthemanuscript.
Funding:Thisresearchreceivednoexternalfunding.
Acknowledgments:ThisarticleispartofS.S.’sPhDresearch.
ConflictsofInterest:F.S.wasaprevious(2011–2019)memberoftheACMDUK;heiscurrentlya
memberoftheEuropeanMedicinesAgency(EMA)PsychiatryAdvisoryBoard.S.S.,A.G.andS.F.
havenoconflictsofinteresttodeclare.
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