Hacking the brain: dimensions of cognitive enhancement

Hacking the Brain: Dimensions of Cognitive Enhancement
Martin Dresler, *,†Anders Sandberg,‡Christoph Bublitz,§Kathrin Ohla,∥Carlos Trenado,⊥,#
Aleksandra Mroczko-W ąsowicz,∇Simone Ku ̈hn,○,◆and Dimitris Repantis¶
†Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen 6525 EN, The Netherlands
‡Future of Humanity Institute, Oxford University, Oxford OX1 1PT, United Kingdom
§Faculty of Law, University of Hamburg, Hamburg 20148, Germany
∥Institute of Neuroscience and Medicine, Cognitive Neuroscience (INM3), Forschungszentrum Ju ̈lich, Ju ̈lich 52428, Germany
⊥Institute of Clinical Neuroscience and Medical Psychology, Heinrich Heine University Du ̈sseldorf, Du ̈sseldorf 40225, Germany
#Department of Psychology and Neurosciences, Leibniz Research Centre for Working Environment and Human Factors, TU
Dortmund, Dortmund 44139, Germany
∇Institute of Philosophy of Mind and Cognition, National Yang-Ming University, Taipei 112, Taiwan
○Max Planck Institute for Human Development, Berlin 14195, Germany
◆Department of Psychiatry and Psychotherapy, University Clinic Hamburg Eppendorf, Hamburg 20246, Germany
¶Department of Psychiatry and Psychotherapy, Charite ́−Universita ̈tsmedizin Berlin, Campus Benjamin Franklin, Berlin 12203,
Germany
ABSTRACT: In an increasingly complex information society, demands for cognitive functioning are growing steadily. In recent
years, numerous strategies to augment brain function have been proposed. Evidence for their e ﬃcacy (or lack thereof) and side
eﬀects has prompted discussions about ethical, societal, and medical implications. In the public debate, cognitive enhancement
is often seen as a monolithic phenomenon. On a closer look, however, cognitive enhancement turns out to be a multifacetedconcept: There is not one cognitive enhancer that augments brain function per se, but a great variety of interventions that canbe clustered into biochemical, physical, and behavioral enhancement strategies. These cognitive enhancers di ﬀer in their mode
of action, the cognitive domain they target, the time scale they work on, their availability and side e ﬀects, and how they
diﬀerentially a ﬀect di ﬀerent groups of subjects. Here we disentangle the dimensions of cognitive enhancement, review
prominent examples of cognitive enhancers that di ﬀer across these dimensions, and thereby provide a framework for both
theoretical discussions and empirical research.
KEYWORDS: Neuroenhancement, brain hacking, neuroethics, cognition, memory, working memory, attention, creativity
1. INTRODUCTION
An increasingly complex world exerts increasing demands on
cognitive functions functions that evolved for a fundamentally
diﬀerent environment. Daily life in an information society and a
postindustrial economy require cognitive skills that have to beacquired through slow, e ﬀortful, and expensive processes of
education and training. Likewise, these skills can becomeobsolete as the world changes ever faster or be lost by theprocesses of aging. People also vary in their mental abilities,allowing them to acquire certain skills more quickly or slower,
which may have signi ﬁcant e ﬀects on life outcomes. Strategies to
improve the acquisition and maintenance of cognitive skills arethus increasingly important on both an individual and societallevel. These challenges of our times have fostered the
Received: October 23, 2018
Accepted: December 14, 2018
Published: December 14, 2018Review
pubs.acs.org/chemneuro Cite This: ACS Chem. Neurosci. 2019, 10, 1137 −1148
© 2018 American Chemical Society 1137 DOI: 10.1021/acschemneuro.8b00571
ACS Chem. Neurosci. 2019, 10, 1137 −1148
This is an open access article published under a Creative Commons Non-Commercial No
Derivative Works (CC-BY-NC-ND) Attribution License, which permits copying and
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exploration of strategies to enhance human brain function.
While people have since time immemorial sought to improve
their performance, the present era is unique in that not only the
challenges are growing rapidly but so are technologies thatpromise to meet them. Just like the hacking culture in the realm
of computer software and hardware, an increasing number of
individuals experiment with strategies to creatively overcomethe natural limitations of human cognitive capacity in other
words, to hack brain function. This development has led to both
enthusiasm and dread, as observers have sharply di ﬀering
intuitions about the feasibility, utility, risks, and eventual impactof enhancement technologies on the world.
One reason for the often polarized debates has been the lack
of hard evidence. Without empirical ﬁndings, it is easy to
maintain any position, as well as regard opponents as havingunfounded views. A further essential source of disagreement and
theoretical confusion is a tendency to view enhancement as a
unitary phenomenon to be judged as a whole, rather than as abroad set of techniques with important di ﬀerences and diverging
implications. Only on the basis of a clear picture on how a
particular enhancement strategy might a ﬀect speci ﬁc cognitive
processes in speci ﬁc populations, along with side e ﬀects and
costs to be expected, an informed theoretical debate can evolve
and a promising empirical research designs to test the strategycan be proposed. In the following, we aim to elucidate sevenessential dimension of cognitive enhancement, namely, (a) its
mode of action, (b) the cognitive domain targeted, (c) personal
factors, (d) its time scale, (e) side e ﬀects, (f) availability, and (g)
social acceptance (see Figure 1 ). Further, we will review
empirical data of prominent examples of cognitive enhancers
that di ﬀer across these dimensions and thereby illustrate some of
their nuanced implications. The aim of our Review is to sketch a
general framework that will foster both theoretical discussions
and empirical research.
2. MODE OF ACTION
A widely cited de ﬁnition characterizes enhancement as
interventions in humans that aim to improve mental functioning
beyond what is necessary to sustain or restore good health.1
While the current bioethical debate on cognitive enhancement isstrongly focused on pharmacological ways of enhancement,improving mental capabilities also by nonpharmacologicalmeans has to be considered as cognitive enhancement properaccording to the given characterization. We have reviewedelsewhere the e ﬃcacy of a number of nonpharmacological
enhancers.
2,3To systematize the vast variety of di ﬀerent
approaches of cognitive enhancement, we suggest clusteringenhancement strategies into three major areas according to their
main mode of action. Even though boundaries are not strict,
most cognitive enhancement strategies can be considered to
work as either biochemical, physical, or behavioral interventions
(Figure 2 ). In the following, we will give an overview on the
diﬀerent cognitive enhancement strategies within these clusters.
2.1. Biochemical Strategies. The prototypical cognitive
enhancers addressed in the public debate are biochemicalagents. However, biochemical interventions are not restricted topharmaceutical “smart drugs ”. Also application of ordinary
substances such as oxygen has been shown to increase, e.g.,memory processes
4,5and neural activation in memory-related
brain regions.6
Biochemical enhancers with the longest tradition in human
history are strategies to make use of certain nutritionalcomponents. Most widely used are probably glucose7and
caﬀeine,8,9which both have demonstrated cognition-enhancing
eﬀects in numerous studies. In addition to co ﬀee, other
beverages from ca ﬀeine-bearing plants such as guarana have
shown to enhance cognition.10While the nonca ﬀeine
components in ca ﬀeine-bearing plants might exert independent
eﬀects on cognition,11it has been doubted that industrially
designed drinks contain cognitive enhancing components thatgo beyond ca ﬀeine, glucose, or guarana extract.12Further
nutritional components with some evidence for cognitiveenhancing e ﬀects are ﬂavonoids, e.g., in cocoa,13,14curry powder
(most likely due to the curcumin that it contains,15,16folic
acid,17or omega-3 fatty acids.18Besides speci ﬁcd i e t a r y
supplements, also the absence of food might enhance cognition:some evidence has been reported that fasting and general caloricrestriction might improve memory in elderly individuals.
19,20
Also certain traditional natural remedies have been discussed
as cognitive enhancers: besides herbs that also grow in Westernregions such as salvia,21particularly traditional Chinese and
Figure 1. Cognitive enhancement interventions di ﬀer across several
interdependent dimensions.
Figure 2. Cognitive enhancement interventions di ﬀerent in their mode
of actions.ACS Chemical Neuroscience Review
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Indian herbal medicines such as Bacopa monnieri have been
ascribed with cognitive enhancing e ﬀects.22,23However, with
ginseng and ginkgo biloba, the most prominent examples of suchtraditional Asian herbal remedies so far have failed toconsistently show positive e ﬀects on cognitive functions in
healthy individuals.
24,25
A further biochemical intervention with a long history
concerns drugs that are being used recreationally and thathave demonstrated the potential to enhance certain cognitivefunctions. For example, nicotine improves attention andmemory,
26−28and even alcohol, despite impairing many
cognitive functions, might enhance others such as creativeprocesses29,30or, retroactively, memory.31
Pharmaceuticals are in particular by the public regarded as
prototypical cognitive enhancers: synthetic stimulants such asamphetamine, methylphenidate, or moda ﬁnil, or antidementia
drugs such as acetylcholinesterase inhibitors and memantine areat the core of public debate on cognitive enhancement.However, evidence for their e ﬃcacy for augmenting brain
function and cognition in healthy subjects is often markedly
lower than assumed in theoretical discussions.
32−37Importantly,
the lack of an objective e ﬀect on cognition can be accompanied
by a considerable placebo e ﬀect: for example, users who believed
to have received mixed-amphetamine salts subjectively ratedthemselves as performing better and even show minor objectiveperformance increases, independent of actual medicationstate.
38
While pharmacological enhancers are typically designed to
aﬀect or mimic certain neurotransmitters, also neural signaling
molecules themselves such as adrenaline,39GABA,40glucocorti-
coids,41ovarian hormones,42and di ﬀerent neuropeptides43−45
have been suggested as cognitive enhancers.
A further biochemical strategy for cognitive enhancement
consists of genetic modi ﬁcations, which have been demon-
strated to augment several learning and memory processes inanimal models.46−51Although progress has also been made in
elucidating the genetic basis of cognitive traits in humans,52
genetic modi ﬁcations in humans still have to be considered as
future strategies rather than currently available enhancementoptions.
2.2. Physical Strategies. The current most widely
discussed physical strategies for cognitive enhancement includea number of brain stimulation technologies. Whereas thecognition enhancing e ﬀects of invasive methods such as deep
brain stimulation
53,54are restricted to subjects with pathological
conditions, several forms of allegedly noninvasive stimulationstrategies are increasingly used on healthy subjects, among themelectrical stimulation methods such transcranial direct currentstimulation (tDCS
55), transcranial alternating current stimula-
tion (tACS56), transcranial random noise stimulation (tRNS57),
transcranial pulsed current stimulation (tPCS58,59), trans-
cutaneous vagus nerve stimulation (tVNS60), or median nerve
stimulation (MNS61). Details of the stimulation procedures
appear to be crucial: commercial do-it-yourself electrical brainstimulators might impair rather than enhance cognition,62and
systematic reviews have shed doubt on a clear and simpleenhancing e ﬀect of electrical brain stimulation on di ﬀerent
cognitive domains also under controlled laboratory condi-tions.
63,64Recent studies have even questioned if some of the
most commonly used setups for electrical brain stimulation haveneurophysiologically meaningful e ﬀects at all.65−68On this
background, the development of noninvasive deep brainstimulation via temporally interfering electric ﬁelds mightprovide a more systematic and targeted mechanism compared
to the currently used approaches.68
Besides electrical stimulation methods, also for transcranial
magnetic stimulation (TMS69), optical stimulation with lasers,70
and several forms of acoustic stimulation, such as transcranial
focused ultrasound stimulation,71binaural beats,72,73or auditory
stimulation of the EEG theta rhythm74or sleep EEG slow
oscillations,75a potential for cognitive enhancement has been
reported.
Physical enhancement methods that target brain processes
more indirectly include whole body vibrations,76stochastic
resonance motor control improvement,77,78and several forms of
neurofeedback,79with, e.g., EEG neurofeedback in the upper
alpha band enhancing memory,80working memory,81and
visuospatial skills.82Besides classical neurofeedback training
that involves unspeci ﬁc but active e ﬀort of the subject, also
neurofeedback interventions that automatically feedback low
energy currents in response to EEG activity have been
developed, thereby allowing the subject to receive the trainingprocedure passively.
83Recently, the use of fMRI neurofeedback,
utilizing multivariate pattern analysis, has shown the potential to
increase sustained attention84or visuospatial memory.85
Finally, humans have always deployed physical tools to assist
cognitive functioning. In current developments that converge
minds and machines, these tools become more closely
integrated with the person.86Crowdfunding or biohacking
communities have developed numerous novel technical devices
to increase cognitive functions transiently with, e.g., wearable
electronic memory aids or augmented reality gadgets,87,88or
more permanently as in the case of cognition enhancing or
extending bodily implants.88,89Neural implants or prosthetics
have progressed; in controlled laboratory settings, implantscould facilitate human memory.
90In addition, Brain −Computer
Interfaces connect the central nervous system with computers
through wearable or implanted electrodes and may a ﬀord a
range of applications that enhance cognitive functions or jointoutputs of minds coupled with machines.
91,92
2.3. Behavioral Strategies. Although not commonly
recognized as such by the public, cognitive enhancers with themost wide use and longest history are probably behavioralstrategies: a rapidly growing body of evidence shows that
everyday activities such as sleep
93or physical exercise94−96
improve cognitive functioning. Also well-established cultural
activities such as musical training,97,98dancing,99or learning a
second language100have been demonstrated to enhance
cognition beyond the speci ﬁcally trained skills.
In addition to these natural and cultural standard activities,
several behavioral strategies have been developed to enhance
certain brain functions intentionally. Two strategies that reach
back to ancient times are mnemonic techniques to enhancelearning and memory
101,102and meditation training to enhance
attention processes and mindfulness.103,104In contrast,
commercial video games105,106and customized computer
trainings107represent historically very recent developments
that are targeted to enhance speci ﬁc cognitive capacities and
skills. In contrast to several years of enthusiasm and widespreadcommercial application, howe ver, more recent controlled
studies and meta-analyses have shed some doubt on the e ﬃcacy
of computerized brain training programs,
108particularly criticiz-
ing claims of “far transfer ”of training gains to cognitive domains
considerably di ﬀerent from the speci ﬁcally trained skills.109,110ACS Chemical Neuroscience Review
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3. COGNITIVE DOMAIN
The human mind is not a monolithic entity, but consists of a
broad variety of cognitive functions. Not surprisingly, no single
cognitive enhancer augments every cognitive function. Instead,
most cognitive enhancers have speci ﬁc proﬁles regarding their
eﬃcacy for di ﬀerent cognitive domains. Memory is, e.g., strongly
enhanced by mnemonic strategies, but not by meditation;
attention, in turn, is strongly enhanced by meditation training,
but not training in mnemonic strategies.101,103,104Sleep, in
contrast, enhances both cognitive capacities.111,112Some
computerized cognitive trainings have been found to enhance
memory, processing speed and visuospatial skills, but not
executive functions or attention.107It is currently highly debated
in how far speci ﬁc training strategies exert transfer e ﬀects also to
nontrained cognitive domains.113
Diﬀerent cognitive tasks require di ﬀerent optimal levels of
receptor activation, thus requiring di ﬀerent doses of pharmaco-
logical enhancers targeting the respective neurotransmitter
system depending on the cognitive domain targeted.114Of note,
eﬀects of pharmacological enhancement on di ﬀerent cognitive
domains might even di ﬀer depending on the cognitive test
battery used, illustrating the fragility of the respective e ﬀects.115
Some interventions might even enhance one but impair
another cognitive domain: Intranasal application of oxytocin has
been shown to enhance social cognition and cognitive ﬂexibility
but impairs long-term memory.116,117Methylphenidate im-
proves the ability to resist distraction but impairs cognitive
ﬂexibility.118Computerized working memory training has been
reported to enhance working memory, reasoning, and arithmetic
abilities; however, it might deteriorate creativity.119Also for
amphetamines and moda ﬁnil, potential impairments on
creativity are discussed besides their enhancing e ﬀects on
other domains.120,34In contrast, alcohol might enhance creative
processes while impairing most other cognitive functions.29
The costs and bene ﬁts of a single cognitive enhancer might
even change through slight changes in the application process:
for example, electrical stimulation of posterior brain regions was
found to facilitate numerical learning, whereas automaticity for
the learned material was impaired. In contrast, stimulation on
frontal brain regions impaired the learning process, whereas
automaticity for the learned material was enhanced.121Brain
stimulation has thus been suggested to be a zero-sum game, with
costs in some cognitive functions always being paid for gains in
others.122This implies that enhancement may have to be tuned
to the task at hand, in order to focus on the currently most
important cognitive demands.
4. PERSONAL FACTORS
The e ﬃcacy of cognitive enhancers does not only di ﬀer for
diﬀerent cognitive domains, but also for di ﬀerent users. An
important factor in this regard are the cognitive skills of the
individual prior to the enhancement intervention. Many
pharmaceuticals, including amphetamine,123moda ﬁnil, and
methylphenidate,124work mainly in individuals with low
baseline performance. In some cases, even impairments in
individuals with higher performance at baseline have been
reported, e.g., in the case of amphetamine,125methylpheni-
date,124nicotine,27or acute choline supplementation.126The
phenomenon of enhanced cognition in individuals with low
baseline performance and impairments in those with high
baseline performance can be explained by the classical inverted
U-model,127,128where performance is optimal at intermediatelevels of the targeted neurochemicals and impaired at levels that
are either too low or too high.129−131For some drugs such as
methylphenidate, enhancement dependency on the baselinemight even di ﬀer between cognitive functions, with performance
in speci ﬁc tasks being improved in low, while impaired in high,
performers,124but showing the opposite pattern for other
tasks.132
The baseline-dependency of cognitive enhancement is not
restricted to pharmaceuticals: also in the case of video games,133
cognitive training,134or brain stimulation,135,136individuals
starting at a lower baseline performance bene ﬁt more than those
with an already high performance at baseline. In contrast, sleepappears to improve memory particularly in subjects with a higherbaseline performance of memory,
137working memory138or
intelligence.139Also mnemonic training appears to work
particularly well in individuals with a higher cognitive baseline
performance.140This has been interpreted in terms of an
ampli ﬁcation model, in which high baseline performance and
cognitive enhancement interventions show synergistic ef-fects.141
Cognitive enhancers can also a ﬀect individuals di ﬀerently
depending on basic biological, psychological, or social factors.For example, e ﬀects of training interventions on selective
attention can depend on the genotype of the trainee;142eﬀects of
methylphenidate on creativity can depend on personalitycharacteristics;143the cognition enhancing e ﬀects of sleep144
or video games145are modulated by gender. In turn, such
modulations of enhancement e ﬀects might reduce existing
diﬀerences in cognitive pro ﬁles, as seen, e.g., in action video
game training, that have the potential to eliminate genderdiﬀerences in spatial attention and decrease the gender disparity
in mental rotation ability.146Also the hormonal status of
subjects a ﬀects how strongly they pro ﬁt, e.g., from sleep144−148
or brain stimulation.149Caﬀeine enhances working memory
particularly in extraverted individuals,150and memory enhance-
ment through sleep151or mnemonic training140has been
reported to depend on the age of subjects. Health status a ﬀects
how much users bene ﬁt from di ﬀerent kinds of cognitive
enhancers, including pharmaceuticals,3mnemonics,152or
sleep.153−156Finally, also socioenvironmental factors such as
social resources, parental occupation, or family composition canmodulate cognitive enhancement interventions, e.g., withcognitive training programs.
157
5. TIME SCALE
Interventions for cognitive enhancement di ﬀer in the speci ﬁc
time scale they require to achieve their aims. The prototypical“smart pill ”discussed in popular accounts of cognitive
enhancement needs practically no preparation time, exerts itseﬀects within seconds or minutes, and lasts for several hours.
While this is close to reality in the case of some pharmacologicalenhancers, the temporal pattern of most other enhancementstrategies di ﬀers strongly from these time scales. In particular,
the time needed for application and the duration of their e ﬀects
markedly varies between enhancement interventions.
Most pharmacological enhancers can be applied quickly and
without further preparation; however, some drugs such as
acetylcholinesterase inhibitors or memantine are thought torequire longer periods of intake to be e ﬀective.
33Also some
nutritional enhancers such as glucose and ca ﬀeine exert their
eﬀects rather quickly, whereas other nutritional supplements
have to be taken over extended periods to show an impact oncognition.158,18Obviously, behavioral strategies like sleep,ACS Chemical Neuroscience Review
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exercise, video games or mnemonic training need hours or weeks
to robustly enhance cognition. Some e ﬀects of meditation might
even take years of training.159For brain stimulation methods,
both immediate e ﬀects of acute stimulation, but also more
delayed e ﬀects after repeated sti mulation haven been
observed.55,69Technological gadgets or implants need some
preparation to be installed and accommodated to, however thenexert their cognition augmenting e ﬀects on demand.
Enhancing e ﬀects of most quickly acting pharmacological or
nutritional cognitive enhancers also wear o ﬀrather rapidly. In
contrast to such transient e ﬀects, interventions such as brain
stimulation,160,161,57sleep,162mnemonic strategies163or genetic
modiﬁcations46have the potential for long-term up to chronic
enhancement. However, in the latter case, the reversibility of theeﬀects (and side e ﬀects) of an enhancement intervention might
be a further aspect to be considered.
Interventions can also di ﬀer regarding the time point of
application relative to the situation when enhanced cognitiveperformance is needed. For example, application of stresshormones such as cortisol or adrenaline before or after memoryencoding enhances memory, whereas application beforeretrieval impairs memory;
41benzodiazepines impair memory
when given before and enhance memory when given afterencoding;164in contrast, ca ﬀeine before learning enhances
memory under certain conditions but might impair memorywhen consumed afterward.165,9Mnemonic strategies on the
other hand work solely when taught/applied before/duringencoding, but can hardly be applied afterward.
Finally, some interventions can also in ﬂuence the timing of
cognitive performance itself: stimulants such as methylpheni-date, moda ﬁnil, and ca ﬀeine might increase the time subjects
take to perform a given task, with impairing e ﬀects under time
pressure and potentially enhancing e ﬀects in the absence of
temporal constraints.
166
6. SIDE EFFECTS
The pharmaceutical platitude that there is no e ﬀect without side
eﬀects holds true also for many nonpharmacological enhance-
ment interventions. It appears obvious that cognitive enhancersdiﬀer in the severity and form of side e ﬀects: prima facie, deep
brain stimulation or implants have higher risks for side e ﬀects
than sleep or cognitive training. However, also more indirectenhancement strategies such as neurofeedback potentially bearthe risk of side e ﬀects up to inducing epileptiform activity,
167
and even gentle intervention such as meditation training might
exert negative e ﬀects on speci ﬁc cognitive domains: a negative
relationship between mindfulness and implicit learning168,169
and an increased susceptibility to false memory formation after
mindfulness meditation170have been observed. Here, the
intended training goal of nonjudgemental mindfulness opposestasks where either a more critical or automatic mindset wasneeded. Further examples of side e ﬀects intrinsically associated
with the enhancement goal are trade-o ﬀs between stability vs
ﬂexible updating of memory systems:
129memories can also
become “too stable ”due to a memory enhancement
intervention, as observed, e.g., for the anti-obesity drug
rimonabant.171
It has been suggested to di ﬀerentiate enhancement strategies
according to their level of invasiveness.172,173However, while
invasiveness has a more or less de ﬁnite meaning in its original
medical context, physically breaching the skin or entering thebody deeply through an external ori ﬁce,174it is di ﬃcult to
determine the level of invasiveness in the context of cognitiveenhancement. Both nutritional supplements and pharmaceut-
icals enter the body, and thus could be considered invasive in anarrow medical sense, as might be certain forms of physicalexercise due to the risk of bruises or scratches as common, e.g., inmartial arts or a hike through the woods. Brain stimulation thatdoes not break the skin would, by contrast, be classi ﬁed as
noninvasive. This taxonomy can be disputed for goodreasons.
175Besides known risks of these stimulation methods
such as scalp burns from tDCS or seizures from TMS, the“known unknowns ”have been suggested to pose potentially
even greater risks: potential build-up e ﬀects across multiple
sessions or in sensitive nontarget areas.176Of note, only few
neuroscientists use brain stimulation on themselves for cognitiveenhancement.176Given the still unclear risks and side e ﬀects of
do-it-yourself brain stimulation use, it has been proposed to
extend existing medical devic e legislation to cover also
nonpharmacological and in particular physically acting cognitiveenhancement devices.177,178In contrast to strict medical
deﬁnitions, the more intuitively assessed level of invasiveness
of an intervention often seems to depend on familiarity andcultural traditions. This leads to the Western attitude accordingto which changing one ’s diet or performing exercise appears less
invasive than taking pharma ceuticals or applying brain
stimulation, independent of their actual e ﬀects on health.
Related to the time scale dimension, side e ﬀects of short- vs
long-term use of cognitive enhancers can be di ﬀerentiated. For
example, while side e ﬀects for the acute use of methylphenidate
include increased heart rate, headache, anxiety, nervousness,dizziness, drowsiness, and insomnia, in the case of long-term useside e ﬀects such as abnormal prefrontal brain function and
impaired plasticity have been reported.
179,180Also addiction is a
well-known side e ﬀect for the long-term use of pharmacological
enhancers, which is particularly detrimental to the aim ofenhancement if combined with tolerance e ﬀects such that larger
doses are needed to achieve the same e ﬀect (or prevent
impairing withdrawal e ﬀects). Also behavioral addictions have
been observed, e.g., physical exercise181or the use of
technological gadgets.182
A somewhat nonobvious negative e ﬀect of some cognitive
enhancers is their illusional e ﬃcacy: users sometimes believe
their performance to be enhanced by amphetamine in absence ofany veri ﬁed and objectively visible enhancing e ﬀects, even if
administered in a double blind manner.183,184,38This is
particularly counterproduct ive in cases of already high-
functioning individuals whose cognitive capabilities might beimpaired rather than enhanced by amphetamine.125,184Also for
caﬀeine, under certain conditions higher subjectively perceived
mental energy in the absence of objectively enhancing e ﬀects
have been observed.185The often subtle e ﬀects of enhancers can
be hidden or ampli ﬁed by placebo e ﬀects.
7. AVAILABILITY
Cognitive enhancers di ﬀer in at least three aspects of availability:
legal status, cost, and application time. In terms of legalregulation, di ﬀerent enhancement methods are regulated by
sometimes drastically varying frameworks. Pharmaceuticals, for
instance, are regulated by strict international control regimes
that e ﬀectively prohibit nontherapeutic uses or by more lenient
domestic drug laws. Brain-stimulation methods, by contrast, fallunder medical device regulations, pertaining to basic safetystandards in terms but not proscribing the uses to which theymight be put.
177,178Behavioral strategies are usually not
regulated at all. The regulatory landscape is thus vast andACS Chemical Neuroscience Review
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possibly incoherent (for a review, see ref 186). Besides practical
hurdles to the acquisition of illicit drugs for cognitiveenhancement, the legal status appears to a ﬀect the motivation
of users to decide which cognitive enhancers to take.166
A common ethical argument in the enhancement debate
concerns distributive justice: also legally available enhancerscome with cost barriers, restricting individuals of low socio-economic status from access.
187A main factor in the costs of
cognitive enhancers is their patentability, which is not restrictedto pharmaceuticals.188However, in particular, behavioral
enhancement strategies are typically not subject to patentabilityor other cost-driving factors: sleep, exercise, meditation, ortraining in mnemonic strategies are largely free of cost and, thus,in contrast to pharmaceuticals or technological strategies, areavailable independent from the ﬁnancial background of the user.
On the other hand, these behavioral strategies require some time
and e ﬀort: the 24/7 working manager as the cliche ́user of
cognitive enhancement drugs might have the ﬁnancial means to
aﬀord quickly taking his expensive smart pill between two
meetings, but might be unable or unwilling to spend extendedperiods of time with sleep, meditation, or mnemonic training.
8. SOCIAL ACCEPTANCE
Largely independent from their speci ﬁc enhancing e ﬀects on
diﬀerent cognitive capacities, social acceptance of cognitive
enhancement interventions di ﬀers strongly depending on
traditions, their perceived naturalness, and the perceiveddirectness of their mode of action. Enhancement interventionswith a tradition of thousands of years such as meditation andnutrition are typically much better accepted than many currentlydebated enhancement strategies such as brain stimulation andpharmaceuticals.
189Also more “natural ”interventions such as
sleep or exercise are seen in a more positive light compared totechnological innovations.190Moreover, in how far the mode of
action is perceived as psychologically mediated or morebiologically direct, a ﬀecting the brain indirectly through the
senses or more directly through the cranium or metabolism,often plays a role for their social acceptance: if an enhancementintervention such as intense cognitive or physical trainingrequires extended e ﬀorts or is seen as a quick and e ﬀortless
shortcut to the same goal as in the case of smart pills or brainstimulation touches di ﬀerent intuitions about human virtues and
is thus valuated di ﬀerently. Even though views based on such
purely intuitive aspects of tradition, naturalness, or directnessoften rely on cognitive biases rather than rational argument,
191a
negative social perception for whatever reason might generateindirect psychological costs for users, which in turn mightinﬂuence also rational evaluations of the respective enhance-
ment intervention.
192
Accordingly, one of the cent ral points in the ethical
controversy revolves around the question of whether enhance-ment strategies only relevantly di ﬀer with respect to their
outcomes, i.e., their bene ﬁts and side e ﬀects,193or also with
respect to their mode of operation.194Some argue that the
relevant ethical distinction runs along the lines of enhancementsthat are active, in the sense of requiring participation, and those
that work on persons more passively.195
Not surprisingly, di ﬀerent views on cognitive enhancement
prevail in di ﬀerent (sub)cultures, with, e.g., a more positive view
on enhancement interventions in Asia196or in younger
populations.197Empirical studies on attitudes toward cognitive
enhancement interventions found medical safety, coercion, andfairness the most common concerns, with nonusers displayingmore concerns regarding medical safety and fairness than
users.198Sometimes readily available substances for cognitive
enhancement such as ca ﬀeine, energy drinks, or herbal drugs are
dubbed “soft enhancers ”;199however, considering that prohib-
ition of substances is not only based on their potential harm, butalso on historical circumstances, this di ﬀerentiation between soft
and hard enhancers appears questionable.
A further aspect that determines the social acceptance of
cognitive enhancement is the aim of the given intervention.Taken by face value, the term cognitive enhancement denotes any
action or intervention that improves cognitive capacities,independent from the speci ﬁc aim of this improvement. The
use of the term in the empirical, philosophical, and sociopoliticalliterature, however, varies with regard of the speci ﬁc aim of
enhancement interventions: people appear to be more tolerant
toward enhancement of traits considered less fundamental to
self-identity,
200and also more tolerant toward enhancement in
individuals with cognitive impairments or low performancebaselines compared to enhancement of normal or highachievers.
201,202At least four di ﬀerent aims can be identi ﬁed,
each leading to di ﬀerent research strategies and di ﬀerent ethical
evaluations of existing or potential enhancement strategies.203
The least problematic concept of cognitive enhancement targetsthose everyday medical or psychological interventions that aremeant to treat pathological de ﬁciencies. Closely related are
those cognitive enhancement interventions that aim to preventor attenuate cognitive decline that is associated also with healthyaging.
204Slightly less accepted appear to be those enhancement
strategies that aim to improve cognition in completely healthyindividuals, but still clearly stay within the normal limits ofcognition. The probably most widely used and ethically mostcontroversial concept of cognitive enhancement aims at theaugmentation of cognitive capacities beyond normal function, asis represented in the cliche ́of high-functioning students or
managers trying to further improve their performance by takingsmart pills.
Besides these di ﬀerentiations between enhancement of
impaired vs healthy cognition, another di ﬀerence in the aims
of cognitive enhancement touches the ultimate deed of theenhancement intervention: due to the central role of cognitivecapacities in de ﬁning humans as a species, it is tempting to
consider the improvement of these de ﬁning human capacities as
a value in itself. However, most philosophical or religiousapproaches do not center on objective cognitive performancemarkers, but propose values only indirectly related to cognitiveperformance such as living a happier or more meaningful life ingeneral. In this light, human enhancement in more general termsdoes not need to aim for individual cognitive or neural processes,
but can also be achieved by sociopolitical reforms targeted at the
population level.
205,206
9. CONCLUSIONS
Cognitive enhancement clearly is a multidimensional endeavor.
However, not every dimension is important for every theoreticalor empirical research question. For example, many empiricalresearchers of cognitive enhancement are primarily interested in
the understanding of the neurobiological and psychological
mechanisms underlying cognitive functions.
207For this aim, the
availability and social accept ance dimensions are largely
irrelevant. In contrast, many theorists are interested in thesocial and ethical implications of cognitive enhancement,208
where these dimensions might be of prime importance. Also sideeﬀects and temporal factors might be of secondary importanceACS Chemical Neuroscience Review
DOI: 10.1021/acschemneuro.8b00571
ACS Chem. Neurosci. 2019, 10, 1137 −11481142
to empirical researchers with an interest in the neural
mechanisms of certain cognitive processes, whereas thesewould be highly relevant for users who ponder the questionwhich cognitive enhancement strategy to choose for a certainaim. When comparing di ﬀerent cognitive enhancement
strategies, di ﬀerent dimensions might thus be di ﬀerently
weighed or completely ignored, depending on the aim of thecomparison.
Up until now, direct comparisons between cognitive
enhancement strategies with radically di ﬀerent modes of actions
have rarely been made (but see, e.g., ref 165), and more
comprehensive comparisons across dimensions might bediﬃcult: practical issues of information availability from the
diﬀerent dimensions aside, interventions typically di ﬀer on
diﬀerent dimensions and are thus di ﬃcult to compare globally.
In addition, multiple interactions between di ﬀerent enhancers
exist, which further complicates the situation. Interactions havebeen reported, e.g., for glucose and ca ﬀeine,
209diet and
exercise,210exercise and working memory training,211video
games and sleep,212video games and brain stimulation,213
exercise and brain stimulation,214and brain stimulation and
sleep.215,216Also di ﬀerent dimensions discussed here can
interact in multiple ways, as, e.g., computerized cognitivetraining can di ﬀerentially enhance di ﬀerent cognitive processes
depending on personal factors such as age;217and social
acceptance of di ﬀerent enhancement strategies depends on both
the baseline performance of users and the cognitive domaintargeted.200,201
Despiteor because of these complexities, in our opinion,
both theoretical discussions and empirical research wouldstrongly bene ﬁt from a more di ﬀerentiated approach. Speci ﬁc
research questions might require the emphasis on somedimensions of cognitive enhancement over others, and forsome research questions some dimensions might be entirelyirrelevant. Nevertheless, keeping in mind that cognitiveenhancement is not a monolithic phenomenon will help tosolve and avoid a number of confusions and disagreements thatare still present in the public debate on cognitive enhancement.
■AUTHOR INFORMATION
Corresponding Author
*Mailing address: Donders Institute for Brain, Cognition and
Behaviour, Kapittelweg 29, 6525 EN Nijmegen, The Nether-lands. Tel. ++31-24-3610984.
ORCID
Martin Dresler: 0000-0001-7441-3818
Author Contributions
All authors developed the concept of this paper and jointly wrotethe manuscript.
Funding
This work was supported by the Volkswagen Foundation,Germany.
Notes
The authors declare no competing ﬁnancial interest.
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ACS Chem. Neurosci. 2019, 10, 1137 −11481148

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