Pharmacological cognitive enhancement: treatment of

Personal View
Pharmacological cognitive enhancement: treatment of
neuropsychiatric disorders and lifestyle use by healthy people
Barbara J Sahakian, Sharon Morein-Zamir
Neuropsychiatric disorders typically manifest as problems with attentional biases, aberrant learning, dysfunctional
reward systems, and an absence of top-down cognitive control by the prefrontal cortex. In view of the cost of common
mental health disorders, in terms of distress to the individual and family in addition to the financial cost to society
and governments, new developments for treatments that address cognitive dysfunction should be a priority so that all
members of society can flourish. Cognitive enhancing drugs, such as cholinesterase inhibitors and methylphenidate,
are used as treatments for the cognitive symptoms of Alzheimer’s disease and attention deficit hyperactivity disorder.
However, these drugs and others, including modafinil, are being increasingly used by healthy people for enhancement
purposes. Importantly for ethical and safety reasons, the drivers for this increasing lifestyle use of so-called smart
drugs by healthy people should be considered and discussions must occur about how to ensure present and future
pharmacological cognitive enhancers are used for the benefit of society.
Introduction
Pharmacological and other treatments are needed
to treat cognition in patients with neuropsychiatric
disorders or brain injury. Although cognitive impair­
ment is a target for treatment of specific disorders,
including Alzheimer’s disease and attention-deficit
hyperactivity disorder (ADHD), cognitive dysfunction is
a feature of all psychiatric disorders. In patients with
Alzheimer’s disease, cholinesterase inhibitors, such as
donepezil, can be given to slow down or compensate for
the decline in cognitive functioning in people with
mild-to-moderate or even severe disease.1,2 Children and
adults with ADHD are given the selective noradrenaline
reuptake inhibitor atomoxetine in addition to stimulants
such as methylphenidate and amphetamines that
specifically target cognitive and behavioural difficulties.3
Other psychiatric disorders are also associated with core
difficulties in cognition, including problems with
attention, learning, memory, and reasoning and decision
making. For example, cognition is regarded as a target
for treatment of schizophrenia, for which, despite
remission of psychosis with antipsychotic drugs, a
patient’s functional recovery is quite poor in terms
of gainful employment, independent living, and manage­
ment of social relationships.4 Moreover, in disorders
ranging from depression to substance misuse, cognitive
problems raise barriers to good functional outcome,
quality of life, and wellbeing.5 Therefore, treatment of
debilitating cognitive symptoms is not only a viable
target, but can also ensure better outcomes. Despite the
recognition of cognition as a target for treatment in
schizophrenia, cognition is not yet regarded as a target
for treatment of depression by the US Food and Drug
Administration.
Continuing research is promoting an improved
understanding of the development of psychiatric dis­
orders and how they change with time. Often, changes in
the brain take place before notable alterations in
behaviour and the onset of symptoms and can manifest
in changes in cognition. In schizophrenia, cognitive
www.thelancet.com/psychiatry Vol 2 April 2015
impairments often become detectable before the onset of
the psychotic syndrome.6 In other psychiatric disorders
(eg, relapsing depression), cognitive scarring occurs,
which hinders treatment outcomes as the disorder
progresses.7 Similarly, key cold cognition (abilities such
as planning, memory, and mental flexibility) and hot
cognition (processes or decision making on the basis of
emotions, self-motivation, or rewards) in psychiatric
disorders, including obsessive compulsive disorder
(OCD) or substance misuse, could change in time with
patients transitioning to more habitual and compulsive
disorders that become less tractable and increasingly
difficult to treat.8–10 Accordingly atomoxetine might be of
benefit early on in the substance abuse cascade into
compulsivity, when behaviour is still mainly impulsive.9,10
Such evidence shows that for effective treatment or
disorder management, cognition should be targeted
early on and often in a sustainable but flexible manner
throughout the progression of the psychiatric disorder.
When treatments to reverse deterioration are not
possible, early identification and intervention, such as in
neurodegenerative disorders including Alzheimer’s
disease, have even greater impetus.10
A range of pharmaceutical substances, from psycho­
tropic drugs to nicotine and caffeine, have been regarded
by health-care providers, patients, researchers, and the
general public to change, improve, and enhance mental
processes. Randomised controlled trials examining acute
or chronic administration of pharmaceutical substances
have shown improvements in cognition in various patient
groups.11 Of note, acute administration of pharmaceutical
substances ranging from methylphenidate to caffeine
results in improved cognitive performance not only in
patients, but also in healthy individuals.12 The effects on
different aspects of cognition vary, but are generally
moderate or small as estimated by Cohen’s d effect size.13
For example, the effect of modafinil on attention had a
moderate effect size of 0·56.14 Noted changes in cognition
include improvements in executive function15 and
emotional processing,16 and effects on alertness and
Lancet Psychiatry 2015;
2: 357–62
Department of Psychiatry
(Prof B J Sahakian PhD)
and Medical Research
Council–Wellcome Trust
Behavioural and Clinical
Neuroscience Institute,
Addenbrooke’s Hospital,
Cambridge, UK
(S Morein-Zamir PhD); and
Department of Psychology,
University of Cambridge,
Cambridge, UK (S Morein-Zamir)
Correspondence to:
Prof Barbara J Sahakian,
Department of Psychiatry
and Medical Research
Council–Wellcome Trust
Behavioural and Clinical
Neuroscience Institute,
Addenbrooke’s Hospital,
Cambridge CB2 2QQ, UK
bjs1001@medschl.cam.ac.uk
357
Personal View
arousal.17 In addition to pharmaceutical cognitive
enhancers, other, often complementary, behavioural
interventions can also promote changes in cognitive
processes—eg, cognitive training is beneficial in patients
with schizophrenia.18 Moreover, factors such as education,
physical exercise, and diet can also affect a patient’s
general functioning and wellbeing.5
Use of an integrative approach to cognition,
behaviour, and function
Assessments of pharmaceutical cognitive enhancers
should consider not only how they are being used and by
whom, but also why various individuals might be using
them. The terminology of pharmaceutical cognitive
enhancers is probably a misnomer because they could
affect both cognitive and motivational processes. In this
Personal View we refer to drugs that are used for the
treatment and enhancement of cognitive processes.
Pharmacological cognitive enhancers are likely to affect a
broad gamut of functioning both directly and indirectly
and in subtle, yet potentially important, ways. Pharmaco­
logical cognitive enhancers might affect a range of aspects
relevant to everyday functioning, including social and
emotional cognition, creativity, and apathy. Thus,
modafinil, a CNS drug promoting wakefulness, has been
shown to improve emotional face recognition in patients
with first-episode psychosis.15 Such effects could be of
importance in alleviation of difficulties with social
behaviours and insight that are characteristic of many
neuropsychiatric disorders, including substance misuse.19
Moreover, the subjective and motivational effects of
stimulants and modafinil are increasingly being
appreciated in the context of improved cognitive
performance and function.17,20,21 Motivational deficits could
be one of the mechanisms by which pharmacological
cognitive enhancers affect ADHD symptoms.22 An
indirect effect of pharmacological cognitive enhancers
could be to increase adherence to other forms of
pharmaceutical or behavioural treatments because
neurocognitive impairment has been associated with
increased treatment dropout.23 Furthermore, these
enhancers might reduce unwanted side-effects of drugs.
For example, side-effects of antidepressants, such as
fatigue and concentration difficulties, might be mitigated
by an adjunct pharmacological cognitive enhancer.24
Another route by which select pharmacological cognitive
enhancers might be beneficial is via their effect on sleep
patterns. Sleep disturbances are common in people with
psychiatric and other medical disorders and even in
people without either, and affect alertness, cognition, and
other aspects of functioning. Some studies25 have
proposed that modafinil might help to clinically improve
stimulant dependence by normalising disrupted sleep
patterns, which could have subsequent cascading effects
on outcomes. Moreover, concurrent effects could be
mediated during initial abstinence via blunting cocaineinduced euphoria26 in addition to possible improved top358
down control.9,27 In summary, pharmacological cognitive
enhancers are likely to affect functional outcome and
wellbeing by changing a patient’s sleeping behaviours,
motivation, and cognition. These effects might account
for the increasing lifestyle use of some pharmacological
cognitive enhancers in healthy individuals.
Superficially, creation of clear divisions between medical
and non-medical use of pharmacological cognitive
enhancers might be useful. However, such categorisation
is only informative to some extent and in practice
boundaries can become blurred. Some seemingly healthy
individuals could be self-medicating for undiagnosed
disorders, whereas patients could be misusing their
prescribed drugs for ostensibly enhancement purposes.28
Moreover, pharmacological treatment for patients,
whether to enhance or prevent future deterioration or
relapse, might not fall neatly into one category or the other.
Differences exist between countries in prescription
of these drugs so that an individual receiving a
pharmacological cognitive enhancer by prescription in a
therapeutic context in one country might not be able to so
in another country. Moreover, the division between
pathological changes and health can shift with time so
that what might have originally been regarded as
enhancement could eventually become a treatment29
What is known
First and foremost, although individual differences
between pharmacological cognitive enhancers cannot
often be accurately gauged, such differences play a key
part in mediating the effectiveness of many of these
drugs. The discipline of pharmacogenomics, or how
genes affect the body’s response to drugs, is still
developing. Therefore, effects might be present in some
individuals but not others, thereby diluting group effects.
Factors such as sex, age, genetic variation, and even
psychosocial elements, ethnic origin, and culture could
affect the effectiveness of pharmacological cognitive
enhancers to varying extents. Baseline levels of
performance can contribute to differential effects of a
drug in complex ways. Thus, for healthy individuals,
several pharmacological cognitive enhancers seemed to
yield improvements in cold cognition, mostly in those
with low baseline performance;30 however, in patients
with schizophrenia these drugs were more effective in
those with higher premorbid intelligence.31 Additional
complex effects have been reported for the catechol-omethyltransferase inhibitor tolcapone, which improved
working memory performance in one genotype group,
but worsened it in another.32 Furthermore, some
stimulant drugs seem to produce an inverted U-shaped
function rather than showing linear effects. A symptom
profile might further mediate pharmacological enhance­
ment. For example, individuals who have difficulty
concentrating, whether they have a diagnosis of ADHD
or not, have reduced left caudate dopamine activity.30
Additionally, illness duration and drug history could both
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Personal View
lead to neuro-adaptive or compensatory changes that
affect subsequent pharmacological actions. To gauge
whether any individual differences are important
necessitates large-scale replicable studies, which are often
not feasible or cost effective. Assessment of so many
factors would be of little practical use, but specification of
some subgroups that could particularly benefit from a
pharmacological cognitive enhancer would be of value.33
The timing of administration of these drugs in addition
to what is measured also affects the robustness, reliability,
and validity of findings. Cognition and behaviour are the
result of a complex interplay between state and trait
variables that fluctuate with time. Impairments might at
times be pronounced and in other circumstances rather
subtle. For example, sleep patterns can vary substantially
over time, and the effects of modafinil on sleep seem to be
more robust in sleep-deprived individuals than in those
who are well rested and healthy.14 Additionally, acute versus
chronic administration can help to establish the effects of
pharmacological cognitive enhancers, with several
neurotransmitters having different modes of action when
released in an acute compared with a chronic manner.20
Hence, modafinil could be more useful when used acutely
in challenging situations than when used chronically.22
Which aspects of cognition and functioning could be
enhanced in the long term and in daily life is unclear.
The complexity of the brain and human behaviour
cannot be understated. Many pharmacological cognitive
enhancers affect several neurotransmitters simul­
taneously—eg, methylphenidate, which affects nor­
adrenaline and dopamine.34 Sometimes there can be
opposing actions in the same neurotransmitter system
via different receptors,12 as shown with noradrenaline α1
and α2 receptors.35 Neuromodulatory systems interact
with one another in localised brain regions and at
network levels with cascading downstream effects.12,30
Moreover, the optimum dose appropriate for some
systems in the brain might be associated with overdosing
in other systems.12 Hence, pharmacological cognitive
enhancers can have a range of effects in the same
individual, enhancing specific aspects of cognition
while simultaneously impairing others. Present
pharmacological cognitive enhancers typically have
wide-ranging effects and side-effects; however, some
drugs, such as atomoxetine, have relatively more
restricted actions.2
Investigations of both acute and chronic administration
are needed to complement each other. Although studies
of acute administration are informative, they do not
provide information about long-term use of drugs,
whereas long-term studies do not provide information
about intermittent use, which is characteristic of many
healthy individuals36 and even of patients who are not
adherent to their drug regimen. A restricted set of
outcome measures further mediates the effects that are
monitored or noted. The disparity between objective and
subjective indices for some pharmacological cognitive
www.thelancet.com/psychiatry Vol 2 April 2015
enhancers further complicates matters. For instance,
stimulants increase enjoyment during monotonous
tasks, but might also convey a subjective perception of
enhanced pleasure.21 Tasks used in laboratory settings
probably do not capture real-life situations in which,
ultimately, the enhancing and motivational effects of
stimulants are determined by individual users.
Alternatively, many of the supposed effects on cognitive
enhancement in the real world could be illusory placebo
effects. So far, many studies suggest moderate or small
effect sizes of pharmacological cognitive enhancers;
additionally, few data are available for the long-term
application of these drugs. Of benefit could be the
identification of subgroups and possibly the development
and use of adequate outcome measures that show broad
functioning both subjectively and objectively.
What is not known
Despite the overlap between medical and non-medical
pharmacological enhancement, non-medical use has
additional unique issues. First and foremost, substantial
data are missing for most aspects of non-medical use. In
fact, many reports about pharmacological enhancement
conclude with a call for more research.37 In addition to
these important questions regarding the real or perceived
effects of pharmacological cognitive enhancers in everyday
settings, not enough is known about who is using these
drugs non-therapeutically, in what ways, and why. Existing
evidence suggests that the main uses of pharmacological
cognitive enhancers by healthy individuals seem to be
for achievement of a competitive advantage at school,
university, or work; to maintain levels of attention and
performance when sleep deprived or jet-lagged; and to
improve task-related motivation.38 Findings from survey
research focusing mainly on non-medical stimulant use in
students in the USA show substantial variability between
populations and geographical locations,39 with estimates of
use varying between 5% and 35%.40,41 Although research in
Europe is even scarcer than findings from other countries,
evidence from German and Swiss students suggests less
widespread use of pharmacological enhancers.36,42 Much
large-scale survey research is not done to gauge use of
pharmacological cognitive enhancers, but rather to
investigate illicit drug misuse.43 In view of the dearth of
studies, the poor consistency, in terms of which pharmaco­
logical cognitive enhancers are being investigated and the
key questions relevant in healthy populations, is un­
surprising. No consensus exists about how to distinguish
between prescription and non-prescription users and the
source of the pharmacological cognitive enhancers are
often not investigated. As a whole, extant scientific literature
about healthy users is severely limited by variable methods,
terminology, and outcome measures, in addition to the
absence of a distinction between different frequency and
patterns of use.44
A further key issue is that most studies of pharmacological
cognitive enhancers have targeted student populations,
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Personal View
which might not be representative of middle-aged or
elderly populations.45 Use of pharmacological cognitive
enhancers by healthy adolescents and young adults
raises a concerning safety issue of the effects of these
drugs on the developing brain. Part of the heterogeneity
in findings is likely to result from wide variation in
the prevalence of different pharmacological cognitive
enhancers in various populations. Only a few studies
have investigated the prevalence of these drugs in other
populations—eg, a survey46 of German surgeons that
suggested some use. Finally, at the level of the individual,
non-medical use raises many safety and ethical concerns.
Risk–benefit considerations are greatly shifted in the
case of healthy individuals taking pharmacological
cognitive enhancers.11 Medical complications and potential
for misuse are key concerns that could go unaddressed
when pharmacological cognitive enhancers are taken
without oversight from health-care professionals.
Clearly, in view of the potential benefits and harms
associated with pharmacological cognitive enhancers,
more research is needed that uses common experimental
designs. Some researchers are now investigating the
combination of pharmaceutical and behavioural
treatments. Many mechanisms exist by which such
integrations could yield summative or overadditive
effects. In patient populations, improved learning,
memory, and cognitive control, in addition to increased
motivation and cooperation levels, all brought about by
use of pharmacological cognitive enhancers, could lead to
improved adherence and reduced dropout of challenging
treatments.23 Pharmacological cognitive enhancers can
also modify the way that neural circuits reorganise in
response to training interventions.47 For schizophrenia,
cognitive remediation and adjunctive rehabilitation could
be strengthened by use of drugs such as memantine,
which acts on glutamate partial N-methyl-D-aspartate
(NMDA) receptors.47 Similar effects have been reported
for the combination of memantine or donepezil and
speech therapy for dysphasia.48 Some drugs might be
effective in combination with therapy even if they are
ineffective when given alone. Accordingly, findings
suggest that administration of D-cycloserine, a partial
NMDA receptor agonist, helps with exposure therapy and
removal of fear in patients who have various anxiety
disorders and OCD.49,50 On the basis of these findings,
addition or integration of several complementary
treatment methods might seem to be a plausible option
in the search for effective treatments to multifaceted
disorders;51 however, this approach also poses many
challenges. For example, the choice of which combination
of therapies and their optimum parameters (eg, dose and
duration) need to be ascertained in addition to testing
in randomised controlled trials with several control
conditions.47
Other avenues of research have allowed for the
development of entirely different experimental designs
and research methods,52 such as use of technology for
360
monitoring, managing, and intervening for improved
health, mental health, and wellbeing.10 The use of
sophisticated embedded sensors together with contextdependent and experience sampling at much finer time
scales (such as hours, minutes, or even seconds) offers
unprecedented opportunities to enhance the external
validity of treatment studies and to ascertain existing use
in healthy individuals.53 New and developing analytical
techniques capture the complexity and volume of data
available at the level of the individual, enabling new
approaches to the study of individual differences and
changes in time. Thus, sophisticated models that
integrate cognition, behaviour, and functioning are
becoming feasible.10
What needs to be known
As health professionals, we need to consider the best way
to reduce harms and ensure that pharmacological
cognitive enhancers are used for the benefit of
individuals.13 Clearly, these drugs could be effective and
useful for some patients, but not for others. Findings
from acute studies could possibly be used to predict the
effects of long-term outcome, but this is yet to be
determined. Evidently, although clinicians report widely
varying attitudes towards providing their patients with
enhancement versus restoration,54 they do tend to place
overwhelming importance on safety.55 By contrast with the
safety concerns of doctors in regard to their patients, such
concerns are less prevalent in healthy non-medical users
of these drugs who show poor appreciation for risks
including side-effects and risks associated with online
purchase.44 This disregard for associated risks is a key
reason why primary care oversight should be extended to
non-medical use of pharmacological cognitive enhancers.56
Health-care professionals are ideally suited for providing
medical supervision and education to individuals who use
these drugs, and possibly to check whether implicit
coercion might be taking place.11,57 Drawbacks of this
option include possible increases on pressure from
individuals and carers demanding cognitive enhancing
drugs even when these are counter indicated for health
reasons.58 Irrespective of whether or not physicians and
psychiatrists want to be responsible for monitoring use of
pharmacological cognitive enhancers, this is likely to
become their responsibility in the future. As a result, the
need to ensure the continuation of education for healthcare providers about advances in pharmacological
cognitive enhancers research and non-medical treatment
options is especially important. Increased awareness
about the possibility of drug diversion (when prescribed
drugs are obtained or used illegally) is also important.28,59,60
Additional empirical data about pharmacological
cognitive enhancers is needed. However, in relation to
existing research funding, data for these drugs is of little
interest to disease-oriented and basic science funders
and is also of little incentive for the pharmaceutical
industry because present regulations promote research
www.thelancet.com/psychiatry Vol 2 April 2015
Personal View
exclusively about disorders or disease.41 In view of present
trends in use and the potential risks and benefits of wider
use of pharmacological cognitive enhancers, this
scenario should no longer be acceptable.61 We call on
funders and policy makers to prioritise research of
pharmacological cognitive enhancers in healthy
individuals and to consider how best to promote rigorous
scientific research in this domain that is socially and
ethically responsible.62 Increased knowledge of the
effectiveness and harms of pharmacological cognitive
enhancers in healthy adults is clearly in the best interest
of health-care professionals and the public. Good
empirical data is crucial to make informed decisions
about regulatory measures and to form a balanced
opinion about the potential risks and benefits not only to
individuals, but also to society.11,61
From a policy perspective, pharmacological cognitive
enhancers are often treated as a single class even though
they have distinct pharmacological mechanisms, effects,
and legal status.44 Therefore a case-by-case discussion of
regulation is needed about the potential for physical and
psychological dependence, and about social harms.44 Policy
proposals have spanned a broad range of approaches, but
should take into account costs, bureaucracy, and present
regulations.63 Although there is great merit in the
development of novel, effective, and safe pharmacological
cognitive enhancers, use of these drugs is likely to, at least
in the near future, stem from off-label expansion64–66 and
online sales to individuals. In the first case, we believe that
health-care providers are facing the responsibility of
making informal policy decisions in practice. Because
knowledge and opinions vary greatly among physicians,55
national medical organisations should provide clear
information and guidelines about benefits, risks, safety,
and potential coercion to these and other health-care
providers,61 and ensure that providers are aware of their
availability. Although every case should be judged
individually, professional oversight is essential in view of
the potential for chronic use over many years and and
possible safety concerns.58 Accessibility via the internet, as
shown in other instances such as legal high purchasing
(used for recreational purposes), is a growing yet poorly
understood issue.67
We conclude that more immediate action is needed
to establish the long-term risks and benefits of
pharmacological cognitive enhancers for healthy people
and to continue to develop novel, more effective
pharmacological cognitive enhancers for people with
impairments associated with brain injury or neuro­
psychiatric disorders.
Contributors
Both authors contributed equally to this Personal View, with both
developing the concept. BJS was the lead author. SM-Z wrote the first
draft of the manuscript. BJS edited the manuscript.
Declaration of interests
BJS consults for Cambridge Cognition, Servier, Otsuka, and Lundbeck,
holds a grant from Janssen/Johnson & Johnson, and has share options
in Cambridge Cognition. SM-Z declares no competing interests.
www.thelancet.com/psychiatry Vol 2 April 2015
Acknowledgments
SM-Z was funded by a Wellcome Trust grant (089589/Z/09/Z) awarded
to BJS and others. All cited psychopharmacological work from BJS
laboratory was funded by a Wellcome Trust Grant (089589/Z/09/Z), and
was done within the Behavioural and Clinical Neuroscience Institute,
which is supported by a joint award from the Medical Research Council
and Wellcome Trust (G00001354). BJS also receives funding from the
Human Brain Project.
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