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 [email protected] 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 www.thelancet.com/psychiatry Vol 2 April 2015 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, 359 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. References 1 Howard R, McShane R, Lindesay J, et al. Donepezil and memantine for moderate-to-severe Alzheimer’s disease. N Engl J Med 2012; 366: 893–903. 2 Zohar J, Nutt DJ, Kupfer DJ, et al. A proposal for an updated neuropsychopharmacological nomenclature. 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