Neurocognitive Enhancement: What for ‘Enhancement’ — That Is, for Improving the Psychological Function of Individuals Who Can We Do and What Should We Do? Are Not Ill

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these drugs are used to treat neurological and SCIENCE AND SOCIETY psychiatric illnesses, and there is relatively little controversy surrounding this use. However, psychopharmacology is also increasingly used Neurocognitive enhancement: what for ‘enhancement’ — that is, for improving the psychological function of individuals who can we do and what should we do? are not ill. The enhancement of normal neurocognitive function by pharmacological means is Martha J. Farah, Judy Illes, Robert Cook-Deegan, Howard Gardner, already a fact of life for many people in our Eric Kandel, Patricia King, Eric Parens, Barbara Sahakian and society, from elementary school children to ageing baby boomers. In some school districts Paul Root Wolpe in the United States the proportion of boys taking methylphenidate exceeds the highest Our growing ability to alter brain function remain in the ‘proof of concept’ stage, but estimates of the prevalence of attention can be used to enhance the mental show substantial promise1.Neurosurgery deficit–hyperactivity disorder (ADHD)5, processes of normal individuals as well as is increasingly considered as a treatment implying that normal childhood boisterous- to treat mental dysfunction in people who for mental illnesses and an array of new pro- ness and distractibility are being targeted are ill. The prospect of neurocognitive cedures are under development, including for pharmacological intervention. The use enhancement raises many issues about the implantation of devices and tissue2.Non- of prescription stimulants (such as methyl- what is safe, fair and otherwise morally invasive transcranial magnetic stimulation phenidate and dextroamphetamine) as study acceptable. This article resulted from a (TMS) of targeted brain areas is the basis of aids by high school and college students meeting on neurocognitive enhancement promising new treatments for depression and who do not have ADHD has recently drawn that was held by the authors. Our goal other psychopathology3. attention, and might include as many as 16% is to review the state of the art in of the students on some campuses6.Sales of neurocognitive enhancement, its attendant nutritional supplements that promise social and ethical problems, and the ways “The enhancement of normal improved memory in middle age and beyond in which society can address these neurocognitive function by have reached a billion dollars annually in problems. the United States alone7,despite mixed pharmacological means is evidence of effectiveness8.In contrast to the Many are predicting that the twenty-first already a fact of life for many other neurotechnologies mentioned earlier, century will be the century of neuroscience. whose potential use for enhancement is still Humanity’s ability to alter its own brain people in our society.” hypothetical, pharmacological enhancement function might well shape history as power- has already begun. fully as the development of metallurgy in the Iron Age, mechanization in the Industrial On the leading edge of neurotechnology is What can we do? Revolution or genetics in the second half of psychopharmacology. Our ability to achieve Many aspects of psychological function the twentieth century. This possibility calls for specific psychological changes by targeted are potential targets for pharmacological an examination of the benefits and dangers neurochemical interventions, which began enhancement, including memory, executive of neuroscience-based technology, or ‘neuro- through a process of serendipity and trial and function, mood, appetite, libido and sleep9,10. technology’,and consideration of whether, error in the mid-twentieth century, is evolving We will use the first two of these, memory when and how society might intervene to into the science of rational drug design. The and executive function, as examples to show limit its uses. psychopharmacopia of the early twenty-first the state of the art in psychopharmaceutical At the turn of the century, neurotechnology century encompasses both familiar, and in enhancement, the ethical issues raised spans a wide range of methods and stages of some cases highly effective, drugs, and a new by such enhancement and the policy implica- development. Brain–machine interfaces that generation of more selective drugs that target tions of these ethical issues. A brief review allow direct two-way interaction between the specific molecular events that underlie of the state of the art in neurocognitive neural tissue and electronic transducers cognition and emotion4.For the most part, enhancement is offered here; additional

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© 2004 Nature Publishing Group PERSPECTIVES information is freely available to readers of this being sought to prevent the consolidation of that the dopamine agonist bromocriptine article at www.nyas.org/ebrief/neuroethics and such memories by pharmacological interven- improved performance on various executive in recent articles by Rose11,Lynch12 and Hall7. tion immediately after the trauma15.Drugs function tasks for individuals with lower- whose primary purpose is to block memories than-average working memory capacity, but Memory enhancement. Memory enhance- are also being developed by the pharma- lowered the performance of those with the ment is of interest primarily to older adults. ceutical industry7.Extending these methods highest working memory capacities18.Whether The ability to encode new memories declines beyond the victims of trauma, to anyone who enhancement can boost the performance of measurably from the third decade of life wishes to avoid remembering an unpleasant already high-performing individuals must be onwards, and by the fourth decade the decline event, is another way in which the neural determined empirically for each drug and for can become noticeable and bothersome to bases of memory could be altered to enhance each type of cognitive ability. normal healthy individuals13.Memory diffi- normal function. Newer drugs might improve executive culties in middle or old age are not necessarily function in different ways, influencing differ- a harbinger of future dementia but can be part ent underlying processes and interacting of the normal pattern of cognitive ageing, “The pursuit of mastery in different ways with individual differences which does not make it any less inconvenient (for example, in working memory capacity) when we misplace our glasses or forget the over our own memories and states (such as restedness). The newest name of a recent acquaintance. What can includes erasing undesirable potential neurocognitive enhancer is the current and imminent neurotechnologies drug modafinil, which is approved for the offer us by way of help? memories as well as treatment of narcolepsy and is increasingly The changes that underlie normal age- retaining desirable ones.” prescribed off-label for other purposes19. One related declines in memory probably differ of the authors (B.J.S.) found that it increases from those that underlie Alzheimer’s disease, performance among healthy young adults on indicating that the optimal pharmacological Enhancement of executive function. Executive a set of executive function tasks that differs approaches to therapy and enhancement function refers to abilities that enable partly from those that are influenced by might also differ. Although donepezil, a flexible, task-appropriate responses in the face methylphenidate, with its effects resulting at cholinesterase inhibitor that is used to treat of irrelevant competing inputs or more least in part from an improved ability to Alzheimer’s disease, did enhance performance habitual but inappropriate response patterns. inhibit impulsive responses20. in one study of healthy middle-aged pilots after These include the overlapping constructs of flight simulator training14,drug companies attention, working memory and inhibitory What should we do? are looking elsewhere for pharmacological control. Drugs that target the dopamine and Ethical problems and policy solutions. Neuro- approaches to memory enhancement in noradrenaline neurotransmitter systems are cognitive enhancement raises ethical issues normal individuals. Recent advances in the effective at improving deficient executive for many different constituencies. These molecular biology of memory have presented function, for example in ADHD, and have include academic and industry scientists who drug designers with many entry points recently been shown to improve normal are developing enhancers, and physicians through which to influence the specific executive function as well16,17. who will be the gatekeepers to them, at least processes of memory formation, potentially For example, one of the authors (B.J.S.) initially. Also included are individuals who redressing the changes that underlie both nor- found that healthy young volunteers per- must choose to use or not to use neuro- mal and pathological declines in memory. formed the Tower of London problem-solving cognitive enhancers themselves, and parents Most of the candidate drugs fall into one of task more accurately after being given who must choose to give them or not to give two categories: those that target the initial methylphenidate than after being given a them to their children. With the advent of induction of long-term potentiation and those placebo when the task was novel16.Methyl- widespread neurocognitive enhancement, that target the later stages of memory consol- phenidate also increased accuracy in a employers and educators will also face new idation. In the first category are drugs that complex spatial working memory task, and challenges in the management and evalu- modulate AMPA (α-amino-3-hydroxy-5- this was accompanied by a reduction in the ation of people who might be unenhanced methyl-4-isoxazole propionic acid) receptors activation of areas of the brain that are related or enhanced (for example, decisions to to facilitate depolarization, including Cortex to working memory, as shown by positron recommend enhancement, to prefer natural Pharmaceuticals’Ampakines12.In the second emission tomography (PET)17.For the latter over enhanced performance or vice versa, category are drugs that increase CREB (the task, the amount of benefit was inversely and to request disclosure of enhancement). cAMP response element-binding protein), proportional to the volunteers’ working Regulatory agencies might find their respon- a molecule that in turn activates genes to memory capacity as assessed by a different sibilities expanding into considerations of produce proteins that strengthen the synapse. working memory task, digit span, with little or ‘lifestyle’ benefits and the definition of accept- One such drug is the molecule MEM1414, no benefit to those with the highest digit span able risk in exchange for such benefits. Finally, which is being tested by Memory Pharma- performances. This is of interest in discussions legislators and the public will need to decide ceuticals7 (a company co-founded by one of of enhancement, because it indicates that, for whether current regulatory frameworks are the authors (E.K)). this medication and this cognitive ability at adequate for the regulation of neurocognitive The pursuit of mastery over our own least, those with lower levels of performance enhancement, or whether new laws must be memories includes erasing undesirable mem- are more likely to benefit from enhancement written and new agencies commissioned. ories as well as retaining desirable ones. than those with higher levels. Indeed, it is To focus our discussion, we will dispense Traumatic events can cause lifelong suffering possible that some drugs would compress with some ethical issues that are important by the intrusive memories of post-traumatic the normal range of performance in both but not specific to neurocognitive enhance- stress disorder (PTSD), and methods are directions. One of the authors (M.J.F.) found ment. The first such issue is research ethics.

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Research on neurocognitive enhancement, as agencies determine what constitutes a suffi- barriers to legal neurocognitive enhancement opposed to therapy, raises special consider- ciently careful search for side effects and what and possibly social barriers as well for certain ations mainly insofar as the potential benefits side effects are acceptable in view of a drug’s groups. Such barriers could compound the can be viewed as smaller, and acceptable benefits. Although consensus will have to disadvantages that are already faced by peo- levels of risk to research subjects would be developed on these issues in connection ple of low socioeconomic status in education be accordingly lower. This consideration is with neurocognitive enhancement, we see no and employment. Of course, our society is largely academic for those neurocognitive reason that the same approach cannot be already full of such inequities, and few would enhancers that come to market first as applied here. restrict advances in health or quality of life therapies for recognized medical conditions, because of the potential for inequitable which includes all of the substances that are Coercion. If neurocognitive enhancement distribution. Unequal access is generally not now available for enhancement, although becomes widespread, there will inevitably be grounds for prohibiting neurocognitive this might not be true in the future. Another situations in which people are pressured to enhancement, any more than it is grounds important ethical issue concerns the use of enhance their cognitive abilities. Employers for prohibiting other types of enhancement, neurocognitive enhancement in the criminal will recognize the benefits of a more attentive such as private tutoring or cosmetic surgery, justice system, in which a large proportion of and less forgetful workforce; teachers will find that are enjoyed mainly by the wealthy. offenders fall in the lower range of cognitive enhanced pupils more receptive to learning. Indeed, in principle there is no reason ability in general21 and executive inhibitory What if keeping one’s job or remaining in that neurocognitive enhancement could control in particular22.Although neurocogni- one’s school depends on practicing neuro- not help to equalize opportunity in our tive enhancement brings with it the potential cognitive enhancement? Such dilemmas are society. In comparison with other forms for subtle coercion in the office or classroom, difficult but are not without useful legal of enhancement that contribute to gaps ‘neurocorrection’ is more explicitly coercive precedent. Many of the relevant issues have in socioeconomic achievement, from good and raises special issues of privacy and liberty been addressed in legislation such as nutrition to high-quality schools, neuro- that will not be discussed here. Finally, the Connecticut’s Statute “Policies regarding the cognitive enhancement could prove easier to ethical problems that are involved in parental recommendation of psychotropic drugs by distribute equitably. decision-making on behalf of minor children school personnel”23 and case law such as are complex and enter into the ethics of Valerie versus Derry Cooperative School Personhood and intangible values. Enhancing neurocognitive enhancement in school District24. psychological function by brain intervention children, but will not be discussed here. is in some ways like improving a car’s perfor- The remaining issues can be classified and mance by making adjustments to the engine. enumerated in various ways. Four general “What if keeping one’s job In both cases the goal is to improve function, categories will be used here to organize and to the extent that we succeed without our discussion of the ethical challenges of or remaining in one’s compromising safety, freedom of choice or neurocognitive enhancement and possible school depends on fairness we can view the result as good. But societal responses. in other ways the two are very different, practicing neurocognitive because modifying brains, unlike engines, Safety. The idea of neurocognitive enhance- enhancement?” affects persons. The fourth category of ethical ment evokes unease in many people, and one issue encompasses the many ways in which source of the unease is concern about safety. neurocognitive enhancement intersects Safety is a concern with all medications and Of course, coercion need not be explicit. with our understanding of what it means procedures, but our tolerance for risk is Merely competing against enhanced co- to be a person, to be healthy and whole, to smallest when the treatment is purely elec- workers or students exerts an incentive to use do meaningful work, and to value human life tive. Furthermore, in comparison to other neurocognitive enhancement, and it is harder in all its imperfection. The recent report comparably elective treatments such as cos- to identify any existing legal framework for of the President’s Council on Bioethics25 metic surgery, neurocognitive enhancement protecting people against such incentives to emphasizes these issues in its discussion of involves intervening in a far more complex compete. But would we even want to? enhancement. system, and we are therefore at greater risk of The straightforward legislative approach of Attempts to derive policies from these unanticipated problems. Would endowing outlawing or restricting the use of neuro- considerations must contend with the contra- learners with super-memory interfere with cognitive enhancement in the workplace or in dictory ways in which different values are their ability to understand what they have school is itself also coercive. It denies people both challenged and affirmed by neuro- learned and relate it to other knowledge? the freedom to practice a safe means of self- cognitive enhancement. For example, we Might today’s Ritalin users face an old age of improvement, just to eliminate any negative generally view self-improvement as a laudable premature cognitive decline? The possibility consequences of the (freely taken) choice not goal. At the same time, improving our natural of hidden costs of neurocognitive enhance- to enhance. endowments for traits such as attention span ment might be especially salient because of runs the risk of commodifying them. We our mistrust of unearned rewards, and the Distributive justice. It is likely that neuro- generally encourage innovations that save sense that such opportunities can have cognitive enhancement, like most other time and effort, because they enable us to be Faustian results. things, will not be fairly distributed. Ritalin more productive and to direct our efforts With any drug, whether for therapy or use by normal healthy people is highest towards potentially more worthy goals. enhancement, we can never be absolutely among college students, an overwhelmingly However, when we improve our productivity certain about the potential for subtle, rare or middle-class and privileged segment of the by taking a pill, we might also be under- long-term side effects. Instead, our regulatory population. There will undoubtedly be cost mining the value and dignity of hard work,

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© 2004 Nature Publishing Group PERSPECTIVES medicalizing human effort and pathologizing a opportunities to learn self-discipline, or could We admit to being less certain about the normal attention span. The self-transformation it in fact have no effect or even help us in right course of action. With respect to the first that we effect by neurocognitive intervention some way? Until we have disentangled the three categories of issue, concerning safety, can be seen as self-actualizing, or as eroding a priori from the empirical claims, and evalu- freedom and fairness, current laws and cus- our personal identity. Neither the benefits nor ated the empirical claims more thoroughly, toms already go a long way towards protecting the dangers of neurocognitive enhancement we are at risk of making wrong choices. society. With respect to the fourth category of are trivial. issue, we believe that there is much more In weighing the dangers of neurocognitive ‘spade work’ (in Fukuyama’s words) to be enhancement against its benefits, it is impor- “The question is therefore not done in sorting out the moral and social tant to note the many ways in which similar implications of neurocognitive enhancement tradeoffs are already present in our society. whether we need policies to before we move from recommendations to For example, the commodification of human govern neurocognitive legislation. We should draw an object lesson talent is not unique to Ritalin-enhanced enhancement, but rather what from the history of federal stem cell legis- executive ability. It is probably more baldly on lation in the USA, which was enacted hastily display in books and classes that are designed kind of policies we need.” in the wake of reported attempts at human to prepare preschoolers for precocious reproductive cloning with limited public reading, music or foreign language skills, understanding of the issues. That legislation is but many loving parents seek out such When not to decide is to decide. Neurocognitive now viewed by many as a setback for respon- enrichment for their children. Americans enhancement is already a fact of life for many sible biomedical research, and two states have admire the effort that was expended in people. Market demand, as measured by sales now enacted their own laws to permit a wider Abraham Lincoln’s legendary four-mile of nutritional supplements that promise cog- range of research activity. walk to school every day, but no-one would nitive enhancement, and ongoing progress in The need for more discussion of the issues do that (or want their child to do that) if a psychopharmacology portend a growing is a predictable conclusion for an article bus ride were available. Medicalization has number of people practicing neurocognitive like this one, but nevertheless a valid one. accompanied many improvements in human enhancement in the coming years. In terms One urgent topic for discussion is the role of life, including improved nutrition and family of policy, we will soon reach the point where physicians in neurocognitive enhancement 27. planning. And if we are not the same person not to decide is to decide. Continuing Although western medicine has traditionally on Ritalin as off, neither are we the same our current laissez-faire approach, with indi- focused on therapy rather than enhancement, person after a glass of wine as before, or on viduals relying on their physicians or illegal exceptions are well established. Cosmetic vacation as before an exam. As these examples suppliers for neurocognitive enhancement, surgery is the most obvious example, but show, many of our ‘lifestyle’ decisions end up risks running afoul of public opinion, drug dermatology, sports medicine and fertility on the right side of one value and the wrong laws and physicians’ codes of ethics. The treatments also include enhancement among side of another, but this does not necessarily question is therefore not whether we need their goals. Enabling a young woman to mean that these decisions are wrong. policies to govern neurocognitive enhance- bank her eggs to allow later childbearing, for ment, but rather what kind of policies we example, is not therapeutic but enhancing. Disentangling moral principle and empirical need. The choices range from minimal mea- Will neurocognitive enhancement join these fact. Since pre-Socratic times, philosophers sures, such as raising public awareness of the practices? If so, will it be provided by specialists have sought ways of systematizing our ethical potential practical and moral difficulties of or family practitioners? What responsibility intuitions, to identify a set of guiding princi- neurocognitive enhancement, to the whole- will physicians take for the social and psycho- ples that could be applied in any situation to sale enacting of new laws and the creation of logical impact of the enhancements they dictate the right course of action. All of us new regulatory agencies. In between these prescribe, and by what means (for example, have ethical intuitions about most situations; extremes lie a host of other options, for informal or formal psychological screening one goal of ethics is to replace case-by- example the inclusion of neurocognitive as used by cosmetic surgeons or fertility case intuitions with principled decisions. enhancement policies in codes of ethics of specialists)? A practical social advantage of ethical princi- the professional organizations of physicians, Beyond these immediate practical issues, ples is that they can provide guidance when scientists, human resource managers and we must clarify the intangible ethical issues intuitions are unclear or inconsistent from educators, and short-term moratoria on that apply to neurocognitive enhancement. person to person. The success of an ethical neurocognitive enhancement. This requires interdisciplinary discussion, discussion depends on the discussants’ ability Francis Fukuyama26 has argued for new with neuroscientists available to identify the to articulate the relevant principles as well as legislation to control the use of neurocogni- factual assumptions that are implicit in the relevant facts about a situation to which tive enhancement, among other biotechnolo- the arguments for and against different the principles apply. gies. He characterizes the work of groups such positions, and ethicists available to articulate In the ethics of neurocognitive enhance- as the President’s Council on Bioethics in the the fundamental moral principles that apply. ment we are still feeling our way towards the USA and the European Group on Ethics in As a society we are far from understanding relevant principles and we still have much to Science and New Technology as the “intellec- the facts and identifying the relevant princi- learn about the relevant facts. Is it a matter of tual spade work of thinking through the ples. With many of our college students principle that ‘medicalization’ is bad, or that moral and social implications of biomedical already using stimulants to enhance executive hard work confers ‘dignity’? Or are these research”,and suggests that “it is time to move function and the pharmaceutical industry moral heuristics, rules of thumb that might from thinking to acting, from recommending soon to be offering an array of new memory- be contradicted in some cases? And is it to legislating. We need institutions with real enhancing drugs, the time to begin this a matter of fact that Ritalin reduces our enforcement powers.” discussion is now.

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This paper is based, in part, on a meeting held at the New York Eric Kandel is at the Center for Neurobiology and Nature Neurosci. 5, 1123–1129 (2002). Academy of Sciences in June 2003, supported by a grant to J.I. Behavior, Columbia University and Howard 10. Farah, M. J. & Wolpe, P. R. Monitoring and manipulating from the National Science Foundation with co-sponsorship of a Hughes Medical Institute, 1051 Riverside Drive, brain function: new neuroscience technologies and their Mushett Family Foundation grant to the Academy. The writing of New York, New York 10032, USA ethical implications. Hastings Center Report (in the press). this paper was supported by NSF and NIH grants to M.J.F. and 11. Rose, S. P. R. ‘Smart drugs’: do they work? Are they an NIH grant and a Greenwald Foundation grant to J.I. Patricia King is at the Georgetown University Law ethical? Will they be legal? Nature Rev. Neurosci. 3, Center, 600 New Jersey Avenue, 975–979 (2002). Competing interests statement NW Washington DC 20001, USA 12. Lynch, G. Memory enhancement: the search for The authors declare competing financial interests: see Web version mechanism-based drugs. Nature Neurosci. 5, for details. Eric Parens is at the The Hastings Center, 1035–1038 (2002). 21 Malcolm Gordon Drive, Garrison, 13. Craik, F. I. M. & Salthouse, T. A. The Handbook of Aging and Cognition (Lawrence Erlbaum, Hillsdale, New Jersey, Online links New York 10524-5555, USA 1992). Barbara Sahakian is at the Department of 14. Yesavage, J. A. et al. Donepezil and flight simulator FURTHER INFORMATION Psychiatry, University of Cambridge, performance: effects on retention of complex skills. Martha Farah’s homepage: Neurology 59, 123–125 (2002). http://www.psych.upenn.edu/~mfarah/ Addenbrooke’s Hospital (Box 189), 15. Pittman, R. K. et al. Pilot study of secondary prevention Judy Illes’s homepage: http://neuroethics.stanford.edu Cambridge CB2 2QQ, UK of posttraumatic stress disorder with propranolol. Biol. Howard Gardner’s homepage: Paul Root Wolpe is at the Departments of Psychiatry 15, 189–192 (2002). http://www.pz.harvard.edu/PIs/HG.htm 16. Mehta, M. A. et al. Methylphenidate enhances working Eric Kandel’s laboratory: Psychiatry, Medical Ethics, and Sociology, Center memory by modulating discrete frontal and parietal lobe http://www.erickandel.org/erickandel/ for Bioethics, University of Pennsylvania, regions in the human brain. J. Neurosci. 20, RC65 (2000). Patricia King’s homepage: 3401 Market Street, Philadelphia, 17. Elliott, R. et al. Effects of methylphenidate on spatial http://www.temple.edu/commsci/faculty_king.htm Pennsylvania 19104-3319, USA working memory and planning in healthy young adults. Barbara Sahakian’s homepage: Psychopharmacology 131, 196–206 (1997). http://www.psychiatry.cam.ac.uk/pages/profiles/sahakian.html Correspondence to M.J.F. or J.I. 18. Kimberg, D. Y., D’Esposito, M. & Farah, M. J. Effects of Paul Root Wolpe: e-mails: [email protected]; bromocriptine on human subjects depend on working http://www.bioethics.upenn.edu/faculty/index.php?profile=20 [email protected] memory capacity. Neuroreport 8, 3581–3585 (1997). NYAS e-briefing on neuroethics: 19. Teitelman, E. Off-label uses of modafinil. Am. www.nyas.org/ebrief/neuroethics doi: 10.1038/nrn1390 J. Psychiatry 158, 1341 (2001). Access to this interactive links box is free online.

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