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12-7-2008

Towards responsible use of cognitive-enhancing drugs by the healthy

Henry Greely University of Stanford, [email protected]

Philip Campbell .com, [email protected]

Barbara Sahakian , [email protected]

John Harris University of Manchester, [email protected]

Ronald C. Kessler Harvard Medical School

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Recommended Citation Greely, H., Campbell, P., Sahakian, B., Harris, J., Kessler, R., Gazzaniga, M., & Farah, M. J. (2008). Towards responsible use of cognitive-enhancing drugs by the healthy. Retrieved from https://repository.upenn.edu/ neuroethics_pubs/42

Reprinted from Nature, December 2008. Publisher URL: http://dx.doi.org/10.1038/456702a

This paper is posted at ScholarlyCommons. https://repository.upenn.edu/neuroethics_pubs/42 For more information, please contact [email protected]. Towards responsible use of cognitive-enhancing drugs by the healthy

Abstract In this article, we propose actions that will help society accept the benefits of enhancement, given appropriate research and evolved regulation. Prescription drugs are regulated as such not for their enhancing properties but primarily for considerations of safety and potential abuse. Still, cognitive enhancement has much to offer individuals and society, and a proper societal response will involve making enhancements available while managing their risks.

Keywords cognitive neuroscience, enhancement,

Disciplines Pharmacology

Comments Reprinted from Nature, December 2008. Publisher URL: http://dx.doi.org/10.1038/456702a

Author(s) Henry Greely, Philip Campbell, Barbara Sahakian, John Harris, Ronald C. Kessler, Michael Gazzaniga, and Martha J. Farah

This journal article is available at ScholarlyCommons: https://repository.upenn.edu/neuroethics_pubs/42 Advance Online Publication|doi:10.1038/456702a|Published online 7 December 2008 COMMENTARY Towards responsible use of cognitive- enhancing drugs by the healthy Society must respond to the growing demand for cognitive enhancement. That response must start by rejecting the idea that ‘enhancement’ is a dirty word, argue Henry Greely and colleagues.

oday, on university campuses around the world, students are striking deals to Tbuy and sell prescription drugs such as Adderall and Ritalin — not to get high, but to get higher grades, to provide an edge over their C. GALLAGHER/SPL fellow students or to increase in some meas- urable way their capacity for learning. These transactions are crimes in the United States, punishable by prison. Many people see such penalties as appro- priate, and consider the use of such drugs to be cheating, unnatural or dangerous. Yet one survey1 estimated that almost 7% of students in US universities have used prescription stimu- lants in this way, and that on some campuses, Adderall is one of several drugs up to 25% of students had used them in the increasingly used to enhance past year. These students are early adopters of cognitive function. a trend that is likely to grow, and indications suggest that they’re not alone2. In this article, we propose actions that will campus to divert to enhancement use. be proven safe and effective, but if one is it will help society accept the benefits of enhance- A newer drug, modafinil (Provigil), has also surely be sought by healthy middle-aged and ment, given appropriate research and evolved shown enhancement potential. Modafinil is elderly people contending with normal age- regulation. Prescription drugs are regulated as approved for the treatment of fatigue caused by related memory decline, as well as by people such not for their enhancing properties but pri- narcolepsy, sleep apnoea and shift-work sleep of all ages preparing for academic or licensure marily for considerations of safety and potential disorder. It is currently prescribed off label for a examinations. abuse. Still, cognitive enhancement has much wide range of neuropsychiatric and other medi- to offer individuals and society, and a proper cal conditions involving fatigue5 as well as for Favouring innovation societal response will involve making enhance- healthy people who need to stay alert and awake Human ingenuity has given us means of enhanc- ments available while managing their risks. when sleep deprived, such as physicians on night ing our brains through inventions such as writ- call6. In addition, laboratory studies have shown ten language, printing and the Internet. Most Paths to enhancement that modafinil enhances aspects of executive authors of this Commentary are teachers and Many of the medications used to treat psychi- function in rested healthy adults, particularly strive to enhance the minds of their students, atric and neurological conditions also improve inhibitory control7. Unlike Adderall and Rita- both by adding substantive information and by the performance of the healthy. The drugs most lin, however, modafinil prescriptions are not showing them new and better ways to process commonly used for cognitive enhancement at common, and the drug is consequently rare on that information. And we are all aware of the present are stimulants, namely Ritalin (methy- the college black market. But anecdotal evidence abilities to enhance our brains with adequate phenidate) and Adderall (mixed amphetamine and a readers’ survey both suggest that adults exercise, nutrition and sleep. The drugs just salts), and are prescribed mainly for the treat- sometimes obtain modafinil from their physi- reviewed, along with newer technologies such ment of attention deficit hyperactivity disorder cians or online for enhancement purposes2. as brain stimulation and prosthetic brain chips, (ADHD). Because of their effects on the cat- A modest degree of memory enhancement should be viewed in the same general category echolamine system, these drugs increase exec- is possible with the ADHD medications just as education, good health habits, and informa- utive functions in patients and most healthy mentioned as well as with medications devel- tion technology — ways that our uniquely inno- normal people, improving their abilities to oped for the treatment of Alzheimer’s disease vative species tries to improve itself. focus their attention, manipulate information such as Aricept (donepezil), which raise levels Of course, no two enhancements are equiva- in working memory and flexibly control their of acetylcholine in the brain8. Several other lent in every way, and some of the differences responses3. These drugs are widely used thera- compounds with different pharmacological have moral relevance. For example, the ben- peutically. With rates of ADHD in the range of actions are in early clinical trials, having shown efits of education require some effort at self- 4–7% among US college students using DSM positive effects on memory in healthy research improvement whereas the benefits of sleep do criteria4, and stimulant medication the stand- subjects (see, for example, ref. 9). It is too early not. Enhancing by nutrition involves changing ard therapy, there are plenty of these drugs on to know whether any of these new drugs will what we ingest and is therefore invasive in a way

702 NATURE|Advance Online Publication|doi:10.1038/456702a|Published online 7 December 2008 OPINION

that reading is not. The opportunity to benefit presumption that mentally competent adults ceutical enhancement as well? And if we answer from Internet access is less equitably distributed should be able to engage in cognitive enhance- ‘no’ to this question, could coercion occur indi- than the opportunity to benefit from exercise. ment using drugs. rectly, by the need to compete with enhanced Cognitive-enhancing drugs require relatively classmates and colleagues? little effort, are invasive and for the time being Substantive concerns and policy goals Questions of coercion and autonomy are are not equitably distributed, but none of these All technologies have risks as well as benefits. particularly acute for military personnel and provides reasonable grounds for prohibition. Although we reject the arguments against for children. Soldiers in the United States Drugs may seem distinctive among enhance- enhancement just reviewed, we recognize at and elsewhere have long been offered stimu- ments in that they bring about their effects by least three substantive ethical concerns. lant medications including amphetamine altering brain function, but in reality so does any The first concern is safety. Cognitive enhance- and modafinil to enhance alertness, and in intervention that enhances cognition. Recent ments affect the most complex and important the United States are legally required to take research has identified beneficial neural changes human organ, and the risk of unintended side medications if ordered to for the sake of their engendered by exercise10, nutrition11 and sleep12, effects is therefore both high and consequen- military performance19. For similar reasons, as well as instruction13 and reading14. In short, tial. Although regulations governing medicinal namely the safety of the individual in question cognitive-enhancing drugs seem morally equiv- drugs ensure that they are safe and effective for and others who depend on that individual in alent to other, more familiar, enhancements. their therapeutic indications, there is no equiv- dangerous situations, one could imagine other Many people have doubts about the moral alent vetting for unregulated ‘off label’ uses, occupations for which enhancement might be status of enhancement drugs for reasons rang- including enhancement uses. Furthermore, justifiably required. A hypothetical example is ing from the pragmatic to the philosophical, acceptable safety in this context depends on an extremely safe drug that enabled surgeons including concerns about short-circuiting the potential benefit. For example, a drug that to save more patients. Would it be wrong to personal agency and undermining the value of restored good cognitive functioning to people require this drug for risky operations? human effort15. Kass16, for example, has written with severe but caused serious adverse Appropriate policy should prohibit coercion of the subtle but, in his view, important differ- medical events might be deemed safe enough to except in specific circumstances for specific ences between human enhancement through prescribe, but these risks would be unacceptable occupations, justified by substantial gains in biotechnology and through more traditional for healthy individuals seeking enhancement. safety. It should also discourage indirect coer- means. Such arguments have been persuasively Enhancement in children raises additional cion. Employers, schools or governments rejected (for example, ref. 17). Three arguments issues related to the long-term effects on the should not generally require the use of cog- against the use of cognitive enhancement by developing brain. Moreover, the possibility of nitive enhancements. If particular enhance- the healthy quickly bubble to the surface in raising cognitive abilities beyond their spe- ments are shown to be sufficiently safe and most discussions: that it is cheating, that it is cies-typical upper bound may engender new effective, this position might be revisited for unnatural and that it amounts to drug abuse. classes of side effects. Persistence of unwanted those interventions. In the context of sports, pharmacological recollections, for example, has clearly negative Children once again represent a special case performance enhancement is effects on the psyche18. as they cannot make their own decisions. Com- indeed cheating. But, of course, “We should welcome An evidence-based approach parisons between estimates of ADHD preva- it is cheating because it is new methods of is required to evaluate the lence and prescription numbers have led some against the rules. Any good set risks and benefits of cogni- to suspect that children in certain school dis- of rules would need to distin- improving our brain tive enhancement. At a mini- tricts are taking enhancing drugs at the behest guish today’s allowed cognitive function.” mum, an adequate policy of achievement-oriented parents, or teachers enhancements, from private should include mechanisms seeking more orderly classrooms20. Govern- tutors to double espressos, from the newer for the assessment of both risks and benefits for ments may be willing to let competent adults methods, if they are to be banned. enhancement uses of drugs and devices, with take certain risks for the sake of enhancement As for an appeal to the ‘natural’, the lives of special attention to long-term effects on devel- while restricting the ability to take such risky almost all living humans are deeply unnatural; opment and to the possibility of new types of decisions on behalf of children. our homes, our clothes and our food — to say side effects unique to enhancement. But such The third concern is fairness. Consider an nothing of the medical care we enjoy — bear considerations should not lead to an insist- examination that only a certain percentage little relation to our species’ ‘natural’ state. ence on higher thresholds than those applied to can pass. It would seem unfair to allow some, Given the many cognitive-enhancing tools we medications. but not all, students to use cognitive enhance- accept already, from writing to laptop comput- We call for an evidence-based approach to ments, akin to allowing some students taking a ers, why draw the line here and say, thus far but the evaluation of the risks and benefits of cog- maths test to use a calculator while others must no further? nitive enhancement. go without. (Mitigating such unfairness may As for enhancers’ status as drugs, drug abuse The second concern is freedom, specifically raise issues of indirect coercion, as discussed is a major social ill, and both medicinal and freedom from coercion to enhance. Forcible above.) Of course, in some ways, this kind of recreational drugs are regulated because of medication is generally reserved for rare cases in unfairness already exists. Differences in edu- possible harms to the individual and society. which individuals are deemed threats to them- cation, including private tutoring, preparatory But drugs are regulated on a scale that subjec- selves or others. In contrast, cognitive enhance- courses and other enriching experiences give tively judges the potential for harm from the ment in the form of education is required for some students an advantage over others. very dangerous (heroin) to the relatively harm- almost all children at some substantial cost to Whether the cognitive enhancement is less (caffeine). Given such regulation, the mere their liberty, and employers are generally free to substantially unfair may depend on its avail- fact that cognitive enhancers are drugs is no require employees to have certain educational ability, and on the nature of its effects. Does it reason to outlaw them. credentials or to obtain them. Should schools actually improve learning or does it just tem- Based on our considerations, we call for a and employers be allowed to require pharma- porarily boost exam performance? In the latter

703 OPINION NATURE|Advance Online Publication|doi:10.1038/456702a|Published online 7 December 2008

case it would prevent a valid measure of the policy that is neither laissez-faire nor prima- as when a patient says “I know I don’t meet diag- competency of the examinee and would rily legislative. We propose to use a variety of nostic criteria for ADHD, but I sometimes have therefore be unfair. But if it were to enhance scientific, professional, educational and social trouble concentrating and staying organized, long-term learning, we may be more willing resources, in addition to legislation, to shape and it would help me to have some Ritalin on to accept enhancement. After all, unlike ath- a rational, evidence-based policy informed hand for days when I really need to be on top of letic competitions, in many cases cognitive by a wide array of relevant experts and stake- things at work.” Physicians who view medicine enhancements are not zero-sum games. Cog- holders. Specifically, we propose four types of as devoted to healing will view such prescribing nitive enhancement, unlike enhancement for policy mechanism. as inappropriate, whereas those who view medi- sports competitions, could lead to substantive The first mechanism is an accelerated cine more broadly as helping patients live better improvements in the world. programme of research to build a knowledge or achieve their goals would be open to consid- Fairness in cognitive enhancements has a base concerning the usage, benefits and asso- ering such a request22. There is certainly a prec- dimension beyond the individual. If cognitive ciated risks of cognitive enhancements. Good edent for this broader view in certain branches enhancements are costly, they may become the policy is based on good information, and there of medicine, including plastic surgery, derma- province of the rich, adding to the educational is currently much we do not know about the tology, sports medicine and fertility medicine. advantages they already enjoy. One could miti- short- and long-term benefits and risks of the Because physicians are the gatekeepers to gate this inequity by giving every exam-taker cognitive-enhancement drugs currently being medications discussed here, society looks to free access to cognitive enhancements, as some used, and about who is using them and why. For them for guidance on the use of these medica- schools provide computers during exam week example, what are the patterns of use outside of tions and devices, and guidelines from other to all students. This would help level the play- the United States and outside of college commu- professional groups will need to take into ing field. nities? What are the risks of dependence when account the gatekeepers’ policies. For this rea- Policy governing the use of cognitive used for cognitive enhancement? What special son, the responsibilities that physicians bear for enhancement in competitive situations should risks arise with the enhancement of children’s the consequences of their decisions are particu- avoid exacerbating socioeconomic inequali- cognition? How big are the effects of currently larly sensitive, being effectively decisions for all ties, and should take into account the validity available enhancers? Do they change ‘cogni- of us. It would therefore be helpful if physicians of enhanced test performance. In developing tive style’, as well as increasing how quickly as a profession gave serious consideration to policy for this purpose, problems of enforce- and accurately we think? And given that most the ethics of appropriate prescribing of cogni- ment must also be considered. In spite of strin- research so far has focused on simple laboratory tive enhancers, and consulted widely as to how gent regulation, athletes continue to use, and be tasks, how do they affect cognition in the real to strike the balance of limits for patient benefit caught using, banned performance-enhancing world? Do they increase the total knowledge and protection in a liberal democracy. Exam- drugs. and understanding that students take with ples of such limits in other areas of enhancement We call for enforceable policies concern- them from a course? How do they affect various medicine include the psychological screening of ing the use of cognitive-enhancing drugs to aspects of occupational performance? candidates for cosmetic surgery or tubal ligation, support fairness, protect individuals from We call for a programme of research into the and upper bounds on maternal age or number coercion and minimize enhancement-related use and impacts of cognitive-enhancing drugs of embryos transferred in fertility treatments. socioeconomic disparities. by healthy individuals. These examples of limits may not be specified by The second mechanism is the participa- law, but rather by professional standards. Maximum benefit, minimum harm tion of relevant professional organizations Other professional groups to which this The new methods of cognitive enhance- in formulating guidelines for their recommendation applies include educators ment are ‘disruptive technologies’ members in relation to cognitive and human-resource professionals. In differ- SPL that could have a profound enhancement. Many dif- ent ways, each of these professions has respon- effect on human life in the ferent professions have a sibility for fostering and evaluating cognitive twenty-first century. A role in dispensing, using performance and for advising individuals who laissez-faire approach or working with peo- are seeking to improve their performance, and to these methods will ple who use cognitive some responsibility also for protecting the leave us at the mercy enhancers. By creating interests of those in their charge. In contrast of powerful market policy at the level of to physicians, these professionals have direct forces that are bound professional societies, conflicts of interest that must be addressed in to be unleashed by the it will be informed by whatever guidelines they recommend: liberal promise of increased the expertise of these use of cognitive enhancers would be expected productivity and competi- professionals, and their to encourage classroom order and raise stand- tive advantage. The concerns commitment to the goals of ardized measures of student achievement, both about safety, freedom and fair- their profession. of which are in the interests of schools; it would ness, just reviewed, may well One group to which this also be expected to promote workplace produc- seem less important than the The prescription drug Ritalin is recommendation applies is tivity, which is in the interests of employers. attractions of enhancement, illegally traded among students. physicians, particularly in Educators, academic admissions officers and for sellers and users alike. primary care, paediatrics and credentials evaluators are normally responsible Motivated by some of the same considera- psychiatry, who are most likely to be asked for for ensuring the validity and integrity of their tions, Fukuyama21 has proposed the formation cognitive enhancers. These physicians are some- examinations, and should be tasked with for- of new laws and regulatory structures to protect times asked to prescribe for enhancement by mulating policies concerning enhancement by against the harms of unrestrained biotechno- patients who exaggerate or fabricate symptoms test-takers. Laws pertaining to testing accom- logical enhancement. In contrast, we suggest a of ADHD, but they also receive frank requests, modations for people with disabilities provide

704 NATURE|Advance Online Publication|doi:10.1038/456702a|Published online 7 December 2008 OPINION

John Harris is at the Institute for Science, Ethics and Innovation, and Wellcome Strategic Programme in The Human Body, its Scope, Limits and Future, University of Manchester, Oxford

MIKA/ZEFA/CORBIS Road, Manchester M13 9PL, UK. e-mail: [email protected] Ronald C. Kessler is at Harvard Medical School, Department of Health Care Policy, 180 Longwood Avenue, Boston, Massachusetts 02115-5899, USA. e-mail: [email protected] Michael Gazzaniga is at the Sage Center for the Study of Mind, University of California, Santa Barbara, California 93106-9660, USA. e-mail: [email protected] Philip Campbell is at Nature, 4 Crinan St, London When should cognitive-enhancing N1 9XW, UK. drugs be permitted in the classroom? e-mail: [email protected] Martha J. Farah is at the Center for Cognitive a starting point for discussion of some of the would be naive to expect rapid or revolutionary Neuroscience, University of Pennsylvania, key issues, such as how and when enhance- change in the laws governing the use of control- 3720 Walnut Street, Room B51, Philadelphia, ments undermine the validity of a test result led substances. Nevertheless, these laws should Pennsylvania 19104-6241, USA. and the conditions under which enhancement be adjusted to avoid making felons out of those e-mail: [email protected] should be disclosed by a test-taker. who seek to use safe cognitive enhancements. The labour and professional organizations And regulatory agencies should allow phar- 1. McCabe, S. E., Knight, J. R., Teter, C. J. & Wechsler, H. Addiction 100, 96–106 (2005). of individuals who are candidates for on-the- maceutical companies to market cognitive- 2. Maher, B. Nature 452, 674–675 (2008). job cognitive enhancement make up our final enhancing drugs to healthy adults provided 3. Sahakian, B. & Morein-Zamir, S. Nature 450, 1157–1159 category of organization that should formu- they have supplied the necessary regulatory (2007). 4. Weyandt, L. L & DuPaul, G. J. Atten. Disord. 10, 9–19 (2006). late enhancement policy. From assembly line data for safety and efficacy. 5. Minzenberg, M. J. & Carter, C. S. Neuropsychopharmacology workers to surgeons, many different kinds of We call for careful and limited legislative 33, 1477–1502 (2008). employee may benefit from enhancement and action to channel cognitive-enhancement 6. Vastag, B. J. Am. Med. Assoc. 291, 167–170 (2004). 7. Turner, D. C. et al. 165, 260–269 (2003). want access to it, yet they may also need protec- technologies into useful paths. 8. Grön, G., Kirstein, M., Thielscher, A., Riepe, M. W. & tion from the pressure to enhance. Spitzer, M. Psychopharmacology 182, 170–179 (2005). We call for physicians, educators, regulators Conclusion 9. Lynch, G. & Gall C. M. Trends Neurosci. 29, 554–562 (2006). and others to collaborate in developing poli- Like all new technologies, cognitive enhance- 10. Hillman, C. H., Erikson, K. I. & Kramer, A. F. Nature Rev. Neurosci. 9, 58-65 (2008). cies that address the use of cognitive-enhanc- ment can be used well or poorly. We should 11. Almeida, S. S. et al. Nutr. Neurosci. 5, 311–320 (2002). ing drugs by healthy individuals. welcome new methods of improving our brain 12. Boonstra, T. W., Stins, J. F., Daffertshofer, A. & Beek, P. J. The third mechanism is education to function. In a world in which human work- Cell. Mol. Life Sci. 64, 934–946 (2007). 13. Draganski, B. et al. Nature 427, 311–312 (2004). increase public understanding of cognitive spans and lifespans are increasing, cognitive 14. Schlaggar, B. L. & McCandliss, B. D. Annu. Rev. Neurosci. 30, enhancement. This would be pro- enhancement tools — including 475–503 (2007). vided by physicians, teachers, col- “Many kinds of the pharmacological — will be 15. Farah, M. J. et al. Nature Rev. Neurosci. 5, 421–425 (2004). 16. Kass, L. R. et al. Beyond Therapy: Biotechnology and the Pursuit lege health centres and employers, employee may increasingly useful for improved of Happiness (President’s Council on Bioethics, 2003); similar to the way that information quality of life and extended work available at www.bioethics.gov/reports/beyondtherapy. about nutrition, recreational drugs benefit from productivity, as well as to stave 17. Harris, J. Enhancing Evolution: The Ethical Case for Making Better People (Princeton Univ. Press, 2007). and other public-health informa- enhancement.” off normal and pathological age- 18. Schacter, D. L. Seven Sins of Memory (Houghton Mifflin, 23 tion is now disseminated. Ideally it related cognitive declines . Safe 2002). would also involve discussions of different ways and effective cognitive enhancers will benefit 19. Moreno, J. D. Mind Wars: Brain Research and National Defense (Dana Press, 2006). of enhancing cognition, including through both the individual and society. 20. Diller, L. H. Hastings Cent. Rep. 26, 12–18 (1996). adequate sleep, exercise and education, and an But it would also be foolish to ignore prob- 21. Fukuyama, F. Our Posthuman Future: Consequences of the examination of the social values and pressures lems that such use of drugs could create or Biotechnology Revolution (Farrar, Straus and Giroux, 2002). that make cognitive enhancement so attractive exacerbate. With this, as with other technolo- 22. Chatterjee, A. Neurology 63, 968–974 (2004). 23. Beddington, J. et al. Nature 455, 1057–1060 (2008). and even, seemingly, necessary. gies, we need to think and work hard to maxi- We call for information to be broadly mize its benefits and minimize its harms. ■ Acknowledgement This article is the result of a Henry Greely is at Stanford Law School, Crown seminar held by the authors at Rockefeller University. disseminated concerning the risks, benefits Funds for the seminar were provided by Rockefeller and alternatives to pharmaceutical cognitive Quadrangle, 559 Nathan Abbott Way, Stanford, University and Nature. enhancement. California 94305-8610, USA. Competing interests B.S. consults for a number of The fourth mechanism is legislative. Funda- e-mail: [email protected] pharmaceutical companies and Cambridge Cognition, mentally new laws or regulatory agencies are Barbara Sahakian is at the Department of and holds shares in CeNeS. R.C.K. consults for and not needed. Instead, existing law should be Psychiatry, University of Cambridge, and has received grants from a number of pharmaceutical brought into line with emerging social norms MRC/ Behavioural and Clinical companies. and information about safety. Drug law is one Neuroscience Institute, Cambridge, UK. Join the debate on this topic at Nature Network of the most controversial areas of law, and it e-mail: [email protected] ➧ http://tinyurl.com/6nyu29

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