Drugs for enhancing cognition and their ethical implications: a hot new cup of tea

The increasing availability of drugs designed to restore mental function in patients with cognitive disorders has introduced the ethical question of whether they should also be used for the purposes of cognitive enhancement in healthy people.

Interest in the prospects of cognitive enhancement has focused traditionally on stimulants. Their attractiveness traverses the history of many cultures. The oldest may be tea, which was relished in China as early as 2700 BC. The popularity of tea, and the fortunes its trade has commanded, arose as much from its stimulant properties as its pleasant aroma. Today, the more strongly caffeinated brews of coffee are filling cups worldwide in a market estimated at US$70 billion [101]. Many tea and coffee drinkers enjoy the feeling of enhanced alertness associated with these flavorful herbal sources of caffeine. Caffeine, which inhibits adenosine transmission in the basal ganglia, is the most widely used psychoactive substance [1] and has been shown to increase alertness, reduce fatigue and improve performance on tasks requiring vigilance [2].

Current neuropharmacology is surpassing caffeine. Advances in neuroscience have led to the development of an assortment of drugs useful for treating dysregulated attention, memory and motivation. A number of prescription drugs, for example, are well established for the treatment of attention deficit hyperactivity disorder (ADHD) [3]. The brain stimulants methylphenidate (Ritalin^®, Equasym^® and Concerta^®), which upregulates dopamine, combinations of dextroamphetamine and amphetamine (Adderall^® and Dexedrine^®), and the nonstimulant atomoxetine (Straterra^®), a norepinephrine reuptake inhibitor, have been shown to improve psychological, social, academic and professional functioning in patients with ADHD [3].

Although prescription stimulants are intended and licensed for the treatment of specific cognitive disorders, surveys and sales figures suggest that they are also being diverted to healthy individuals for enhancement purposes. University students in increasing numbers are turning to methylphenidate, in particular, as a convenient means to intensify mental focus, stay awake through the night to prolong studying, or otherwise gain a competitive academic edge [4–6]. This pattern of misuse raises questions of longterm safety, academic fairness and what value should be placed on mental performance.

Some new drugs target sleep neurophysiology. One question these drugs raise is whether pharmacological means are the best way to achieve the laudable goal of preventing vehicular accidents or professional error caused by drowsiness in the absence of a neurological disorder that impairs alertness. The wakefulness-promoting agent modafinil (Provigil^®) is licensed for the treatment of excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea and shiftwork sleep disorder. Some 90% of prescriptions for modafinil, however, are being written for off-label uses such as jet lag, depression, nonspecific symptoms of fatigue, tiredness, lack of energy or as an occasional substitute for sleep among busy professionals [102]. Following warnings from the US FDA that its manufacturer has promoted modafinil for unapproved uses [103], the Cephalon website still invites patients to talk to their doctor about excessive sleepiness [104]. The power of suggestion of a way to a more energetic lifestyle in advertising to physicians and in direct marketing to patients should not be underestimated. If the interests of the pharmaceutical industry and its stockholders were invariably confined to drug applications that most benefited patients, there would be less need for such persuasion through marketing.

Neuroscience has an ethical obligation to pursue research that seeks to supply the means to help patients from whom dementia has robbed their cognitive faculties. Thus, a committed effort is underway to find drugs that can improve memory. Acetylcholinesterase inhibitors, such as donepezil (Aricept^®), galantamine (Reminyl^®) and rivastigmine (Exelon^®), and the N-methly-D-aspartate (NMDA) receptor antagonist memantine (Namenda^®, Ebixa^®) temporarily improve memory in patients with Alzheimer’s disease. Although these drugs do not significantly enhance memory in normal individuals, the prospect that coming generations of memory-enhancement drugs might, have attracted considerable interest from investors who foresee a coming industry of ‘smart pills’ [105]. Already the sale of ‘nootropics’, which are drugs and over-the-counter nutritional supplements such as Gingko biloba touted as boosting cognitive performance, approach US$1 billion annually in the USA alone, despite scientific evidence for their efficacy that is at best marginal [7]. Worldwide, the most commonly sold nootropic, piracetam, finds robust demand despite uncertain or unproven scientific efficacy. Forecasters predict a potential global market for nootropics worth billions [106]. Gingko biloba, piracetam, and other nootropics are currently being marketed to cognitively normal people as mind food, the means to revitalize intellect, to achieve greater mental fitness or mind sculpting. Independent of medical need, a market for cognitive enhancement most definitely exists.

Whether medicine is ethically obligated to provide cognitive enhancement has been a matter of debate. The traditional goal of medicine is treatment of bodily disorders and alleviation of the symptoms wrought by disease. The physician, as healer, works to restore the ill person to normal or nearly normal functional capacity. Enhancement of healthy individuals, on the other hand, has not historically been understood to lie within the professional sphere of medicine. Cognitive enhancement can refer to interventions that increase, amplify or intensify mental capacities such as alertness, vigilance or problem-solving ability in excess of that which constitutes normal health for an individual or for humankind. Hence, the enterprise of cognitive enhancement has earned the classification cosmetic neurology [8]. Whereas the end point of therapy is restoration of normality, the objective of enhancement is openended and potentially insatiable. The physician as enhancer, has, in some measure, stepped beyond the role of healer in the traditional sense. The enhancement enterprise may also place the patient in the role of a consumer who looks to the physician as a provider of happiness.

Drugs to enhance cognition have in common a perhaps irresistible universal appeal, particularly when they target, not disease, but subjective symptoms present in greater or lesser degree in most healthy people. Here, the distinction between therapy and enhancement blurs. Many forms of cognitive inefficiency exist in graded degrees along a spectrum in which some features of disease may overlap with normality. Consider the decline in cognitive function that accompanies normal aging. It is not immediately apparent whether restoring mild forgetfulness at the age of 50 years to the mental receptiveness of age 25, if that were possible, would be treatment or enhancement. Attempts to impose strict distinctions between what is therapy and what is enhancement risk oversimplification of the human intellect. A fully human understanding of cognitive capacity must take into account age, personality, relationships, and individual and cultural biography. Most 25 year olds are better able to learn a foreign language, while most 50 year olds have acquired an unquantifiable store of wisdom through life experience. Which capacities would be the preferred target of enhancement is no simple question. In the economy of lifetime cognitive development, it may be that some capacities must eventually be lost in order for others to attain their proper development.

An important set of ethical questions concern safety. All drugs, obviously, have potential adverse effects. Ongoing research seeks to design drugs that selectively target such cognitive domains as alertness, vigilance, memory formation, thought organization and planning, while minimizing unintended effects of cardiovascular or neuromuscular overstimulation, euphoria associated with the risk of recreational use and addictive behavior, or disruption of other brain systems important for well-adjusted social life. Longitudinal studies are needed to assess the enduring or delayed effects of medications that alter cognitive function. The need is particularly great in the case of drugs prescribed for children and adolescents, as the long-term effects of stimulants and other psychoactive drugs on the developing brain have been insufficiently studied [9]. The astonishing complexity and delicate fragility of the human nervous system require that pharmacological interventions be undertaken with utmost caution and care.

The availability of drugs that can enhance academic performance may become quite appealing to some parents who desire that their children compete for access to top universities. If pharmacological enhancements were to become accepted to enable schoolchildren to get ahead, their implementation in the workplace would soon follow, particularly if studies were able to show that their use could enhance job productivity or cut rates of error [10]. The ethical obligation to ensure safety to individual users would, in these scenarios, fall to the medical profession.

There are concerns beyond the safety issues. If, hypothetically, cognitive-enhancing drugs could be designed to be nontoxic, free from the potential for recreational abuse or addiction, devoid of any long-term risk of impairing cognition, and incapable of prompting criminal behavior, then crucial ethical concerns would yet remain. Although more philosophical than practical, they are nevertheless profoundly capable of reshaping our lives and our cultures.

Consider the potential social consequences of the widespread use of cognitive-enhancing drugs. Competitive academic performance is but one example. A Yale University (Connecticut, USA) undergraduate boasted during an interview of having read all 576 pages of Dostoevsky’s Crime and Punishment and written a 15-page paper, all within 30 h with the help of Adderal [107]. Another student estimated that two-thirds of the student body had used the drug as a study aid [107]. Some 10 or 20 years ago, a student choosing to abstain from caffeine among coffee-drinking classmates would probably not, by so doing, have taken the path of academic disadvantage, but could have competed on more or less equal terms for admission to graduate or professional school based on that individual’s innate ability and character, proven through effort, discipline and perseverance. A generation later, so-called study aids have surged to a level of potency and prevalence of use where students may perceive that they have no choice but to take these drugs in order to compete. This unjust advantage gained in such a way that others become disadvantaged parallels the debate over the use of steroids in athletics. Looking ahead, routine use of enhancing drugs could elevate personal and societal expectations to a point where more and more people left behind the accelerating performance curve, either because of medical contraindications to taking enhancing drugs or simply by choice, would eventually fail.

Arguments to legitimize cognitive enhancement often appeal to the respect for individual autonomy or the right to exert control over one’s own life. However, use of technologies introduced as optional, once they are widely adopted, often become expected. What might seem at first a method to give individuals more control over their sleep and wake cycles could, in the hands of others, become a systematic instrument to nudge us more and more into a 24-h society in which people are expected to always be available to perform. Nor can academic use of smart drugs be justified solely on the basis of a right of individual autonomy on a campus where such drugs have gained widespread use. Peer pressure would, in such cases, exert more than slight coercion on the unenhanced.

Aside from safety concerns, even if equal access to medication were provided, the widespread use of cognitive-enhancing drugs among students would signal a shift in how human intelligence, and hence people, are valued. The exaltation of material performance would risk commodifying human traits. The medicalization of perceived underperformance could lead to imposing medical categories on our understanding of normal human diversity, expression, effort and achievement. Not all human problems, to be sure, are medical or are best dealt with through pharmacology.

A realistic view of human intelligence takes into account cognitive dimensions untouched by drugs designed to enhance the easily defined and quantifiable measures of cognition. Pharmaceutical companies are not likely to begin producing drugs to enhance human inspiration, subtlety of language, nuanced humor, altruism, sacrificial love, relational commitment or religious devotion. Too much emphasis on cognitive productivity might damage our appreciation of the creative and sensitive natures of ourselves and others.

There is a time to remember and a time to forget. Enhanced cognitive abilities do not necessarily translate to a better, happier life. The Doogie mouse is a genetically modified mouse with enhanced memory due to overexpression of the NR2B subunit of the NMDA receptor. Interestingly, this mutation also enhances the mouse’s capacity to experience and remember pain [11].

There may, after all, be benefits to a sometimes unfocused mind and unseen purpose to a sometimes distractible mind. A mind that is not vigilantly seeking personal perfection is a mind more receptive to new ideas and to the needs of others. There is also wisdom in making time for periodic sleep and rest, which are essential to sound mental and physical health [12].

A society steeped in performance expectations may find in cognitive-enhancing drugs a bittersweet cup of new tea. Medicine, therefore, should approach the prospects of pharmacological cognitive enhancement cautiously, remaining mindful that human dignity transcends measures of mere performance.