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How smart are smart drugs?
Perspectives
The art of medicine How smart are smart drugs?
Science Photo Library
Cognitive decline, and in particular memory loss, are key features of the early stages of Alzheimer’s disease, so it is scarcely surprising that the focus of research aimed at treatment has been on identifying drugs to alleviate or reverse this decline. But once such drugs are available, might they not also be more broadly useful? If mild cognitive decline is a fact of life for many of us over the age of about 50 years, as some maintain, perhaps we should all be taking the pills, much as many now take statins and aspirin? And how about students revising for exams, or businessmen wishing to gain a competitive edge? This, essentially, is the case for cognitive enhancers or nootropics, known more colloquially as smart drugs. The quest for such enhancers is not new, but since antiquity has preoccupied people in many cultures. Read the newspaper small ads, check out Google, or visit a health food store, and the shelves are groaning with additives ancient and modern, from Ginkgo biloba and fish oils through lecithin and vitamin concoctions supposed to aid concentration, improve memory, and boost IQ. Sadly, a cool look at the evidence suggests that none are particularly helpful. A recent much hyped but poorly controlled trial in which children were fed omega-3 supplements showed no positive effects. But then, even
198
more sadly, the same could be said for the prescription drugs currently available to treat Alzheimer’s disease. In the UK the recent analysis by The National Institute for Health and Clinical Excellence (NICE) of the four licensed drugs (donepezil, galantamine, rivastigmine, and memantine, three of which enhance cholinergic, and the fourth glutamatergic function) makes clear that they are only marginally effective as cognitive aids, but do nothing to reverse the slow decline typical of the course of the disease. However, drugs that do enhance normal cognition indirectly by affecting concentration and sleep patterns are widely available, ranging from caffeine and nicotine through methylphenidate and modafinil. The number of methylphenidate prescriptions has risen dramatically in the UK over the past two decades—from around 2000 a year in the early 1990s to over 300 000 today. Although prescribed to treat the supposed epidemic of attention deficit hyperactivity disorder, and originally claimed to be effective only in improving attention in children with that dubious condition, in the USA the Food and Drug Administration has claimed that the drug is widely traded among school students revising for exams. Modafinil was originally developed to treat narcolepsy, but has come into wider use to prevent sleepiness—for instance, among US pilots flying long-range bombers during the Iraq war. Earlier this year Nature, which had carried an article about ethical issues arising from the development of smart drugs, asked its readers for views on their use. Of the 1400 who replied from some 60 countries, about a fifth claimed to use methylphenidate, modafinil, or β blockers as work and concentration aids. More evidence, if any were required, that we are living in an increasingly competitive and pharmacologically tolerant age. These may not be the hoped-for pure nootropics, any more than caffeine is, but they are, it seems, serving a purpose until one comes along. Meanwhile, with the increasing incidence of Alzheimer’s disease in the ageing populations of the industrial world, the prize for developing a better treatment is huge. The biochemical pathways leading to the accumulation of amyloid plaques characteristic of the disease have been elucidated, making more rational pharmacological interventions possible, and most big pharma companies and many university laboratories are in the hunt for third-generation drugs. Although the primary target of such drugs will be the biochemical pathways leading to the neuronal cell death that characterises Alzheimer’s disease, it is probable that some at least will affect the processes involved in “normal” memory retention that are disrupted in that disease. So it is predictable that, within the next decade at the www.thelancet.com Vol 372 July 19, 2008
latest there will be a variety of more effective cognitive enhancers on the market. Viagra for the brain, some commentators have described the potential enhancers; indeed, Viagra for the share price of the several start-up biotech companies that have claimed to have such drugs in the pipeline. This prospect has inevitably attracted the attention of bioethicists, agonising over the ethical, legal, and social implications of the availability of enhancing drugs. Bioethicists tend to come in two flavours. A minority— both religious and secular—cry doom and propose ethical, social, and legal controls on the application of the new biotechnologies. They fret especially about what they see as the permeable borderlines between therapy and enhancement. Treating memory loss in patients with dementia is clearly one thing, but popping a pill before going to a party for those of us irritatingly forgetful of people’s names is—perhaps—another. They see the enhancers as the equivalent of steroids and related performance enhancers for athletes, and therefore to be banned for people sitting competitive examinations for fear of unfair advantage. By contrast, most professional bioethicists—primarily American—have a libertarian, anything-goes approach to enhancement, cloning, and the rest, embracing the inevitably progressive onward march of science and medicine even towards what has been called transhumanism. Before we get too het up about the tricky boundaries between therapy and enhancement, it is worth thinking a little more about the question of what is fair. No-one doubts that plagiarising an exam answer from the internet is cheating, but having access to the internet and exploring its resources before answering the question, when some of your fellow students may be deprived of such access? Taking a pill so as to stay awake to revise before an exam? Coming from a rich enough household that you can be sent to a private school or have special coaching? These are all inherently unfair advantages when others—the majority—are deprived of them. And they are enhancing just as much as taking a nootropic would be. Struggling for a fairer, more just world is a matter more of politics than of psychochemistry. So maybe in debating therapy versus enhancement we are dealing with a distinction without a difference? Or maybe no distinction at all, granted that we can alter our body chemistry by activities such as training or focused attention just as we can alter our capacity for focused attention by changing our body chemistry. Training before a race alters muscle physiology and biochemistry, but no-one regards that as cheating—even if there have been efforts to ban those, such as some Ethiopians, judged to have a genetic advantage in long-distance running—from competing in marathons. Along with magic memory-enhancing chemicals come a flurry of www.thelancet.com Vol 372 July 19, 2008
Graham Dean/The Bridgeman Art Library
Perspectives
multimedia advertisements for activities such as “Braingym”, groups of simple puzzles claimed to keep one’s brain active into older age. In an age of increasingly complex use of psychochemicals that change mood and behaviour, perhaps we should just relax, and leave worrying over doping scandals to the sports officials. In this view, what is needed are safety checks, quality control, and a regulated market. Meantime, it is worth asking, as a distinguished gerontologist did at a seminar debating cognitive enhancers a few years back, whether restoring fading memories in elderly patients is such an obvious benefit (a question the prescient Aldous Huxley raised many years ago in his novel After Many a Summer). Sure, if taking a pill in the morning will help someone in the early stages of Alzheimer’s disease to remember where they put the car keys or whether they have done the shopping, this must help preserve a person’s independence longer, and there are surely few among us who would deny themselves that possibility. But if a feature of “normal” ageing is a degree of benign forgetfulness, maybe that is no bad thing. And without a treatment for a progressive disease, insisting that we remember that we are suffering from it may not be so self-evidently desirable. And even before we enter that stage in our lives, it is worth reflecting on the fact that memory is an evolved biological property, for the proper functioning of which forgetting is also essential. Remembering too much, being unable to forget, as both novelists and neuropsychologists have pointed out, is a potentially lethal liability. Surely something to ponder on as the pharmaceutical industry races ahead, and each of us ages, at first imperceptibly and then with increasing speed as the years pass by.
Steven Rose Professor of Biology and Director, Brain and Behaviour Research Group, Open University, Milton Keynes MK7 6AA, UK [email protected]
Further reading Goldacre B. The trial that never was. The Guardian, March 29, 2008. http://www. badscience.net/?p=649 (accessed July 1, 2008). Sahakian B, Morein-Zamir S, 2007. Professor’s little helper. Nature 2008; 450: 1157–59. Subsequent correspondence, Nature 2008; 451: 520–21. British Medical Association. Boosting your brainpower: ethical aspects of cognitive enhancements. A discussion paper. London: British Medical Association, 2007. Rose S. The 21st century brain. London: Jonathan Cape, 2005. Rees D, Rose S, eds. The new brain sciences: perils and prospects. Cambridge: Cambridge University Press, 2004.
199
The art of medicine How smart are smart drugs?
Science Photo Library
Cognitive decline, and in particular memory loss, are key features of the early stages of Alzheimer’s disease, so it is scarcely surprising that the focus of research aimed at treatment has been on identifying drugs to alleviate or reverse this decline. But once such drugs are available, might they not also be more broadly useful? If mild cognitive decline is a fact of life for many of us over the age of about 50 years, as some maintain, perhaps we should all be taking the pills, much as many now take statins and aspirin? And how about students revising for exams, or businessmen wishing to gain a competitive edge? This, essentially, is the case for cognitive enhancers or nootropics, known more colloquially as smart drugs. The quest for such enhancers is not new, but since antiquity has preoccupied people in many cultures. Read the newspaper small ads, check out Google, or visit a health food store, and the shelves are groaning with additives ancient and modern, from Ginkgo biloba and fish oils through lecithin and vitamin concoctions supposed to aid concentration, improve memory, and boost IQ. Sadly, a cool look at the evidence suggests that none are particularly helpful. A recent much hyped but poorly controlled trial in which children were fed omega-3 supplements showed no positive effects. But then, even
198
more sadly, the same could be said for the prescription drugs currently available to treat Alzheimer’s disease. In the UK the recent analysis by The National Institute for Health and Clinical Excellence (NICE) of the four licensed drugs (donepezil, galantamine, rivastigmine, and memantine, three of which enhance cholinergic, and the fourth glutamatergic function) makes clear that they are only marginally effective as cognitive aids, but do nothing to reverse the slow decline typical of the course of the disease. However, drugs that do enhance normal cognition indirectly by affecting concentration and sleep patterns are widely available, ranging from caffeine and nicotine through methylphenidate and modafinil. The number of methylphenidate prescriptions has risen dramatically in the UK over the past two decades—from around 2000 a year in the early 1990s to over 300 000 today. Although prescribed to treat the supposed epidemic of attention deficit hyperactivity disorder, and originally claimed to be effective only in improving attention in children with that dubious condition, in the USA the Food and Drug Administration has claimed that the drug is widely traded among school students revising for exams. Modafinil was originally developed to treat narcolepsy, but has come into wider use to prevent sleepiness—for instance, among US pilots flying long-range bombers during the Iraq war. Earlier this year Nature, which had carried an article about ethical issues arising from the development of smart drugs, asked its readers for views on their use. Of the 1400 who replied from some 60 countries, about a fifth claimed to use methylphenidate, modafinil, or β blockers as work and concentration aids. More evidence, if any were required, that we are living in an increasingly competitive and pharmacologically tolerant age. These may not be the hoped-for pure nootropics, any more than caffeine is, but they are, it seems, serving a purpose until one comes along. Meanwhile, with the increasing incidence of Alzheimer’s disease in the ageing populations of the industrial world, the prize for developing a better treatment is huge. The biochemical pathways leading to the accumulation of amyloid plaques characteristic of the disease have been elucidated, making more rational pharmacological interventions possible, and most big pharma companies and many university laboratories are in the hunt for third-generation drugs. Although the primary target of such drugs will be the biochemical pathways leading to the neuronal cell death that characterises Alzheimer’s disease, it is probable that some at least will affect the processes involved in “normal” memory retention that are disrupted in that disease. So it is predictable that, within the next decade at the www.thelancet.com Vol 372 July 19, 2008
latest there will be a variety of more effective cognitive enhancers on the market. Viagra for the brain, some commentators have described the potential enhancers; indeed, Viagra for the share price of the several start-up biotech companies that have claimed to have such drugs in the pipeline. This prospect has inevitably attracted the attention of bioethicists, agonising over the ethical, legal, and social implications of the availability of enhancing drugs. Bioethicists tend to come in two flavours. A minority— both religious and secular—cry doom and propose ethical, social, and legal controls on the application of the new biotechnologies. They fret especially about what they see as the permeable borderlines between therapy and enhancement. Treating memory loss in patients with dementia is clearly one thing, but popping a pill before going to a party for those of us irritatingly forgetful of people’s names is—perhaps—another. They see the enhancers as the equivalent of steroids and related performance enhancers for athletes, and therefore to be banned for people sitting competitive examinations for fear of unfair advantage. By contrast, most professional bioethicists—primarily American—have a libertarian, anything-goes approach to enhancement, cloning, and the rest, embracing the inevitably progressive onward march of science and medicine even towards what has been called transhumanism. Before we get too het up about the tricky boundaries between therapy and enhancement, it is worth thinking a little more about the question of what is fair. No-one doubts that plagiarising an exam answer from the internet is cheating, but having access to the internet and exploring its resources before answering the question, when some of your fellow students may be deprived of such access? Taking a pill so as to stay awake to revise before an exam? Coming from a rich enough household that you can be sent to a private school or have special coaching? These are all inherently unfair advantages when others—the majority—are deprived of them. And they are enhancing just as much as taking a nootropic would be. Struggling for a fairer, more just world is a matter more of politics than of psychochemistry. So maybe in debating therapy versus enhancement we are dealing with a distinction without a difference? Or maybe no distinction at all, granted that we can alter our body chemistry by activities such as training or focused attention just as we can alter our capacity for focused attention by changing our body chemistry. Training before a race alters muscle physiology and biochemistry, but no-one regards that as cheating—even if there have been efforts to ban those, such as some Ethiopians, judged to have a genetic advantage in long-distance running—from competing in marathons. Along with magic memory-enhancing chemicals come a flurry of www.thelancet.com Vol 372 July 19, 2008
Graham Dean/The Bridgeman Art Library
Perspectives
multimedia advertisements for activities such as “Braingym”, groups of simple puzzles claimed to keep one’s brain active into older age. In an age of increasingly complex use of psychochemicals that change mood and behaviour, perhaps we should just relax, and leave worrying over doping scandals to the sports officials. In this view, what is needed are safety checks, quality control, and a regulated market. Meantime, it is worth asking, as a distinguished gerontologist did at a seminar debating cognitive enhancers a few years back, whether restoring fading memories in elderly patients is such an obvious benefit (a question the prescient Aldous Huxley raised many years ago in his novel After Many a Summer). Sure, if taking a pill in the morning will help someone in the early stages of Alzheimer’s disease to remember where they put the car keys or whether they have done the shopping, this must help preserve a person’s independence longer, and there are surely few among us who would deny themselves that possibility. But if a feature of “normal” ageing is a degree of benign forgetfulness, maybe that is no bad thing. And without a treatment for a progressive disease, insisting that we remember that we are suffering from it may not be so self-evidently desirable. And even before we enter that stage in our lives, it is worth reflecting on the fact that memory is an evolved biological property, for the proper functioning of which forgetting is also essential. Remembering too much, being unable to forget, as both novelists and neuropsychologists have pointed out, is a potentially lethal liability. Surely something to ponder on as the pharmaceutical industry races ahead, and each of us ages, at first imperceptibly and then with increasing speed as the years pass by.
Steven Rose Professor of Biology and Director, Brain and Behaviour Research Group, Open University, Milton Keynes MK7 6AA, UK [email protected]
Further reading Goldacre B. The trial that never was. The Guardian, March 29, 2008. http://www. badscience.net/?p=649 (accessed July 1, 2008). Sahakian B, Morein-Zamir S, 2007. Professor’s little helper. Nature 2008; 450: 1157–59. Subsequent correspondence, Nature 2008; 451: 520–21. British Medical Association. Boosting your brainpower: ethical aspects of cognitive enhancements. A discussion paper. London: British Medical Association, 2007. Rose S. The 21st century brain. London: Jonathan Cape, 2005. Rees D, Rose S, eds. The new brain sciences: perils and prospects. Cambridge: Cambridge University Press, 2004.
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