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can participate, very modestly, in one of the major efforts of humanity, which is to gobeyond the Platonic question ‘Who are we?’… Man is not going to wait passively for millions of years before evolution offers hima better brain … To develop a pharmacology of integrative action of the brain, in thenootropic sense, seems to me to have a placein this far-reaching human objective.” in a book entitled Smart Drugs and Nutrients the treatment of memory loss that results arrival of drugs that will prevent such an and subtitled “how to improve your memory from Alzheimer’s disease or stroke, there impairment, describing them as ‘Viagra for the and increase your intelligence using the latest brain’1, and certainly functioning as Viagra for discoveries in neuroscience”5, argued that: share values. And when Tang et al.2 reported “The concept of a fixed intelligence is … (N-methyl-D-aspartate) receptors in the ability raises an important issue — the use, and scholars are looking for the kind of ‘edge’ by healthy people, of such pharmacological in the Morris water maze (a test of spatial that athletes get from science … Research also tools as cognitive enhancers. Here, I review memory), the paper attracted massive inter- shows that you may increase your intelligence national publicity owing to the suggestion by taking certain substances that have recently supposed ‘nootropics’, and the ethical, that the “genetic enhancement of mental and cognitive attributes such as intelligence and taking ability, better job performance and enhancement of ‘normal’ cognition.
increased productivity [as well as] … delaying enhancement’ with a more general ‘cognitive enhancement’ — a cloudy issue that I discuss performance are age old; magic potions to below in more detail. However, the suggestion Here, I review the evidence on which such produce immortality, superhuman strength, that it might be possible to produce drugs claims are based, before turning to some of potency and wisdom feature in the myths of with a ‘purely’ cognitive effect dates back to the ethical, legal and social issues that the most cultures. In the Western tradition, they potential of such agents might raise.
run from the ancient Greeks to the contem- ‘nootropic’ in the 1970s to describe their func- tion3. The term is derived from the Greek noos Why enhance cognition?
Obelix. The shelves of health-food stores for ‘mind’, and tropein, meaning ‘towards’.
Our personal memories — the autobiograph- groan with pills that offer to improve every- Sara4 quotes the following translation of ical record — are in many ways what define thing from children’s IQ scores to memory in each of us as individuals. And in an increas- old age. A quick scan of the Internet offers an ingly skills-driven and socially interactive even wider range of both approved and non- “…do we realise as individuals or as a world, memory — individual or technologi- approved drugs. Many are reportedly avail- species, all of our genetic potential? … A cally enhanced — is one of the keys to success.
able over the counter at a variety of ‘smart This is perhaps why loss of memory — an bars’ across the west coast of the United States.
more feasible and acceptable at all levels of inability to remember — is so mysterious and While pharmaceutical companies race to pro- interface between genome and environment.
frightening a condition. There are many dis- vide potential treatments for memory loss in This is the target of the Nootrope endeavour.
ease states that are characterized by impaired Alzheimer’s disease (AD), there are wider con- These drugs, devoid of toxicity or secondary memory and cognition. Some are genetic — cerns about ‘age-associated memory impair- ment’, which supposedly affects the majority of plasticity of those neuronal processes directly associated with accidental brain damage (such the population over fifty years of age. Start-up related to the ‘Noosphere’ … Pharmacology as the much studied amnesic patients with VOLUME 3 | DECEMBER 2002 | 9 7 5
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hippocampal or temporal lobe damage), with only route to overcoming such problems.
developed to affect these processes without stroke or with the vitamin deficiencies that Memory — for names, hands of cards dealt, or peripheral or other central effects. Both result from alcoholism (Korsakoff ’s syn- even recalling π to hundreds of decimal places drome). Above all, there are the broad groups — can be trained using non-pharmacological of senile dementias such as AD and Lewy body techniques that date back to antiquity8,9.
other cerebral processes — perception, atten- diseases. As the incidence of these disorders In this context, it is worth querying the tion and arousal. All engage both peripheral increases with age, and the age profile of pop- assumption that a perfect long-term memory ulations in the industrial world is shifting is desirable. The psychological mechanisms of Although the processes that are involved in steadily upward, there is a strong medical and perceptual filtering, and of short-term, recog- recall are less well studied, it is safe to assume social drive for research to develop neuro- that remembering places similar demands on protection strategies, or at least to reduce the beneficial in blocking the accumulation of the brain. So, agents that affect any of these rate and degree of decline. ‘Solving’ AD has irrelevant or transiently required informa- processes might also function to enhance (or tion in longer-term stores. The wisdom of the institutions and the pharmaceutical industry.
psychotherapeutic ‘recovery’ of past traumatic But in addition to such relatively clearcut memories has been questioned in the context, tasks is affected by plasma steroid levels14, conditions (although clouded in diagnostic for example, of psychoanalysis, and even the adrenaline15 and even glucose16. At least one uncertainty until post mortem), there are veracity of such apparent memories has been agent that has been claimed to function as a those of us who fret over our inability to recall challenged in the context of ‘false memory names or past events, and who are concerned syndrome’10,11. The literature is full of anecdo- a smart drug — piracetam17 — seems to act, tal accounts of the problems faced by those at least in part, through the modulation of to suffer from some form of age-associated few people who are apparently unable to use peripheral steroid levels18. Central processes forgetting mechanisms to assimilate necessary everyone else seeking that competitive ‘edge’ anxiety, enhancing attention or increasing referred to by Dean and Morgenthaler5.
most famous case is that of Shereshevkii, the the salience of the experience to be learnt and Few would doubt the value of neuroprotec- patient who was studied over many years by tion or amelioration of the effects of stroke or the neuropsychologist Alexander Luria12.
date (Ritalin), antidepressants and anxiolytics AD. But outside this lies the murky area in probably act in this way19. Other agents that which ‘normality’ itself becomes a medical apparently inexhaustible memory, recalling are regularly cited as potential smart drugs, condition. Some features of cognitive function not merely complex nonsense formulae, but such as adrenocorticotropic hormone (ACTH) — notably, speed of processing — seem to also the exact context in which he learnt and vasopressin20, might function in a similar decline progressively with age. As one ages, them. His inability to forget made it impossi- fashion. Last, there is evidence from animal more trials are required to acquire simple con- ble for him to hold down a career other than ditioned reflexes, such as an eye blink in as a memory performer. His case poignantly response to a light or tone. But given enough echoes that of Funes, the ‘memorious’ — the time and trials, the reflex can be acquired and fictional character created by the novelist growth factors (such as brain-derived neuro- little seems to distinguish the final perfor- trophic factor22), will enhance long-term mance of people on the grounds of age alone6.
Old people often acquire better strategies for “…[Funes] remembered the shapes of the claimed neuroprotective effect of oestrogen, solving problems than young people, and in a clouds in the south at dawn on the 30th of as evidenced by the lower incidence of AD in less speed-obsessed age, this could be thought April of 1882, and he could compare them in his recollection with the marbled grain in the replacements23, is still awaiting epidemiologi- might often be associated more with depres- design of a leather-bound book which he had cal verification; if proven, it might be that this sion7. So, targeting ‘memory’ per se might not seen only once, and with the lines in the spray effect is mediated through interconversions be an appropriate strategy. The deficits associ- which an oar raised in the Rio Negro on the ated with AD and other conditions relate to eve of the battle of the Quebracho … These specific biochemical or physiological lesions.
recollections were not simple; each visual Approaches to enhancement
There is therefore no a priori reason — irre- The lay literature, health-food stores and spective of ethical concerns or any other argu- thermal sensations. … He told me: I have Internet sites propose lecithin and a variety of ments — to suppose that, in the absence of more memories in myself alone than all men multivitamins — notably, the B complex and have had since the world was a world … my vitamin C — as neuroprotective, along with of such processes will necessarily enhance memory sir, is like a garbage disposal…”13 herbal extracts of ginseng, ginkgo biloba and memory or cognition, which might already be other substances derived from non-Western, ‘set’ at psychologically optimal levels. If they It is no accident that, in the story, Funes non-allopathic traditions as cognition and dies young — of an overdose of memory, so pharmacological deficit, but other social or personal life-history reasons. This is not to ment have tended to follow clinical fashion in minimize the distress that most of us feel in Nootropes, remembering and forgetting
identifying the physiological or biochemical our daily life as a consequence of lapses of The implication of Giurgea’s nootropic con- memory. And, as politicians, card sharps and cept is that there are brain processes that are deficit and focusing on ameliorating them.
competitors for the Guinness Book of Records concerned with ‘pure’ cognition, memory for- Suggestions that one of the main problems of know, pharmacological intervention is not the mation or retrieval, and that drugs can be cognition in ageing lay in deficits in general 9 7 6 | DECEMBER 2002 | VOLUME 3
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is hard to imagine their more general use Box 1 | Some alleged ‘smart drugs’ and cognitive enhancers
Agents once supposed to act through glutamatergic mechanisms
impairment (or as nootropics in the Giurgea Piracetam | Aniracetam | Nefiracetam | Oxiracetam | Pramiracetam | Fipexide | Pyroglutamate
sense), they are apparently under trial1.
Glutamatergic agents under clinical trial
Recent advances in elucidating the molec- Ampakine | Memantine
ular cascade that is involved in memory for-mation in animal models (for reviews, see Agents that affect GABA (γ-aminobutyric acid) function
REFS 29,30) have implicated glutamatergic GABA receptor antagonist CGP 36742 | Methylphenidate (Ritalin)
mechanisms, and especially the NMDA recep- Serotonergic agents
tor complex, as being crucially involved in the Ondansetron
initial stages of acquisition in many learning Cholinergic agents (licensed for Alzheimer’s disease)
Galantamine | Rivastigmine | Donepazil
cholinergic and glutamatergic processes alsopoints to these as possible sites of intervention.
Adrenergic agents
Even before the current research era, it was Adrenaline
suggested that the acetams (such as piracetam, Agents that act on cerebral circulation or calcium homeostasis
Vinpocetine | Hydergine | Phenytoin | Nifedipine | Nimodipine | Idebenone
Hormones and neurohormones
pyroglutamate (2-oxo-pyrrolidone carboxylic Dehydroepiandrosterone (DHEA), DHEA-sulphate | Vasopressin |
acid) features in the smart-drug catalogues for Adrenocorticotropic hormone
the same reasons32,33. Mondadori’s demonstra-tion that the acetams act peripherally by Miscellaneous others
Acetyl-L-carnitine | Choline | Lecithin | Gingko biloba | Ginseng | Antioxidants | B, C and
enhancing corticosteroid release18 has not E vitamins | Nicotinic acid, xanthinol nicotinate | Orotic acid | D-Cycloserine
entirely ruled out the possibility of a centraleffect. However, the evidence for its effective-ness in humans is slight. The report that cerebral metabolism provided the impetus for The cholinergic hypothesis for the memory increasing the numbers of hippocampal NR2 nootropics that were supposed to boost the deficits associated with AD led to an intensive receptors improves the performance of mice circulation and use of oxygen. The findings search for drugs that might restore cholinergic in the Morris water maze2 has drawn further that cholinergic cells are among the first to die function. Again, animal models pointed the way. A routine procedure has been to block receptors as effective sites of intervention for could be involved in memory formation, led cholinergic function with scopolamine, and to the search for potential cholinomimetics.
then to test agents that might restore learning More recent evidence on the involvement of or retention. Several candidate drugs were indicate that synaptic events are followed by GABA (γ-aminobutyric acid)- and glutamate- identified in this way. However, most proved an intracellular cascade that involves calcium mediated processes has shifted the focus of to be ineffective at ameliorating the deficits of fluxes, a variety of protein kinases, and activa- AD in humans, still less as general memory or tion of transcription factors and immediate cognition enhancers27. This is not really sur- early genes such as c-Fos, c-Jun and Zif-268 prising, as the logic of the animal experiments (REFS 29,30). An important step in this sequence as potential nootropics. An example is co- was essentially circular: scopolamine produces involves the cyclic-AMP-responsive-element- dergocrine mesilate (Hydergine), an anti- learning deficits, so agents that block or hypertensive ergot extract that is claimed reverse scopolamine activity prevent these deficits (although the cholinesterase inhibitor Drosophila34 and mice35. At least two compa- intelligence, memory, learning and recall” nies have been set up to explore the role of among a dazzling array of other virtues5. The selectivity of perceptual processing during CREB as a key site of potential smart-drug British National Formulary, by contrast, working memory in young volunteers28).
action1, although it should be pointed out states that “the drugs have not been shown that, even in animal models, the role of CREB clinically to be of much benefit”24. A more humans is indeed caused by a scopolamine- in retention seems to depend rather sensitively solid approach followed the hypothesis that like blockade of cholinergic function, it is not on the training protocols that are used36.
cerebral metabolism was affected by changes likely to respond in the same way. Tacrine, an in calcium homeostasis during ageing25.
early cholinesterase blocker that was reported Data from several animal models indicated to have some alleviating effects, was effective at present. But this illustrates a more general that L-type calcium channel blockers, such only in a minority of cases and often produced issue: the relevance of animal models in the severe adverse reactions. Two drugs licensed in field of memory and cognition. It is striking the United Kingdom, donepazil (Aricept) and that, despite clearcut evidence that a variety of galantamine (Reminyl), are reversible inhibi- agents — the acetams, L-type calcium channel attempts to apply the findings of pharmaco- tors of acetylcholinesterase; another, rivastig- blockers, glutamatergic and cholinergic ago- logical intervention in animal learning to mine (Exelon), is a reversible, non-competitive nists — can enhance memory-related perfor- clinical use, trials of these drugs in humans inhibitor. All of them can produce unpleasant mance in animals, they have generally proved have proved to be ineffective at enhancing adverse reactions and are only mildly effica- to be disappointing when taken to clinical trial cious in a proportion of patients. Although it in treating cognitive decline and dementia.
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There are several possible reasons for this.
by Sacks38 in the context of the use of L-DOPA One is that the biochemical specificity of the example, the recent Nuffield report39). The processes that lead to decline in humans might issues are analogous to those raised by the differ from the effects of pharmacological ter strategy. But once again, it is not an manipulation in animal models. Perhaps more unequivocal good. Some of the genetic and enhancers in athletics, where a sort of arms importantly, assumptions about the similarity environmental risk factors for AD are under- race has developed between the athletes who of human memory to animal models of learn- stood, but almost all (other perhaps than the ing and recall (which must always be tested by small percentage of familial early-onset AD the criterion of performance of some task, cases) are at best only weakly predictive. One whether it be maze navigation or the expres- would have to weigh carefully the risks and Generations of students (to say nothing of sion of preference) might be false. Animal creative artists or dealers in frenetic stock models cannot reprise the subtleties of human penumbras of its perhaps inappropriate use markets) have used such stimulants as have by the so-called ‘worried well’, concerned been available — caffeine, alcohol, ampheta- memory. General ‘cognition’ is hard to test in about failing memory and the peculiar diag- mines — to sharpen concentration as they nosis of age-associated memory impairment.
revise for and sit examinations. Would the tasks with primates), and memory is but one As a society, we are becoming familiar with availability of genuinely effective new drugs make any difference in principle? Perhaps example, with the use of antihypertensives not, but one can foresee interesting legal Do we want cognitive enhancement?
and statins to reduce the risk of coronary issues arising if the losers in some competi- It might seem a priori self-evident that protec- heart disease for those who are judged vulner- tive examination cry foul and seek redress.
tion against cognitive impairment and the able. However, the assessment of risk factors The clutch of insurance and related cases recovery of cognitive functions in the absence that surround the use of Prozac, especially in of proactive treatment, if possible, are desir- the United States40, are a foretaste of what able. But to “give a 70-year old the memory of might arise in this new context. The truth is a 20-year old”, as the claim for one of the that are better understood than cognition.
that social thinking and policy on the uses of potential enhancers has put it, requires a little Growing old is not a disease but a condition chemicals that affect brain or body perfor- more discussion before nodding and passing of life, and one can question the consequences of creating a society that refuses to accept age- legal and purchasable over the counter (alco- founds at least two distinct phenomena. In lay ing — at least for the wealthy. However, it is hol, nicotine), others are on the verge of at discussion, it generally implies loss of long- beyond dispute that both social and pharma- least decriminalization (cannabis), some are term episodic, semantic and autobiographical acceptable in general but not in competitive memory, arguably the feature of patients with (World Health Organization) goal of ‘adding situations (steroids), some are available only AD that is most distressing to carers. Drug life to years’ are to be welcomed.
treatment is conceived of as aiding in the Beyond these potential clinical and neuro- Internet (Viagra, Ritalin), and some are ille- recovery of these lost memories, but there is protective uses for the cognitive enhancers is gal (ecstasy, heroin). Within the foreseeable no indication that any of the agents under dis- the terrain that raises most ethical and legal future, cognitive enhancers — or agents cussion as putative cognitive enhancers or for concern — their potential for improving, as that are claimed to function as cognitive therapeutic intervention in AD will achieve Dean and Morgenthaler put it5, school and enhancers, whether or not they are genuinely this. Rather, they might serve to prevent loss of effective — are set to join this eclectic set.
short-term memory for recent events — that edge. Is such enhancement theoretically pos- My best guess is that, as with steroids for is, to aid in the transition between short- and sible? Despite the problems that those of us athletes, they will turn out to be virtually long-term memory (although more effectively, with ‘weak memories’ experience in our daily uncontrollable legally, and as a society, we are it is to be hoped, than the current, relatively life, more does not necessarily mean better.
going to have to learn to live with them41. But ineffective generation of anticholinesterases).
some forms of regulation will be needed, and As forgetfulness for recent events (Did I do the deficits such as those in AD were developed, these can best be achieved by some sort of shopping? Where did I leave my keys?) is one democratic consensus, perhaps by way of dis- of the characteristic features of the earlier supernormal level of the relevant molecule cussions in the varying forms of citizen’s would produce supernormal performance.
enhancers, including those that reverse some Think of the classical inverted ‘U’ for the European countries have been experimenting of the specific biochemical lesions, could func- effects of steroids, for example. Where brain with in the context of developments in genet- tion to alleviate these early features, enabling processes depend on a subtle balance between ics. But it is important that we try to be those suffering from AD to remain indepen- proactive in advance of the technological dent for longer. It is improbable that they will their multiple receptors, simply adding more development, rather than constantly trying to reverse or prevent the progression of the dis- of one (such as an NMDA receptor) might be close already open stable doors. And perhaps ease (unlike the hopes surrounding the recent we ought to begin by asking a different ques- vaccination trials37). And if an agent could be Even if this proved not to be the case, and tion: what is it about the way we live today in developed that did awaken long-dormant or safe and effective enhancers of ‘normality’ advanced industrial societies that drives peo- could be produced, there is a fine medical and ple to seek pharmacological fixes? Should advanced stages of the disease, they might not ethical line between correcting deficits and we be spending less time looking to adjust necessarily be welcome, as such re-awakenings improving on ‘normality’, as has been exten- sively discussed in the context of the potential 9 7 8 | DECEMBER 2002 | VOLUME 3
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scientific figures of the second half of the The bulk of Bernard’s early neurological nineteenth century2–6. Even though Bernard 30. Izquierdo, I. & Medina, J. H. Memory formation: the sequence of biochemical events in the hippocampus and has been the subject of an impressive number VOLUME 3 | DECEMBER 2002 | 9 7 9
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Source: http://www.physiology.gu.se/medfys/neurokognition/Rose.pdf