brain booster - NEUBDSCIENCE BRAIN

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Unformatted text preview: NEUBDSCIENCE BRAIN éétiié‘éi‘ééiéii‘iiéé322%é2%éiiiiiiéiiiiéfiiiiiiiiiiiiiiitié‘fiififiiii Will a pill at breakfast improve concentration and memory—and will it do so without long-term detriment to your health? By Gary Stix 46 SCIENTIFIC AMERICAN “ he symbol H+ is the co e Sign 11 by some futurists to denote an enhanced version of humanity. The plus version of the human race would deploy a mix of advanced technolo- gies, including stem cells, robotics, cognition- enhancing drugs, and the like, to overcome basic mental and physical limitations. The notion of enhancing mental functions by gulping down a pill that improves attention. memory and planning—the very foundations of cognition—is no longer just a fantasy shared by futurists. The 1990s, proclaimed the decade of the brain by President George H. W. Bush, has been followed by what might be labeled “the de- cade of the better brain.” Obsession with cognitive enhancers is evi- denced in news articles hailing the arrival of what are variously called smart drugs, neu roen- hancers, nootropics or even “Viagra for the brain.” From this perspective, an era of enhance— ment has already arrived. College students rou- tinely borrow a few pills from a friend's Ritalin prescription to pull an all-nighter. Software pro- grammers on deadline or executives trying to October 2009 SFlASHLllel ~— _—._e——.—‘< .r— r... k— maintain a mental edge gobble down modafinil, a newer generation of pick-me-ups. Devotees swear that the drugs do more than induce the wakefulness of a caramel maCchiato, providing instead the laserlike focus needed to absorb the nuances of organic chemistry or explain the eso- terica of collateralized debt obligations. An era of enhancement may also be advanced by scientists and drugmakers laboring to trans- late research on the molecular basis of cognition into pharmaceuticals meant specifically to im- prove mental performance—mainly for people suffering from dementias. But a drug that works for Alzheimer’s or Parkinson’s patients might in- evitably be prescribed by physicians far more broadly in an aging population with milder im- pairments. Wider publicized debates over the ethics of enhancement have reinforced the sense that pills able to improve cognition will one day be available to us all. Academic and news articles have asked wheth- er cognitive enhancers already give some students an unfair advantage when taking college entrance exams or whether employers would step over the www.ScientificAmerican.¢om line if they required ingestion of these chemicals to meet a company’s production deadlines. But even as articles are published on the “ boss turns pusher,” doubts have arisen about the real- ity of drugs for strengthening brainpower. Do current drugs developed for attention problems or excessive sleepiness really allow a student to do better on an exam or an executive to perform flawlessly under sharp questioning from a board ofdirectors? Will any drug that Fiddles with basic brain functions ever be safe enough to be placed on pharmacy shelves alongside nonprescription pain relievers and antacids? All these questions are now provoking heated deliberations among neuroscientists, physicians and ethicists. Ethical Dissonance Arguments about safety, fairness and coercion aside, demand is indeed high for cognitive en- hancers that are otherwise prescribed for condi- tions such as ADHD. Based on government data gathered in 2007, more than 1.6 million people in the U.S. had used prescription stimulants non- medically during the previous 12 months. Legal KEY CONCEPTS _ I College students and executives ingest stimu- lant drugs to enhance routine mental perfor- mance, although the com- pounds were never ap- proved for that purpose. Some ethicists and neuro- scientists have raised the prospect of making these drugs widely available for enhancement of healthy people who do not suffer from dementia. Questions remain about whether any drug that tinkers with basic mental functioning will be suffi- ciently safe and effective to be consumed like coffee or tea. ——The Editors SCIENTIFIC AMERICAN Why Enhance? An aging population (graph), ubiquitous Internet pharmacies, and a workforce and student population strapped with deadlines and performance pressures (photographs) help to explain the fascination with cognitive~enhancing drugs. ‘ a » PROJECTED INCREASE IN LONGEVITY (1994-2020) Percentage Increase in the Population of Senior Citizens (65 or older) 200 SINGAPORE COLOMBIA SOUTH KOREA MEXKO NIGERIA One ethicist has proposed a plan in which Ritalin could end up alongside Pepto-Bismol on drugstore shelves. 48 SCIENTIFIC AMERICAN medicines in this category include methylpheni- date (Ritalin), the amphetamine Adderall. and modafinil (Provigil). On sortie campuses, one quarter of students have reported using the drugs. And an informal online reader survey by Nature last year showed 20 percent of 1,427 respondents from 60 countries polled about their own use said they had used either methylpheni- date. tnodafinil or bet-a blockers (the last for stage fright). Overall, a need for improved concentra- tion was the reason cited most frequently. People often manage to acquire the drugs on the Inter- net or from doctors, who can prescribe medicines approved for one purpose to treat something else (drugmakers. however, cannot legally promote such “off label” uses). Ingestion of these chemicals will likely grow along with an aging population and an increas— ingly globalized economy. “lf you're a 65-year- old living in Boston and your retirement savings have decreased dramatically and you have to stay on the job market and compete with a 23-year- old in Mumbai to stay alert and stay effective. you may feel pressured to turn to these com- pounds." says Zack Lynch, executive director of the Neurotechnology Industry Organization. The recent push for ethical guidelines, of course, presumes that these drugs are better than placebos and do in fact improve some aspect of cognition. be it attention, memory or “executive function" (planning and abstract reasoning. for instance). Given that assumption. many argue, it behooves ethicists to consider the ramifications ofthe popularity ofthese drugs. Such logic led in 2002 to a new academic discipline. neuroethics, meant in part to address the moral and social questions raised by cognition~enhancing drugs and devices (brain implants and the like). Taking a highly provocative stand, a group of ethicists attd neuroscientists published a corti- mentary in Nature last year raising the prospect of a shift away frotn the notion of drugs as a treatment pritnarily for illness. The article sug- gested the possibility of making psychosrimu- lants widely available to the able-minded to im— prove performance in the classroom or the board- room, provided the drugs are judged to be safe and effective enough for healthy people. Citing research demonstrating the benefits of these drugs on memory and various forms of mental processing, the investigators equated pharma- ceutical enhancement with "education. good health habits, and information technology— ways that our uniquely innovative species tries to improve itself.“ Six tnonths later one of the article's authors, John Harris, a bioethicist at the University of Manchester in England, went further in an opin- ion piece in the British Mt'dicttljom'rrul. Harris, editor of the journal of Medical Ethics and a book called Err/Juncng lii'olution, noted that if inethylplienidate is iudged safe enough to be used in children, it should be considered stifli- ciently innocuous for consumption by adults in- terested in turbocharging their brains. In a later interview. Harris said he foresaw a gradual loos- ening of restrictions, and if no safety problems arise, the drug (a controlled substance in the U.S.) could ultimately become an over-the-coun- ter purchase, like aspirin. These musings have not gone unchallenged. Other researchers and ethicists have questioned whether drugs that modulate mental processes will ever have a safety profile that will justify their being dispensed in the same fashion as October 2009 ’~ l‘tA-l ill a nonprescription painkiller or coffee or tea. “People say that cognitive enhancement is (US! like improving vision by wearing glasses." says James Swanson. a researcher at the Univer- sity of California, Irvine. \\ ho was involved \vith clinical trials for both Adderall and rnodafinil for ADHI). “I don't think people understand the risks that occur when you hav e a large number of people accessing these drugs. Some small per- centage will likely become addicted. and some people may actually see mental performance de- cline. That‘s the reason I’m opposed to their geri- eral use." Along these lines. the British Home Office, the interior ministry, is awaiting a report from an advisory panel on whether the potential harm from nonmedical use of enhancers re- quires new regulations. Other scientists assert that the debate may be moot because improving smarts might not be possible through any means but the tedious exer- cise ofcraniming for a calculus exam. home who have tried to develop drugs to reverse the memo- ry loss of dementia doubt whether enhancement of the healthy is anything but a remote possibil- ity. "I would not worry much about implications of cognitive enhancers in the healthy. because there are no cognitive enhancers to worry about," says Rusiko Bourtchouladze, author of a popu- lar book about the science of memory and a re- searcher who contributed to the work that led to a Nobel Prize for Eric R. Kandel in 2000. “To talk about cognitive enhancement, it‘s too. too early, and these drugs may not arrive even in our lifetime. There‘s too much noise about this.“ In this view, the complex mix ofchemical sig- nals, enzymes and proteins that collaborate to form a memory creates a self-regulating balance that resists tinkering unless disrupted by disease. The decline in thought processes and sense of identity that comes with dementia might be ad- dressable by compensating for losses of key chemicals and might merit the risk of untoward side effects from drug intervention. But upset- ting the fragile stasis in the healthy could pro— duce unintended consequences: as just one ex- ample. any improvement in long-term memory (the place where recollections of childhood and last year‘s vacation reside) could be countered by diminished capacity for working memory (the mental scratch pad where your brain stores a telephone number temporarily). Some critics of those who argue over the eth- ics of neuroenhancement attribute the current flap to what they call “speculative ethics." This tendency also besets nanotechnology and other www.ScientificAmerican.com technological endeavors in which ethicists, sci- entists and policy makers are diverted by dis- cussions of the social implications of technolo~ gies yet to he invented. be they smart pills or nanorobots run amok. “A significant part of the debate on human enhancement suffers from inflated expectations and technology hype.“ notes Maartie Schermer of Erasmus University Rotterdam and her colleagues in the journal Nenroetbics. A Checkered History The notion that existing drugs might enhance cognition in the healthy dates back for the better part of a century and has produced ambiguous results. Chemist (Jordon Alles introduced amph- etamine for medical use in 1919, a synthetic drug chemically similar to the Chinese herb ephed- rine. (Alles also devised the drug Ecstasy, anoth- er amphetamine.) Various forrns were dispensed on both sides during World War II to keep sol- diers awake and alert and to bolster courage. The Germans and japanese ingested methamphet- amine, while the British and Americans used Benzedrine. a similar drug to Adderall. .J [0N PHARMACY SHELVES] BRAIN BOOSTERS. REALLY? the scientific literature and popular press commonly cite the medicines below approved f neurological disorders as having potential to improve mental functioning in unimpaired people. ihe evidence is decidedly mixed, however, and even if the drugs do prove helpful, their risks may keep the agents from gaining approval by regulators for marketing to healthy individuals. Eff“ llVENESS MfDlU-ll USE ASENHANCER Methylphenl- Stimulants used Increase cognitive date (Ritalin. for treatment of performance on certain Concerto and attention-deficit tasks under conditions others) and hyperactivity disorder of fatigue: may improve amphetamines (ADHD) and narco- planning and one type (Adderall and lepsy (uncontrollable of working memory; others) If" sleep spells) appear to increase ‘ ‘ functioning on dull, repetitive tasks Modafinil Newer-generation Appear to augment (Provigil) stimulant for narco- mental focus and better Iepsy and excessive performance on a limited . sleepiness because of set of cognitive mea- w—J shift work or obstruc- sures, such as recall of live sleep apnea long strings of numbers Donepexll Treatment for the Might aid in learning or (Aricept) cognitive deficits of memory. but overall Altheimer's disease; results are equivocal; increases the neu- may take several weeks rotransmitter acetyi- to work and is not as ‘ choline to improve widely used off-label cognition as the drugs above Could worsen performance in a subset of users or on complex tasks; cardiovascular complications and seizures. hallucina- tions and addiction May have a higher potential for addic- tion than originally thought; may cause serious skin rashes Could cause a slight deterioration in cognitive perfor- mance in healthy individuals SCIENTIFIC AMERICAN 49 [MECHANISMS] Scientists soon wanted to know whether the perceiyed benefit in performance was genuine. . l’s‘y ‘holo'i ‘al assessments In both British and Some purported enhancers, such as methylphenidate and ~ L 2“ L ‘ amphetamines, alter the activity of the neurotransmitter dopamine in the synapses, the junction between neurons. Enhanced dopamine signaling may improve learning by focusing attention and interest on a task, Americans during the l9-ltls fotind that users self-rated their performance highly on tests that measured reading speed, multiplication and other factors. But their test scores, in most tasks, were no better than those earned by sub . . . . '-‘.\‘o' “s’ ‘tifl'n‘.)“‘)‘t. f;‘ Whenadopammewoducmg"gum"ls “We. itcts \h ingt ttdcil Ll L ltili in lllLL,lll ici, vesicles (sacs) in that signal-transmitting (piesyn- aptic) neuron release the neurotransmitter 1, Some of the neurotransmitter molecules cross the tiny gap, or (left, between neurons and attach to receptors on the signal—receiving (postsynaptitl neuron, activating them 2 and thereby control ling firing by the bound cell. Pumps on the transmitting tell then pull dopamine from the (left and back into the transmitting cell 3. cotild decline on more comples tasks. “because of their mood-elevating effects, amphetamines tend to make us feel we are performing especially well, when in fact we are not,“ says Nicolas Ras» t),[.5y.mml( mussen, a historian of science at University of """'”” New South Wales iii Sydney and author of the book ()11 Speed (New York University Press, 2008). “In simplistic lab tests assessing perfor- mance on boring tasks, they boost scores by in» creasing diligence, but that‘s not the same as tak ing a law school exam or llying in combat." Methylpbenidate, a close Chemical relative of the amphetamines, emerged in 1950 as a suppos- edly milder and gentler form of stimulant ("the happy medium in psychomotor stimulation," in SV'W’” the words of the drugmaker), bttt both its bio» Dopamine chemical and psychological effects are similar ,m [i . . , , . ' "eu'mmnsnm m when adiusted for dose. lhe halcyon era forain» l ' Dopamine ieuptake , . . . pump consumption reached as much as ll) billion pills phetamines occurred nearly 40 years ago. US. in the late I‘l(a()s before the Food and Drug /\d~ __ Rewpw,S ministration clamped down and labeled them as 1 controlled substances that required a special Postsynaptic neuron prescription. Neuroscientist Michael S. (Ea/la- niga of the Uniyersity of California, Santa Bar- bara, one of the authors of the Nature L‘UlltlllL‘ll' (Mann and concern, ta r), remembers his father sending him Ben/e» for instance) blocks the reuptake of dopamine. More dopamine is available to attach to a postsynaptic neuron, which amplifies the strength of the signal transmitted from the presynaptic neuron. and other amphetamines enter the presynaptic neuron through the pumping mechanism and cause dopamine to be displaced into the synaptic cleft, increasing the amount of neurotransmitter available to act on the postsynaptic cell. drine for sttidying when he was in college in the early I‘lolls. In the mid-this the growing use of meth- ylphenidatc for treatment of .‘\l)l ll) prompth researchers to deploy novel brain-imaging teche / I niclues and sophisticated neuropsychological tests to examine effects of the drug in healthy subjects. supplying a baseline for comparison with patients with A [)1 ID and other neuropsy- chiatric disorders. A I99- paper in l’s‘yc/m/i/Jar- 1i? I " ‘ Hiacology by Barbara bahakian,'l'rcyor Robbins and their colleagues at the Uniyersity of (iam— | Ritalin Aildeiall bridge showed that methylphenidatc improved cognitiye performance on seyeral measures (spa- tial working memory and planning" in particu- lar) in a group of rested, healthy young males but not on others, including attention and Verbal flu- ency. As testing progressed, the volunteers seemed to make more errors in their responses, 1") A ~ SCIENTIFIC AMERICAN October 2009 ' FE '. perhaps because of impulsiv ity induced by effects of the drug. [be same researchers found little cognitive benefit iii healthy elderly males. And in 1005 a group at the University of Florida Medical School at (iainesville could not turn up any cog- nitive boost from the drug among 20 sleep- deprivcd medical students. Another impediment to methylphenidate ever being placed alongside Nobox and other caffeitie pills is its potential for causing cardiac arrhythmias and for abuse as a recreational drug. Addiction is rare with normal dositig. But in the W'Us methylphenidate users routinely became addicted after inhaling or iii- iecting the drug that they called “West Coast.“ The Always-0n Drug The checkered legacy of amphetamines prompt- ed neuroscientists and physicians to hail the ar— rival of modafinil as a wakefubless-promoting agent with a seemingly more favorable side effect atid abuse profile than the amphetamines. The ability of modafinil (introduced in the [1.5. iti l998) to allow people to work long stretches without the need for breaks has turned it into a lifestyle drug for the jet-lagged who attempt to live in four time zones at once. Jamais (lascio. an associate of the Institute for the liuture iii I’alo Alto. (Ialif.. obtained a pre- scription for modafinil frotii his physician after hearing about it from friends who traveled a lot. 0n trips overseas, he noticed that it made him feel not only tiiore awake but also sharper. “'I'lie percei\ ed increased cognitive focus atid clarity was very much of .i surprise. but it was a very pleasant surprise." says (:Jsc‘lt). who has men» tiotied the drug in some articles he has written. “My experience was not that I‘d become a super- brain. It was more an experience of more easily slipping into a state of cognitive Ilow. a state of being able to work without distraction.“ 'I'esting has confirmed some of ( ascio‘s im— pressions. In 2003 Sahakian and Robbins found that (it) tested. healthy male volunteers did better on a few neuropsychological measures, such as recall of numerical sequences. but results were unchanged on others. Investigators elsewhere have also found benefits for the drug. although. as (lascio noted. it will not make a dunce into a genius. None ofthese studies. moreover. has test- ed effects on cognition over extended periods. Unregulated availability ofeitlier modafinil or methvlphenidate also remains unlikely because the drugs tend to affect individuals in different ways. Users with lower IQs appear to deri\e a www.ScientificAmerican.¢om / large performance boost from modatinil. where— as those with more innate ability show little or no benefit. With methylphenidate. those having poor working memory improved when tested: those having a naturally higher memory capacity showed much smaller benefits. As with amphetamines. modafinil did not emerge from a basic understanding of the tinder- lying biology ofhow the brain works. Present re- search sliows. however, that the drug seems to involve multiple neurotransmitters. the chemi- cals that trigger the firing of specific clusters of neurons. The drug‘s exact mechanism remains to be elucidated. But recently Nora I). \'olkow. di~ rector of the National Institute on Drug Abuse. atid her colleagues discovered that one of those neurotransmitters is dopamine, the same chemi- cal that is boosted by amphetamines and that im- bues those drugs with their addiction potential. “It appears that niethylphenidate and modafinil are \ery similar in what they‘re doing to the do- pamine system in the brain. contrary to w hat \\ as believed," says Volkow. although she adds that it is not practical to smoke or ingest modafinil to produce a strong high. so the possibility of abuse is lower. Another roadblock to wider use ap- peared in 2006. when the HM rejected the drug as a treatment for ADHD in children because of reports about serious skin rashes. Repackagingold attention-boosting drugs as cognitive enhancers for students, executives and [A LONG HISTORY] «5': T *‘N. A WARRIOR'S L TTLE HELPER Ihe notion that a pill ( nulil Inipiove mental and phyin al petioiuiant e in healthy people gained I IEth'liU' lllIIlIit) Woiltl Wu” H Both sales in the ( onilu I miisuined millions ol .iiiiphi-Ianiities, ‘il|( h .is these "wakey wakey” pills tlistiibult-(l by .i IIiitish Royal Ali Ion e IIIHllLdl llllll or to .i IIH‘IIIlH‘I Ill .i lioiuliei llitiht tiew SCIENTIFIC AMERICAN O 3 / New enhancers may derive from the biochemical processes underlying memory formation. [IN THE PIPELINE] software programmers may produce only ma r— ginal benefits ov er consuming .1 double espresso. The question of what exactly is .iii enhancer has prompted the convening of a group within the American College of Neuropsychopharmacol- ogy to discuss the standards that any drug should meet to be classified as a cognitive boost- er. Ultimately, enhancement drugs may come from another sphere of research. Insights into how we translate a baby‘s image or a friend’s name into lasting memories has laid the ground- work for new drugs specifically designed to achieve better functioning in people with All- heimer‘s or other dementias. Optimism about a new generation of pharma- ceuticals derives in part from advances in basic research into the biochemical processes underly- ing memory formation. More than 30 types of gene-altered mice have demonstrated the ability to both acquire information and store it in long- term memory better than the average mouse. “This is the first time in the history of neurosci— ence that we have the backbone of the molecular PROSPECTS FOR ENHANCERS Drugmakers have plans to counter various forms of dementia, ranging from that found in Alzheimer's disease to the common memory loss that occurs with aging (age—associated memory impairment). These compounds, a selection of which are included here and many of which have yet to reach late-stage clinical trials, might eventually be used by healthy people who want to improve mental functioning, although questions remain about how safe or effective they would be for people without a cognitive deficit. DRUG CLASS HOWlT WORKS DEVELOPERS Nicotinic Either increase levels of the neurotransmitter Abbott, CoMentis, EnVivo, acetylcholine acetylcholine in the synapse of a neuron, TargaceptlAstraZeneca receptor or the drugs themselves take the place and this activators of acetylcholine in the synapse to activate the nicotinic acetylcholine receptor, enhancing attention. memory and other facets of cognition Ampakines Act on AMPA receptors to strengthen Cortex Pharmaceuticals; neuronal responses to the neurotransmitter Eli Lilly, GlaxoSmithKlineI glutamate. activity that should facilitate Neurosearch, Organon, Pfizer the laying down of long-term memories and Servier lsee box on opposite page] Phospho~ One type of PDE blocker enables a signaling Helicon Therapeutics, diesterase molecule, cyclic AMP. to remain active longer Hoffmann—La Roche (PDE) in brain neurons, thereby enhancing the activity and Merck inhibitors of a protein called (kit! that is important to long-term memory [see box on opposite page] Antihistamines Block a histamine receptor called the H3 GlaxoSmithKline, receptor, thereby improving wakefulness, attention and cognition. One drug that interacts Johnson & Johnson and Medivation/Plizer with the H1 receptor, developed as a treatment for hay fever in Russia, has entered late-stage clinical trials as an enhancer 54 SCIENTIFIC AMERICAN and cellular biology of memory." says Alcino _]. Silva. a neurolnologist .it the University of Cali- fornia. l.os Angeles. "\\'hat this means for soci- ety is that for the first time we can use it to start changing how we learn and remember." But truly effective memory drugs are proba- bly a long way off. in part because of the scien— tific challenges. Most of the 100 gene mutations introduced into mice by researchers worldwide caused deficits. Silva remembers one mouse in his laboratory that illustrated the possible trade- offs that researchers will confront during devel- opitieiit of a cognitive enhancer. The animals learned faster than normal. unaltered mice but were unable to complete an elaborate puzzle ad- ministered by the investigators. “If you taught them something simple. they acquired it fast. but for anything more complicated. they couldn‘tac- quire it." Silva says. He estimates that it may take decades before drugs from this research are routinely used. The logistical challenges are daunting as well. Several of the first companies to enter the fray. including ones founded by leading academics. have faltered. In 2004 Science magazine cited four new firiiisa Sention. (.ortex Pharmaceuti- cals. Memory Pharmaceuticals and Helicon Therapeutics—as esemplars of a trend. Sention went out of business. (fortex is ailing and des- perately seeking a partner. Last year Hoffmann— La Roche purchased at a penny-stock price lless than $1) Memory. co-founded by Nobelist Kan- del. after it had experienced layoffs and a num- ber of failed clinical trials. Helicon has survived because of the largesse of billionaire Kenneth Dart. the Styrofoam cup magnate. who was eti- ticed by the prospect of memory drugs—the company has been developing a drug that would modulate a pathway related to glutamate. a neu- rotransmitter that triggers an intricate cellular signaling path related to the formation of long— term memories lsee box on opposm’ page]. .-\ sister company. Dart NeuroScience. novv handles development of new drug candidates. leaving the job of conducting clinical trials to Helicon. So far I lelicon has received more than S llli) million in funding but has yet to reach late- stage clinical trials for any of its drug candi- dates. “l he way I like toexplain this to audienc- es when I give talks is that when Helicon was formed I thought that l was making memory en- hancers for my parents and I had no gray hair." says 'l‘im Tully. Helicon's chief scientific officer. who co-founded the company when he was at (Iold Spring l larbor Laboratory. “They 're now October 2009 [MAKING BETTER MEMORIES] DfiUGS TOWREMEMBER I Piesynaptic neuitin Glutamate 1-! Calcium I ’ fi 1,. DRUG TARGET I i“ 2 Calcium NMDA(‘A_ inllux Postsynaptic ’ IIPIIIOIT 6c \ 4 ‘ 0“ i“ L 3 5y DRUG TARGET Syria ser strengt iening Neuron proteins nucleus Activated CREE dead, I‘m fully gray; and I'm fully cognizant of the fact that this is a race for me riot them." ’Iully, 55, adds that he does not foresee his creations ever becoming the next Viagra or Pro lac. “What the media loves to totally ignore is the side-effect potential and jump right to the wich speculation of this as a lifestyle drug," 'l‘ul- ly says. “And I think it‘s iust missing the mark. The reality is that it you‘ve got a debilitating form of memory impairment these drugs may be helpful, but they‘re probably going to be too dangerous for anyone else." Despite these cautionary tales. drngmakers continue trying to develop cognitive enhancers for [\l/heimer‘s and other dementias [see table on opposite/higel. Among the compounds under consideration are ones that alter the effects of neurotransmitters other than glutamate! including receptors switched on by the nicotine in tobacco (though not the one linked to ad diction). One of the reasons that people smoke is because nicotine helps to sharpen attention. www.ScientificAmerican.com Researchers have labored, in one instance for almost 20 years, on drugs that enhance cognition by acting on molecules involved in long-term memory. Neuroscientists postulate that long-term memory involves attachment of the neurotranstnit‘ ter glutamate to two types of receptorsonrecipient ,urons. After the AMPA receptor is bound 1 , it leads the other bound recep- tor the NMDA type ~ to open a channel, allowing an influx of calci- um 2 . Calcium sets off a train of signaling that activates a mole- cule, cyclic AMP 3, which, in turn, switches on other molecules that migrate to the cell's nucleus anti turn on the CREB protein 4 . CREE acts on DNA in a way that triggers synthesis at proteins that then move back to the synapse and strengthen the signaling connec- tion between the glutamate-emit- ting and glutamate— receiving new rons 5 Drugs that make this pro- cess more efficient~-either by enhancing signaling through AMPA receptors or by keeping cyclic AMP working longetfihave gone through a few clinical trials, . MORE TO EXPLORE Memories Are Made of This: How Memory Works in Humans and Animals. Rusiko Bouttchouladze, Columbia University Press, 2002. Towards Responsible Use of Cognitive-Enhancing Drugs by the Healthy. Henry Greely et al. in Nature, Vol. 456, pages 702—705; December 11, 2008. The Molecular and Cellular Biology of Enhanced Cognition, Yong Seok Lee and Alcino J. Silva in Nature Reviews Neuroscience, Vol. 10, pages 126—140; February 2009. The Future of Psychopharma- cological Enhancements: Expectations and Policies. Maartje Schermer et al. in Neuro- ethics, Vol. 2, pages 75 787; July 2009. Lessons learned from drugs developed for de mentia could lead to agents that case the milder cognitive problems associated with normal ag ing, assuming these compounds do not arrive burdened with intolerable side effects. If suffiA cieiitly benign. these pills could find their way into college dorms or e\ecutiye suites. “Within the pharmaceutical field, people recognize that a successful cognitive enhancer could be the best selling pharmaceutical olall time," says Peter Ii. Reiner, a professor ofneuroethics at the Univer- sity of l’mtish Columbia. Near to Market t\s scientifically satisfying as it would be for researchers to discover cognition-enhanciiig drugs through detailing the molecular process es that underlie cognition. the first new agents to reach the market for dementia and other cog nitive disorders may not spring from deep insight into neural functioning. They may come from the serendipitous discovery that some compound approved for another purpose litls effectson cognition. lior iiistziiicc" one drug cali— didate that recently entered late»stage trials for the cognitive dysluiictions of i\l/heimer‘s was developed in Russia as an antihistamine for hay fever and was later found to have antidementia properties. The potentially huge market has led sortie companies to take unorthodox routes to market, revisiting a failed drug or one that did not complete clinical trials and selling it as a dietary supplement or as a less stringently regu lated “medical food.“ Similarly, new medicines may arrive because regulatory agencies approve a broadening ofal- lowed uses for a drug already known to inllu~ ence cognition. (Iephalon, maker of modalinil. took this route, obtaining FDA permission to market the substance for shift workers. who compose a much larger group than the narcolep- tics (who suffer from uncontrolled sleep Cplr sodesl for whom it was originally approved. ((Iephalon also paid nearly $444 million to two states and the federal government for promoting three drugst including modafinil. for unap- proved uscs.) The impulse to improve cogni tion—whether to intensify mental locus or to help recall a friend's phone number—may prove so compelling to both drugmakers and consum- ers that it may overshadow the inevitable risks of toying with the neural circuitry that imbues us with our basic sense of sell. I (Jury SHIV is a it'ri/er at Scientific American. r'r' SCIENTIFIC AMERICAN OJ ...
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