Are we asking the right questions about smart drugs? Marek Kohn looks at what they can do for us — and what they can't.
"You know how they say that we can only access 20 per cent of our brain?" says the man who offers stressed-out, blank-screened 'writer' Eddie Morra a fateful pill in the 2011 film Limitless. "Well, what this does, it lets you access all of it." Morra, played by Bradley Cooper, is instantly transformed into a superhuman by the fictitious drug NZT-48. Granted access to all cognitive areas, he learns to play the piano in three days, finishes writing his book in four, and swiftly makes himself a millionaire.
Limitless is what you get when you flatter yourself that your head houses the most complex known object in the universe, and run away with the notion that it must have powers to match. More down to earth is the idea that we always have untapped cognitive potential, but that life gets between us and the best we could possibly manage.
Most people's best days still leave them wondering what might have been. Life is interference, acute and chronic: the broken night's sleep, the replayed arguments with our nearest and dearest, the suspected slight from a colleague, the mortgage, middle age, the buzzing fly. This is what preoccupation means. Noise, alarms and gnawing unease all occupy the cortex and commandeer its resources, leaving the brain short of space for other demands.
Even small differences in cognitive performance can make a world of difference — between a good CV and an outstanding one, between a second-class degree and a first, and between a winner and an also-ran. According to widespread reports, some students recognise this by using drugs to enhance their performance, particularly ahead of exams or coursework deadlines. How many of them are doing so is unknown: it may be fewer than you would think from reading both mainstream media coverage and scientific journals, but it's undoubtedly going on.
It's also been suggested that some students are taking cognitive enhancement drugs on into their professional lives after they graduate — in a report in New York magazine, for example, which dubbed the wake-promoting agent modafinil 'the real Limitlessdrug'.
The drugs concerned are the 'classic' psychostimulants: amphetamines (often prescribed under the name Adderall) and methylphenidate (also known by its brand name Ritalin) — both extensively prescribed to children and young adults for the burgeoning diagnosis of attention deficit hyperactivity disorder (ADHD) — as well as modafinil, which is indicated for sleep disorders, including those produced by shift work.
None of these drugs are new. The performance-enhancing effects of amphetamine were reported as far back as the 1930s, among adolescent boys taking the Stanford achievement test. Even the youngest of these drugs, modafinil, was first synthesised in the 1970s, when the term 'nootropics' was coined to define a class of drugs that improves the mind. And yet cognitive enhancement drugs are usually depicted as a distinctly contemporary phenomenon, with the implication that more of them are down the road, offering new capacities and increasing ethical challenges.
When scientists talk about cognitive enhancers today, they are often discussing drugs that mitigate the effects of the dementias and other cognitive disorders, whether they are new candidates or ones already in use such as donepezil and galantamine. Their aim is to recover function or reduce impairment, not improve on healthy levels — although, as populations age, dementias and other cognition disorders will climb healthcare priority lists, and the drugs developed to treat them may also turn out to aid cognition among healthy people, young and old.
By contrast, when futurists and ethicists talk about 'smart drugs' or cognitive enhancement, they tend to mean reaching levels of performance that were previously unattainable even under ideal conditions or acquiring new kinds of mental capability altogether.
One scientist who is eager to peer at the horizon is Gary Lynch, a professor in the School of Medicine at the University of California, Irvine. What excites him is what he sees as "the ultimate description of enhancement", the production of new capacities. "I'm interested in [the] capability to do things you can't do now, thoughts that you can't think, ideas that you can't form." He suggests extreme memory enhancement as an example of something you can't do now: the concerted boosting of attention, learning and memory could enable you to repeat a conversation verbatim or do mental maths at a far higher level than normal.
Thoughts that can't be thought and ideas that can't be formed are, by nature, difficult — if not impossible — to imagine. "It's at the fringe; it's beyond current cognitive science," Lynch admits. For the time being, we remain in the Amphetamine Age of cognitive pharmacology.
Cognition is a suite of mental phenomena that includes memory, attention and executive functions. Executive functions are not clearly defined, but you know them when you see them. They occupy the higher levels of thought: reasoning, planning, directing attention to information that is relevant (and away from stimuli that aren't), and thinking about what to do rather than acting on impulse or instinct. You activate executive functions when you tell yourself to count to ten instead of saying something you may regret. They are what we use to make our actions moral and what we think of when we think about what makes us human. Any candidate cognition drug would have to enhance executive functions to be considered truly 'smart'.
These are quite abstract concepts, though. There is a large gap, a grey area in between these concepts and our knowledge of how the brain functions physiologically — and it's in this grey area that cognitive enhancer development has to operate. Amy Arnsten, Professor of Neurobiology at Yale Medical School, is investigating how the cells in the brain work together to produce our higher cognition and executive function, which she describes as "being able to think about things that aren't currently stimulating your senses, the fundamentals of abstraction. This involves mental representations of our goals for the future, even if it's the future in just a few seconds."
At the front of the brain is the prefrontal cortex. This is the zone that produces such representations, and it is the focus of Arnsten's work. "The way the prefrontal cortex creates these representations is by having pyramidal cells — they're actually shaped like little pyramids — exciting each other. They keep each other firing, even when there's no information coming in from the environment to stimulate the circuits," she explains.
Several chemical influences can completely disconnect those circuits so they're no longer able to excite each other. "That's what happens when we're tired, when we're stressed." Drugs like caffeine and nicotine enhance the neurotransmitter acetylcholine, which helps restore function to the circuits. Hence people drink tea and coffee, or smoke cigarettes, "to try and put [the] prefrontal cortex into a more optimal state".
In a broad sense, it's enhancement; in a stricter one, it's optimisation. "I think people think about smart drugs the way they think about steroids in athletics," Arnsten says, "but it's not a proper analogy, because with steroids you're creating more muscle. With smart drugs, all you're doing is taking the brain that you have and putting it in its optimal chemical state. You're not taking Homer Simpson and making him into Einstein."
What's more, the brain is complicated. In trying to upgrade it, you risk upsetting its intricate balance. "It's not just about more, it's about having to be exquisitely and exactly right. And that's very hard to do."
Scientists are frequently reminded of the difference between 'more' and 'right' when they administer cognitive enhancers. Methylphenidate improves working memory in rats performing tasks that involve the prefrontal cortex, but only in a narrow range of doses. The graphs rise, level off and drop, tracing a path from 'not enough' to 'too much' in the shape of an inverted 'U'. Outside the lab, this point can be illustrated by comparing the effects of the first coffee of the day with those of the second or third.
A drug's scope for enhancement may also be compromised by differences in optimal doses among the various circuits it affects. "What's good for one system may be bad for another system," says Trevor Robbins, Professor of Cognitive Neuroscience at the University of Cambridge. And it may be bad for the system as a whole.
"It's clear from the experimental literature that you can affect memory with pharmacological agents, but the problem is keeping them safe," Robbins observes, "because this inverted-U-shape issue does give you the problem of possible epilepsy, convulsions and so forth."
The defining cognitive challenge of modern life is how to divide attention efficiently among multiple tasks and stimuli: not just how to concentrate, but how to compartmentalise. It's about switching rapidly and smoothly between tasks, keeping the unresolved material from each to hand while the processor swivels round to the next. It's the difference between the classical ideal of scholarship, of unqualified absorption in a single theme, and the reality of mental operations in a multiple-choice world where we are constantly beset by competing bids for our attention.
"Those two types of attention are really in opposition to each other," says Barbara Sahakian, Professor of Clinical Neuropsychology at the University of Cambridge. The implication is that if you enhance focused attention, it will be at the expense of divided attention, and vice versa.
However, Martin Sarter, a professor at the University of Michigan, sees it differently. According to Sarter, "pretty much everybody" in the field agrees that we deal with multiple tasks by 'time-sharing', tackling "one task at a time and using more or less complicated scripts to flip between tasks. This comes down to working memory plus focused attention."
Increasing focus, Sarter argues, increases the amount of work the brain gets done on a task before it switches to another, and thus reduces the amount of unfinished material from the task that has to be held in working memory until its turn comes round again. A drug that enhances focused attention will lower demands on both working memory and the control systems that monitor and manage the tasks in hand.
"That, we understand a bit," says Sarter. "How to enhance working memory capacity or executive control independently, I don't think we do understand, but that would be a neat trick."
People have known for a long time that stimulants can make users warm to their tasks. In 1916, when a man named Horace Kingsley was arrested in a pub on England's south coast for selling cocaine to soldiers, the authorities charged him with 'selling a powder to members of His Majesty's Forces, with intent to make them less capable of performing their duties'. On the contrary, he argued: "It makes you most keen on what you are doing."
Although it doesn't produce the buzz that hedonistic drug-takers pursue, modafinil may have other, more subtle attractions. Researchers at the University of Cambridge found it increased people's enjoyment of the cognition tests they were set, without improving their general mood.
"Under placebo, there's not much pleasure there at all, but under modafinil suddenly these tests seem very pleasurable," remarks Sahakian. Performance in planning and working memory improved, too. Sahakian considers modafinil a true cognition enhancer, enabling young and healthy people to perform better on difficult tasks than when they are given a placebo.
Other scientists are sceptical about whether any of these drugs enhance cognition directly, rather than by improving the user's state of mind. "I'm just not seeing the evidence that indicates these are clear cognition enhancers," says Sarter, who thinks they may be achieving their effects by relieving tiredness and boredom. "What most of these are actually doing is enabling the person who's taking them to focus," says Steven Rose, emeritus professor of life sciences at the Open University. "It's peripheral to the learning process itself."
It may, however, be central to the person's experience of what the learning experience feels like. Judging by accounts such as those gathered at an elite (unnamed) American university by researcher Scott Vrecko and published in 2013, the magic of cognitive enhancers lies in their ability to make study a pleasure. They overcome lethargy, reluctance and lack of confidence.
"I'll get out my books, laptop, and stuff, but even that can be a challenge," a student called Sarah told Vrecko. But when the Adderall takes effect, "all of a sudden I'll just be like, 'Oh wait. I can do this.'"
The doors of engagement open, as described by another student: "I remember getting just completely absorbed in one book, and then another, and as I was writing I was making connections between them [and] actually enjoying the process of putting ideas together. I hadn't had that before."
These students did not see their drug use as anything more than the removal of things that got between them and studying. They didn't think drugs made them smarter. Yet even so, it would be unwise to assume that the effects were as impressive as their users thought they were.
As the psychologist Derek Russell Davis drily observed back in 1947, "the subject who has taken amphetamine usually judges the effects more favourably than the experimenter". By way of illustration, he recalled how "a research colleague, left to his own devices after a dose of amphetamine, spent a morning preparing with great thoroughness a grandiose research-plan, of which he would never find time to carry out even a quarter."
One finding from a 2010 review of research that may come as a surprise to students who trust stimulants is that methylphenidate does not enhance attention and may even interfere with it. A recent study of Adderall at the University of Pennsylvania showed the drug failed to significantly affect cognition in healthy young adults — although those who took it mostly believed that it had.
In this kind of drug-taking, sensation isn't the goal but the effect of pursuing other goals. Recognising it as a distinct form of drug use — for neither medication nor recreation, but for application — raises several questions: one is whether these drugs are effective over sustained periods (the 2010 review of work on modafinil and methylphenidate found only two studies for each drug that looked at the effects of repeated doses, and the longest of those lasted just six weeks), and another is what effects they might have on their users' health. Sahakian emphasises the need for a long-term study "to determine whether these cognitive-enhancing drugs are safe for healthy people to use," adding that "our brains are in development into late adolescence and even young adulthood, [so] these safety concerns are particularly great for young, healthy people."
Drugs and catastrophe are seemingly never far apart, whether in laboratories, real life or Limitless. Downsides are all but unavoidable: if a drug enhances one particular cognitive function, the price may be paid by other functions. To enhance one dimension of cognition, you'll need to appropriate resources that would otherwise be available for others.
"There are costs to narrowing your attention," Sarter points out. "Not only all the stuff in the periphery that might be very significant that you might be missing, but internally — if you narrow your attentional field, it also narrows the range and scope of associations you could bring into your thought process."
In many settings that could well prove costly — but in others, where you're not being asked to think about the meaning of life, it could be beneficial. The inability to attend to one's internal network of associations would be desirable in an air traffic controller, for example.
If paying Paul always requires robbing Peter, we can't expect drugs to produce a general, cortex-wide expansion of cognition. But by allocating extra resources to one domain or the other, could you surpass the maximum levels you could previously have attained or even the highest levels attained by anyone?
"I think you can and you will," says Sarter, "but you will do so with respect to very defined functions within very defined task contexts."
For example, one of cognitive psychology's most famous findings is that people can typically hold seven items of information in their working memory. Could a drug push the figure up to nine or ten? "Yes. If you're asked to do nothing else, why not? That's a fairly simple function."
Scientists' opinions differ on the prospects for progressing beyond the Amphetamine Age. Rose thinks that because most drugs work by affecting multiple brain processes, the idea of a pure 'nootropic' that very specifically affects coding is implausible and has "long gone by the board". At the other end of the neuro-optimism scale, Lynch says "we are very close to being able to allow people to encode better".
Lynch argues that recent advances in neuroscience have opened the way for the smart design of drugs, configured for specific biological targets in the brain. "Memory enhancement is not very far off," he says, although the prospects for other kinds of mental enhancement are "very difficult to know… To me, there's an inevitability to the thing, but a timeline is difficult."
Lynch speaks after spending many years in an ultimately unsuccessful bid to develop a class of molecules called ampakines as a treatment for Alzheimer's disease. "The ampakines have been around for quite a while," he acknowledges. "They have gone into trials on ADHD; they have been in trials on memory. The problem has always been [that] there are side-effects."
Echoing Robbins's caveat about convulsions, Lynch draws a somewhat alarming lesson from his experience for researchers seeking new drugs to organise larger cognitive networks within the cortex: "The trick is not just to expand the networks, but to expand the networks without increasing the likelihood of seizures or some kind of psychosis. That may, in fact, be the most difficult part of the problem."
Lynch points to nicotinic receptor agents — molecules that act on the neurotransmitter receptors affected by nicotine, without necessarily being related to nicotine itself — as ones to watch when looking out for potential new cognitive enhancers. So does Sarter, who also emphasises the importance of basing cognitive enhancer research on neurobiological knowledge. A class of agents known as α4β2* nicotinic receptor agonists seem to act on mechanisms that control attention, Sarter says, "and to do so in a very orderly fashion that maps them to the neurobiology." Among the currently known candidates, he believes they come closest "to fulfilling the criteria for true cognition enhancers."
He is downbeat, however, about the likelihood of the pharmaceutical industry turning them into products. Its interest in cognitive enhancers is shrinking, he says, "because these drugs are not working for the big indications, which is the market that drives these developments. Even adult ADHD has not been considered a sufficiently attractive large market."
A substance called piracetam was once widely touted as a smart drug, as Rose recalled in a commentary piece published in 2002. Piracetam still has its enthusiasts, but its name is now mostly a reminder that candidate drugs come and go. "There have been a lot of clinical trials for a lot of substances that didn't do anything," observes Sarter.
Frustrated by the lack of results, pharmaceutical companies have been shutting down their psychiatric drug research programmes. Traditional methods, such as synthesising new molecules and seeing what effect they have on symptoms, seem to have run their course. A shift of strategy is looming, towards research that focuses on genes and brain circuitry rather than chemicals. The shift will prolong the wait for new blockbuster drugs further, as the new systems are developed, and offers no guarantees of results.
Lynch, Sarter and the pharmaceutical industry all agree that developing smarter drugs will require smarter science. A few new drugs (perhaps nicotinic receptor agonists, as Lynch and Sarter suggest) might emerge in the current system, but to find out what's possible beyond that will need a reinvented research programme. For real success, research needs to show what these drugs can do at the level of systems neuroscience and to establish systematic relationships between drug effects on circuits, receptors, behaviour and cognitive operations.
In the meantime, with no end to the Amphetamine Age in sight, smarter answers are needed for the unanswered questions about the drugs people already take in the hope of enhancing their cognitive powers — questions about whether they work, how they work, whether they work differently in people with different gene variants, the effects they have on the mind after their initial novelty has worn off, and the effects they may have on our health and wellbeing in the long term.
Despite decades of study, a full picture has yet to emerge of the cognitive effects of the classic psychostimulants and modafinil. Recent reviews indicate that they may help to lay down long-term memories and perhaps help keep information present to hand in working memory. They may also enhance 'cognitive control', the ability to adapt behaviour in changing conditions, particularly in people whose powers of cognitive control are modest to start with.
Part of the problem is that getting rats, or indeed students, to do puzzles in laboratories may not be a reliable guide to drugs' effects in the wider world. Drugs have complicated effects on individuals living complicated lives. Determining that methylphenidate enhances cognition in rats by acting on their prefrontal cortex doesn't tell you the potential impact that its effects on mood or motivation may have on human cognition.
It may also be necessary to ask not just whether a drug enhances cognition, but in whom. Researchers at the University of Sussex have found that nicotine improved performance on memory tests in young adults who carried one variant of a particular gene but not in those with a different version. In addition, there are already hints that the smarter you are, the less smart drugs will do for you. One study found that modafinil improved performance in a group of students whose mean IQ was 106, but not in a group with an average of 115.
There are smarter questions to ask about fairness and cognition-affecting drugs. So far, the ethical anxieties have revolved around elite competition: whether students who take drugs to enhance performance are cheating, and whether they will put pressure on their peers to do likewise to avoid being at a competitive disadvantage. But attention is not just a problem for the minority who reach higher education or certain professions.
In their book Scarcity: Why having too little means so much, Sendhil Mullainathan and Eldar Shafir describe how they dumbed people down by inducing them to think about the cost of living. Recruiting shoppers from a New Jersey mall, they prefaced cognition tests with a hypothetical question that invited respondents to imagine they had to get their cars serviced. They also asked the shoppers to disclose their household incomes. When the price of the service was given as $US300, the scores of rich and poor were indistinguishable. When it was $US3,000, the poorer shoppers scored worse; in fact, their scores were worse than those of people who did similar tests after a night without sleep. Their results implied a drop in IQ of 13 or 14 points, the difference between average and 'borderline deficient' intelligence.
Mullainathan and Shafir argue that the increase in the imaginary cost triggered a reallocation of mental capacity among those for whom such a sum would be a serious problem in real life. It activated thought processes that would not shut off, reducing the computational power available to process the intelligence tests. If that is what a hypothetical problem can do, the effects of poverty and money worries in the real world must be a cognitive scandal of staggering proportions.
Mullainathan and Shafir's work points towards a bigger picture of fairness in cognitive enhancement. One message that has emerged from the research so far is that cognition-affecting drugs do more for lower performers than high-fliers and that they can offset disadvantages, such as lack of sleep. Drugs that promote concentration might help poor people in their efforts to better themselves — studying at night school while fatigued from long hours of labour, for example — or, if Sarter is right about how improving focused attention can make it easier to deal with multiple demands, in coping with bills that outnumber earnings.
It's certainly better to enhance cognitive performance through healthy living, fitness and educational opportunities than by taking pills. But we also have to recognise that it is far harder for the poor to achieve best cognitive practice than the rich. The question of whether drugs could help people get out of poverty, by offsetting its cognitive impact on them, might actually be the smartest question we can ask about smart drugs.
This article first appeared on Mosaic and is republished here under Creative Commons licence. Mosaic is dedicated to exploring the science of life. Each week, it publishes a feature on an aspect of biology or medicine that affects our lives, our health or our society; it tells stories with real depth about the ideas, trends and people that drive contemporary life sciences. Mosaic is published by the Wellcome Trust, a global charitable foundation that seeks to drive extraordinary improvements in human and animal health. It covers subjects that fit with the Trust's mission and vision, but isn't limited to the research the Trust funds.