The symbol H+ is the code sign used by some futurists to denote an enhanced version of humanity. The plus version of the human race would deploy a mix of advanced technologies, 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 century of the better brain.”

Obsession with cognitive enhancers is evidenced in news articles hailing the arrival of what are variously called smart drugs, neuroenhancers, nootropics or even “Viagra for the brain.” From this perspective, an era of enhancement has already arrived. College students routinely borrow a few pills from a friend's Ritalin prescription to pull an all-nighter. Software programmers on deadline or executives trying to 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 esoterica of collateralized debt obligations.

An era of enhancement may also be advanced by scientists and drugmakers laboring to translate research on the molecular basis of cognition into pharmaceuticals meant specifically to improve mental performance—mainly for people suffering from dementias. But a drug that works for Alzheimer's or Parkinson's patients might inevitably be prescribed by physicians far more broadly in an aging population with milder impairments. Widely 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 whether cognitive enhancers already give some students an unfair advantage when taking college entrance exams or whether employers would step over the 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 reality 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 of directors? Will any drug that fiddles with basic brain functions ever be safe enough to be sold alongside nonprescription pain relievers and antacids? 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 enhancers that are otherwise prescribed for conditions such as ADHD. Based on government data gathered in 2011, more than 2.7 million people in the U.S. had used prescription stimulants nonmedically during the previous 12 months. Legal medicines in this category include methylphenidate (Ritalin), the amphetamine Adderall and modafinil (Provigil). On some campuses, one quarter of students have reported using the drugs. And an informal online reader survey by Nature in 2008 showed 20 percent of 1,427 respondents from 60 countries polled about their own use said they had used either methylphenidate, modafinil or beta blockers (the last for stage fright). Overall, a need for improved concentration was the reason cited most frequently. People often manage to acquire the drugs on the Internet 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 most likely grow along with an aging population and with an increasingly globalized economy. “If 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 compounds,” asserts 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 of the popularity of these 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 and neuroscientists published a commentary in Nature in 2008 raising the prospect of a shift away from the notion of drugs as a treatment primarily for illness. The article suggested the possibility of making psychostimulants widely available to the able-minded to improve performance in the classroom or the boardroom, 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 pharmaceutical enhancement with “education, good health habits, and information technology—ways that our uniquely innovative species tries to improve itself.”

Six months later one of the article's authors, John Harris, a bioethicist at the University of Manchester in England, went further in an opinion piece in the British Medical Journal. Harris, at the time an editor of the Journal of Medical Ethics and author of the 2007 book Enhancing Evolution, noted that if methylphenidate is judged safe enough to be used in children, it should be considered sufficiently innocuous for consumption by adults interested in turbocharging their brains. In a later interview, Harris said he foresaw a gradual loosening of restrictions, and if no safety problems arise, the drug (a controlled substance in the U.S.) could ultimately become an over-the-counter 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 a nonprescription painkiller or coffee or tea.

“People say that cognitive enhancement is just like improving vision by wearing glasses,” says James Swanson, a researcher at the University of California, Irvine, who was involved with clinical trials for both Adderall and modafinil for ADHD. “I don't think people understand the risks that occur when you have a large number of people accessing these drugs. Some small percentage will likely become addicted, and some people may actually see mental performance decline. That's the reason I'm opposed to their general use.” Along these lines, the British Home Office, the interior ministry, has been considering for years whether the potential harm from nonmedical use of enhancers requires new regulations.

Other scientists assert that the debate may be moot because improving smarts might not be possible through any means but the tedious exercise of studying for a calculus exam. Some who have tried to develop drugs to reverse the memory loss of dementia doubt whether enhancement of the healthy is anything but a remote possibility. “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 popular book about the science of memory and a researcher 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 of chemical signals, 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 addressable by compensating for losses of key chemicals and might merit the risk of untoward side effects from drug intervention. But upsetting the fragile stasis in the healthy could produce unintended consequences: as just one example, 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 ethics of neuroenhancement attribute the current flap to what they call “speculative ethics.” This tendency also besets nanotechnology and other technological endeavors in which ethicists, scientists and policy makers are diverted by discussions of the social implications of technologies yet to be 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 Maartje Schermer of Erasmus University Rotterdam and her colleagues in the journal Neuroethics.

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 Gordon Alles introduced amphetamine for medical use in 1929, a synthetic drug chemically similar to the Chinese herb ephedrine. (Alles also devised the drug Ecstasy, another amphetamine.) Various forms were dispensed on both sides during World War II to keep soldiers awake and alert and to bolster courage. The Germans and Japanese ingested methamphetamine, while the British and Americans used Benzedrine, a similar drug to Adderall.

Scientists soon wanted to know whether the perceived benefit in performance was genuine. Psychological assessments by both British and Americans during the 1940s found 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 subjects who ingested caffeine. Performance, in fact, could decline on more complex 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 Rasmussen, a historian of science at University of New South Wales in Sydney and author of the book On Speed (New York University Press, 2008). “In simplistic lab tests assessing performance on boring tasks, they boost scores by increasing diligence, but that's not the same as taking a law school exam or flying in combat.”

Methylphenidate, a close chemical relative of the amphetamines, emerged in 1956 as a supposedly milder and gentler form of stimulant (“the happy medium in psychomotor stimulation,” in the words of the drugmaker), but both its biochemical and psychological effects are similar when adjusted for dose. The halcyon era for amphetamines occurred more than 40 years ago. U.S. consumption reached as much as 10 billion pills in the late 1960s before the Food and Drug Administration clamped down and labeled them as controlled substances that required a special prescription. Neuroscientist Michael S. Gazzaniga of the University of California, Santa Barbara, one of the authors of the Nature commentary, remembers his father sending him Benzedrine for studying when he was in college in the early 1960s.

In the mid-1990s the growing use of methylphenidate for treatment of ADHD prompted researchers to deploy novel brain-imaging techniques and sophisticated neuropsychological tests to examine effects of the drug in healthy subjects, supplying a baseline for comparison with patients with ADHD and other neuropsychiatric disorders. A 1997 paper in Psychopharmacology by Barbara Sahakian, Trevor Robbins and their colleagues at the University of Cambridge showed that methylphenidate improved cognitive performance on several measures (spatial working memory and planning, in particular) in a group of rested, healthy young males but not on others, including attention and verbal fluency. As testing progressed, the volunteers seemed to make more errors in their responses, perhaps because of impulsivity induced by effects of the drug.

The same researchers found little cognitive benefit in healthy elderly males. And in 2005 a group at the University of Florida Medical School at Gainesville could not turn up any cognitive boost from the drug among 20 sleep-deprived medical students. Another impediment to methylphenidate ever being placed alongside NoDoz and other caffeine pills is its potential for causing cardiac arrhythmias and for abuse as a recreational drug. Addiction is rare with normal dosing. But in the 1970s methylphenidate users routinely became addicted after inhaling or injecting the drug that they called “West Coast.”

The Always-On Drug
The checkered legacy of amphetamines prompted neuroscientists and physicians to hail the arrival of modafinil as a wakefulness-promoting agent with a seemingly more favorable side effect and abuse profile than the amphetamines. The ability of modafinil (introduced in the U.S. in 1998) 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 Cascio, an associate of the Institute for the Future in Palo Alto, Calif., obtained a prescription for modafinil from his physician after hearing about it from friends who traveled a lot. On trips overseas, he noticed that it made him feel not only more awake but also sharper. “The perceived increased cognitive focus and clarity was very much of a surprise, but it was a very pleasant surprise,” says Cascio, who has mentioned the drug in some articles he has written. “My experience was not that I'd become a superbrain. It was more an experience of more easily slipping into a state of cognitive flow, a state of being able to work without distraction.”

Testing has confirmed some of Cascio's impressions. In 2003 Sahakian and Robbins found that 60 rested, 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 Cascio noted, it will not make a dunce into a genius. None of these studies, moreover, has tested effects on cognition over extended periods.

Unregulated availability of either modafinil or methylphenidate also remains unlikely because the drugs tend to affect individuals in different ways. Users with lower IQs appear to derive a large performance boost from modafinil, whereas 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 underlying biology of how the brain works. Present research shows, however, that the drug seems to involve multiple neurotransmitters, the chemicals that trigger the firing of specific clusters of neurons. The drug's exact mechanism remains to be elucidated. But recently Nora D. Volkow, director of the National Institute on Drug Abuse, and her colleagues discovered that one of those neurotransmitters is dopamine, the same chemical that is boosted by amphetamines and that imbues those drugs with their addiction potential. “It appears that methylphenidate and modafinil are very similar in what they're doing to the dopamine system in the brain, contrary to what was 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 appeared in 2006, when the FDA rejected the drug as a treatment for ADHD in children because of reports about serious skin rashes.

Repackaging old attention-boosting drugs as cognitive enhancers for students, executives and software programmers may produce only marginal benefits over consuming a double espresso. The question of what exactly is an enhancer has, at times, prompted professionals in the field to consider standards that any drug should meet to be classified as a cognitive booster. 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 groundwork for new drugs specifically designed to achieve better functioning in people with Alzheimer's or other dementias.

Optimism about a new generation of pharmaceuticals derives in part from advances in basic research into the biochemical processes underlying 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 neuroscience that we have the backbone of the molecular and cellular biology of memory,” says Alcino J. Silva, a neurobiologist at the University of California, Los Angeles. “What this means for society is that for the first time we can use it to start changing how we learn and remember.”

But truly effective memory drugs are probably a long way off, in part because of the scientific challenges. Most of the 200 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 development of a cognitive enhancer. The animals learned faster than normal, unaltered mice but were unable to complete an elaborate puzzle administered by the investigators. “If you taught them something simple, they acquired it fast, but for anything more complicated, they couldn't acquire 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 firms—Sention, Cortex Pharmaceuticals, Memory Pharmaceuticals and Helicon Therapeutics—as exemplars of a trend. Sention went out of business. Cortex merged with Pier Pharmaceuticals in 2012 and now focuses entirely on treatments for breathing disorders. In 2008 Hoffmann–La Roche purchased at a penny-stock price (less than $1) Memory, co-founded by Nobelist Kandel, after it had experienced layoffs and a number of failed clinical trials. The research program of Helicon—the company merged with Dart NeuroScience in 2012—has survived because of the largesse of billionaire Kenneth Dart, the Styrofoam cup magnate, who was enticed by the prospect of memory drugs. The company has been developing a drug that would modulate a pathway related to glutamate, a neurotransmitter that triggers an intricate cellular signaling path related to the formation of long-term memories.

Before the merger, Helicon received more than $100 million in funding but failed to reach late-stage clinical trials for any of its drug candidates. “The way I like to explain this to audiences when I give talks is that when Helicon was formed I thought that I was making memory enhancers for my parents and I had no gray hair,” says Tim Tully, Dart's executive vice president and chief scientific officer, who co-founded Helicon when he was at Cold Spring Harbor Laboratory. “They're now dead, I'm fully gray, and I'm fully cognizant of the fact that this is a race for me not them.”

Tully, 60, adds that he does not foresee his creations ever becoming the next Viagra or Prozac. “What the media loves to totally ignore is the side-effect potential and jump right to the wild speculation of this as a lifestyle drug,” he says. “And I think it's just missing the mark. The reality is that if 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, drugmakers continue trying to develop cognitive enhancers for Alzheimer's and other dementias. 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 addiction). One of the reasons that people smoke is because nicotine helps to sharpen attention.

Lessons learned from drugs developed for dementia could lead to agents that ease the milder cognitive problems associated with normal aging, assuming these compounds do not arrive burdened with intolerable side effects. If sufficiently benign, these pills could find their way into college dorms or executive suites. “Within the pharmaceutical field, people recognize that a successful cognitive enhancer could be the best-selling pharmaceutical of all time,” says Peter B. Reiner, a professor of neuroethics at the University of British Columbia.

Near to Market
As scientifically satisfying as it would be for researchers to discover cognition-enhancing drugs through detailing the molecular processes that underlie cognition, the first new agents to reach the market for dementia and other cognitive disorders may not spring from deep insight into neural functioning. They may come from the serendipitous discovery that some compound approved for another purpose has effects on cognition.

For instance, one drug candidate, which ultimately failed for the cognitive dysfunctions of Alzheimer'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 some 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 regulated “medical food.”

Similarly, new medicines may arrive because regulatory agencies approve a broadening of allowed uses for a drug already known to influence cognition. Cephalon, maker of modafinil, took this route, obtaining FDA permission to market the substance for shift workers, who compose a much larger group than the narcoleptics (who suffer from uncontrolled sleep episodes) for whom it was originally approved. (Cephalon also paid nearly $444 million to two states and the federal government for promoting three drugs, including modafinil, for unapproved uses.) The impulse to improve cognition—whether to intensify mental focus or to help recall a friend's phone number—may prove so compelling to both drugmakers and consumers that it may overshadow the inevitable risks of toying with the neural circuitry that imbues us with our basic sense of self.