Brain boosters: exploring the grey area of off-label ‘smart drugs’

The growing trend for the unlicensed use of cognitive-enhancing drugs to improve performance is prompting calls for more research into the field. Has the era of brain-boosting ‘smart pills’ arrived, and what do we still need to find out about the safety and efficacy of drugs like modafinil and methylphenidate in healthy adults?


The concept of chemically enhancing the functionality of the human brain is not a new one. For well over a century, some of the world’s foremost academics and visionary thinkers have been enthusiastic users of recreational drugs. Sigmund Freud had an extensive relationship with cocaine and viewed it as a wonder drug with a range of potential clinical applications, while British molecular biologist Francis Crick and his team reportedly took regular small doses of LSD as a ‘thinking tool’ as they worked to identify the structure of the DNA molecule at Cambridge University in the 1950s.

Paul Erdos, one of the most prolific mathematicians of the 20th century, was so dependent on amphetamines that after he stopped taking the drug for a month to win a bet, he quipped to the loser of the wager: “You’ve set mathematics back a month.”

Despite the storied relationship between academics and illicit, mind-altering drugs, a relatively new trend in the concept of so-called ‘smart drugs’ has emerged in the modern medical era. The off-label use of cognitive drugs developed by the pharma industry to treat various conditions – from methylphenidate (Ritalin et al) for attention deficit hyperactivity disorder (ADHD) to modafinil (Provigil et al) for narcolepsy and other sleep-related disorders – seems to have been steadily increasing among healthy adults in an attempt to boost focus, memory and other aspects of normal cognitive function.

There is an increasing bank of data noting the potential cognitive benefits of such drugs, which has sparked a growing debate about how they could influence the choices of university students, military personnel and even the average office worker. Still, there is also a massive dearth of data on the effects of long-term usage of modafinil and the like by healthy adults, and no shortage of warnings on the potential risks involved.

Off-label nootropics: increasingly mainstream

Although data in this area is hardly comprehensive, various surveys suggest that the off-prescription use of cognitive enhancers (also described as nootropics) is becoming an increasingly mainstream option for students, the military and those who work in high-pressure jobs. Many studies have focused on the use of modafinil, methylphenidate and other nootropics by students at US universities, with usage estimates varying from as low as 5% to as high as 35%.

Back in 2008, the Nature journal surveyed 1,400 of its readers in 60 countries, and found that nearly one in five had used drugs off-label to stimulate their focus, concentration or memory.

More recently, a survey presented at the 2014 Pediatric Academic Societies annual meeting found that a similar proportion of students attending prestigious Ivy League universities in the US were using prescription stimulants while studying, while a third thought that taking these drugs didn’t amount to cheating.

And there is increasing evidence that off-label nootropics are playing a more prominent role in the day-to-day lives of office workers. A 2015 survey of 5,000 workers at a German health insurance company found that 6.7% were using cognitive-enhancing drugs to boost performance or deal with stress, an increase on the 4.7% who admitted doing the same in 2009. Some Silicon Valley start-ups have reportedly even started taking a leaf out of Crick and co.’s book by ‘micro-dosing’ LSD to improve creative thinking.

Various militaries, meanwhile, have tested the likes of modafinil as a performance enhancer for soldiers and pilots who regularly have to operate with little sleep.

While a detailed global picture on unlicensed nootropics usage by adults without cognitive disorders has not emerged, the piecemeal data that does exist seems to confirm that ‘smart drugs’ are going through a mainstreaming process. Who knows where these statistics might cap out in the future, but the prevalence of their use today means that if there are any health issues involved, they are likely to affect a great many people.

Checkmate: benefits of nootropics as performance enhancers

With so many people potentially using nootropics as performance enhancers, there’s an obvious question: do they work? Indeed, there is a solid evidence base suggesting that methylphenidate, modafinil and others are effective at boosting cognitive functions.

In March, results were revealed from a double-blind, randomised controlled trial that was the first study to measure the effects of modafinil, methylphenidate and caffeine on chess players. The German-Swedish study, which was published in the March edition of the peer-reviewed journal European Neuropsychopharmacology, found that certain drugs did have a measurable effect on the performance of the 39 male chess players who participated.

The volunteers were each dosed with either modafinil, methylphenidate, caffeine or a placebo, and then played a series of time-limited games against a computer opponent. After a total of 3,000 chess games, the study found that modafinil and methylphenidate both significantly improved players’ scores, while caffeine was found to have a more modest effect that was deemed not statistically significant. Interestingly, players using nootropics generally took longer to make decisions, and more often lost by running out of time.

“We were surprised to see that players on the drugs played more slowly than normal, indicating that their thought processes seemed to be deeper,” said the study’s lead author Professor Klaus Lieb.

Other studies have concluded that modafinil can be effective and is relatively safe in terms of its side effects profile in non-sleep deprived users. A 2015 systematic review by researchers from Harvard University and Oxford University investigated 24 studies and found a consensus that modafinil improved planning and decision-making, while making little difference to memory or flexibility of thought.

Longer and more complex tasks were associated with more consistent benefits from the drug, while 70% of studies that looked into side effects found that they were, in the words of review co-author Dr Anna-Katharine Brem, “vanishingly few” in the short term, with only occasional reporting of insomnia, headaches, stomach aches or nausea.

Longer-term risks: more data needed

Longer-term impacts from regular nootropics use could be a different story. Virtually all of the studies suggesting the short-term efficacy and/or safety of cognitive enhancers in healthy adults strongly emphasise the limitations of their research, and explicitly recognise the need for a bigger evidence base to validate early results and expand knowledge in the field.

“So long as [nootropics] are safe in the long-term for healthy people to use, and if they are demonstrated to be effective, that would be good,” Cambridge University professor of clinical neuropsychology Barbara Sahakian, who co-authored a personal view piece on the topic in the Lancet Psychiatry journal, told Sky News in August last year. “But we don't have as yet these long-term safety studies.”

In fact, there is some suggestion that drugs such as modafinil and methylphenidate could pose long-term risks for healthy users, especially young people. A 2014 National Institutes of Health-funded review of data by Dr Kimberly Urban and Dr Wen-Jun Gao of the University of Delaware and Drexel University College of Medicine, respectively, found that the performance-enhancing effects of such drugs may come with a long-term cost for brain plasticity, which is important for complex motoric learning, adaptive flexibility in behaviour and advance planning.

“The human brain continues to develop until our late twenties or early thirties,” said Urban. “Young people are especially prone to abuse smart drugs, but also more vulnerable to any side-effects. We simply don't know enough about the long-term effects of these drugs on the developing brain to conclude they are safe.”

But the extensive ongoing research required to properly investigate the long-term effects of off-label cognitive enhancers doesn’t seem to be getting the funding it needs. Somewhat understandably, studying the effects of performance-enhancing drugs for healthy people falls fairly low on the global list of research priorities, not to mention the inherent ethical issues of research that might be seen as encouraging the misuse of prescription medication.

“It appears that funding for drug-based studies on healthy individuals fails to attract typically medical-oriented grants and awards,” Brem told Tech Insider in June last year.

A smarter future?

Nevertheless, the lack of data in this area essentially leaves this ‘brain boosting’ nootropics market in the hands of informal Internet ‘group buying’ schemes, as well as the less-regulated supplements industry. Given that the non-medical use of these compounds is unlikely to regulate itself, a broader and deeper knowledge base will be vital to establish firm national policies and regulations on their administration.

Beyond that, the incredibly complex ethical implications of widespread ‘smart drug’ usage in universities and workplaces are, for the most part, still to come. Will some students and people working in stressful careers feel pressured to use these drugs to avoid falling behind? Could off-label use of these drugs prompt harmful addictive behaviours? And in what sense might using these drugs constitute ‘cheating’ – if athletes are banned from taking physical performance enhancers, should academics be banned from using cognitive drugs?

The thinking on these topics is only starting to develop. Duke University in North Carolina, for example, has amended its honest code to include “unauthorised use of prescription medication to enhance academic performance” as a form of cheating, although actually enforcing this policy is another matter entirely.

The future of brain-boosting ‘smart drugs’ appears to be upon us, whether we are ready for it or not. Now is the time to focus research on working out exactly what it might mean for our health and the limits of our intelligence.