# The billion dollar business of being smart

BMJ 2015; 351 (Published 14 September 2015) Cite this as: BMJ 2015;351:h4829
1. Krishna Chinthapalli, neurology advanced trainee, Royal North Shore Hospital, Sydney, Australia
1. kchinthapalli{at}bmj.com

Demand for cognitive enhancement is huge and growing

The prolific French novelist Honore de Balzac wrote for 15 hours a day with the help of his “precious essence.” After a dose, he said, “Ideas march into motion like battalions . . . Memories charge in . . . The cavalry of metaphor deploys with a magnificent gallop; the artillery of logic rushes up.”1 He eventually took it up to 50 times a day. As far as de Balzac was concerned, caffeine was his “smart drug.”

Caffeine is still the drug of choice for many college students in search of the same effects. Most have used coffee, caffeine drinks, or caffeine tablets to help them study.2 In the United States, caffeine is now being supplanted by the prescription stimulants Adderall (amphetamine plus dextroamphetamine), methylphenidate, and modafinil. Some 5-15% of college and university students report taking these stimulants to help academic performance but most do so only occasionally (40% had used them only once or twice).3 Colleges with higher entry criteria have a higher prevalence of stimulant use. In high schools, too, 7% of final year students took a prescription stimulant without a prescription in 2014.4

The number of students using stimulants legally has also been increasing because these drugs are indicated in the treatment of attention deficit hyperactivity disorder (ADHD). One in nine US children has a diagnosis of ADHD, and the prevalence is increasing by 5% a year.5 Some of this increase may be due to malingering, with a quarter of college students thought to be feigning symptoms (for prescriptions or incentives such as extended time).6

The UK has fewer data, but a 2012 online survey of university students showed that lifetime prevalence of drug use to help academic performance was 24% for caffeine pills, 6% for modafinil, 4% for methylphenidate, and 2% for amphetamine.7 Two thirds of remaining students said that lack of access was the only reason they had not tried such drugs.

## Growing market

Aside from stimulants, other tools purport to keep your brain sharp. Crosswords are being replaced by brain training games, now a billion dollar industry. Overstated claims by software companies led to a consensus statement last year by more than 60 neuroscientists warning that evidence was sparse and of poor quality. They concluded, “If an hour spent doing solo software drills is an hour not spent hiking, learning Italian, making a new recipe, or playing with your grandchildren, it may not be worth it.”8

International sales of non-prescription supplements for cognition also exceed $1bn (£650 000; €880 000) a year and are rapidly growing. Ginkgo biloba, vitamins, and even caffeine are common ingredients. Some add piracetam (related to the epilepsy drug levetiracetam), jellyfish proteins, or even “edible pure 23.5 carat gold flakes.” Prescription drug manufacturers have been keen to take a slice of this market. Cephalon, which released modafinil in 1998 for narcolepsy, was marketing the drug for off-label uses such as fatigue or depression with little clinical support.9 It worked: 80% of modafinil prescriptions were for off-label use between 2001 and 2006, but it eventually also led to a$425m fine imposed in 2008.10 This was the first time a drug company was prosecuted for promoting off-label uses that lacked scientific evidence. The company also extended the patent from 2001 by obtaining a patent on a specific formulation that ran until 2014. Generic companies could circumvent this new patent by creating different formulations, and four of them applied to do just that. In May 2015 the Federal Trade Commission fined Cephalon $1.2bn for unlawfully extending its monopoly by paying the generic companies$300m to delay their generic drugs until 2012.11 Meanwhile, modafinil sales were $1bn a year. Cephalon had a longer term plan, common in the drug industry, known as “product hopping.” Cephalon wanted to switch users from modafinil to its newer compound armodafinil, which has a patent until 2016, before generic modafinil became available in 2012. Armodafinil has a patent until 2016. To do this, it raised the price of modafinil tablets from$5.50 to $13.60 over five years until 2009 and introduced armodafinil at$9 a tablet.12

Methylphenidate and amphetamine work by increasing extracellular dopamine levels, but the mechanism of action of modafinil is not fully understood. It may increase cortical levels of catecholamines, glutamate, and serotonin.13 Whatever its mechanism, modafinil has fewer side effects, particularly producing less dependence. A recent systematic review concluded that modafinil improves executive functions.14 However, 22 of the 24 studies considered only a single dose of modafinil for effects on cognitive tasks and side effects.

## Banned in chess

“With Adderall, I’d characterize the effect as . . . correction of an underlying condition. Provigil [modafinil] feels like enhancement,” Paul Phillips, a professional poker player, told the New Yorker.15 Phillips won more prize money within six months of taking amphetamine than in the previous four years. Stimulants are allowed in poker tournaments but banned in chess.

In the competition for grades, Duke University in the US has banned stimulants, stating that “the unauthorized use of prescription medication to enhance academic performance” constitutes cheating.16 There has been little public debate about the ethics of powerful “smart drugs,” which may arrive soon due to increasing consumer demand and increasing research into dementia treatments. For now we can still have a cup of coffee.

## Notes

Cite this as: BMJ 2015;351:h4829

## Footnotes

• Competing interests: I have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.

• Provenance and peer review: Commissioned; externally peer reviewed.