'Smart' drugs may backfire when used as cognitive enhancers, study finds

This is a MedPage Today story.

"Smart" drugs -- prescription stimulants used as cognitive enhancers by people without attention deficit-hyperactivity disorder (ADHD) -- reduced performance in complex everyday activities, a small double-blind randomized trial showed.

Cognitive enhancers -- methylphenidate (Ritalin), dextroamphetamine (Dexedrine), or modafinil (Provigil) -- led to small decreases in accuracy and efficiency and large increases in time and effort on a complex task, reported Dr. Peter Bossaerts of the University of Cambridge in England and the University of Melbourne in Australia, and co-authors in Science Advances.

Because the drugs induce dopamine, the researchers expected to see increased motivation. But the exertion caused by this motivation may have led to more erratic thinking when participants were faced with hard problems, they suggested.

"We were skeptical that motivation and attention alone were sufficient to be good at combinatorial tasks, as opposed to tasks one can easily do with reinforcement learning," Bossaerts told MedPage Today.

"The drugs have an impact on motivation, attention, and maybe working memory, but a combinatorial task requires one to approach a problem in systematic ways," he pointed out. "You don't solve jigsaw puzzles by randomly throwing pieces in the air until they accidentally fall into place."

The trial tested 40 people without ADHD on the knapsack optimization problem, a task involving a virtual knapsack with a set capacity. Participants selected items of varying weights and values to maximize the value of the knapsack's contents. The test is designed to model complex decision-making and problem-solving in everyday life.

When participants used cognitive enhancers, their effort -- defined as decision time and the number of steps it took to find a solution -- increased compared with placebo. On methylphenidate, for example, participants took around 50% longer on average to complete the knapsack task.

Productivity -- defined as the average value gained per move -- decreased compared with placebo when participants used cognitive-enhancing drugs.

Differences also emerged in subgroups. People who performed at a higher level on placebo tended to show a bigger decrease in performance and productivity after taking any of the three cognitive enhancers.

Those in the top 25% of productivity with placebo often ended up in the bottom 25% with methylphenidate, for example.

Conversely, some below-average performers on placebo improved their effort quality with cognitive-enhancing drugs, but they spent more time on the task.

"We did not expect this heterogeneity across participants, something rarely mentioned in drug studies," Bossaerts said.

The trial randomized participants on four visits to a single dose of one of the three drugs (30 mg of methylphenidate, 15 milligrams of dextroamphetamine, or 200 milligrams of modafinil) or placebo before being asked to solve eight instances of the knapsack task.

The four visits took place in Melbourne and were at least ine week apart from each other. Participants were ages 18 to 35; 17 were male and 23 were female.

"Because the knapsack task encapsulates difficulty encountered in everyday problem-solving, our paradigm could help shed light on how medications such as methylphenidate improve the day-to-day functioning of patients suffering from, e.g., ADHD," Bossaerts and co-authors observed.

The knapsack task also can facilitate comparisons across people with and without ADHD, the researchers added.

"For subclinical populations, our paradigm provides a convenient framework with which to eventually discover the genuinely smart drugs, i.e., the drugs that not only increase effort but also enhance quality of effort," they wrote.

Disclosures: This work was supported by the University of Melbourne. Bossaerts had no competing interests. A co-author reported relationships with Takeda/Shire, Medice, Novartis, Servier, Oxford University Press, and Cambridge University Press.