Cognition-Boosting 'Smart Drugs' Not So Smart for Healthy People

Liam Davenport

October 21, 2022

UPDATED November 1,  2022 // Editor's note: This story has been updated with additional comments from Dr Andrew Westbrook of Brown University.

VIENNA, Austria — Prescription drugs designed to boost cognition in neurodevelopmental disorders do not increase overall cognitive performance in healthy individuals — and may even reduce productivity, new research suggests.

In a randomized controlled trial, 40 healthy adults were given the attention-deficit/hyperactivity disorder (ADHD) treatments methylphenidate or dexamphetamine or the wakefulness-promoting drug modafinil vs placebo.

While receiving the so-called "smart drugs," participants spent more time and made more moves more quickly while solving each problem on a complex cognitive task than when given the placebo. But with no significant improvement in overall performance, all drugs were associated with a significant reduction in efficiency.

The findings "reinforce the idea that, while the drugs administered were motivational, the resulting increase in effort came at a cost in the loss of productivity," said study presenter David Coghill, MD, PhD, chair of developmental mental health, The University of Melbourne, Victoria, Australia.

This was especially true for individuals who scored high when receiving placebo, "who ended up producing below average productivity when on the drugs," he noted.

"Overall, these drugs don't increase the performance. Instead, they cause a regression to the mean, and appear to have a more negative effect on those who performed best at baseline," Coghill added.

He presented the findings here at the 35th European College of Neuropsychopharmacology (ECNP) Congress.

Past Evidence Ambiguous

Coghill noted that prescription-only stimulant drugs are increasingly used by employees and students as "smart drugs" to enhance workplace or academic productivity.

He conducted the study with colleagues from the Department of Economics at his institution, because of "their interest in people using cognitive enhancers within the financial industry, in the hope that that would increase their productivity in what is a very competitive industry on the floor of the trading rooms."

However, while "there's a subjective belief" that these drugs are effective as cognitive enhancers, the evidence to actually demonstrate that in healthy individuals "is, at best, ambiguous," he told meeting attendees.

Improvements in cognitive capacities, such as working memory and improved planning, are most evident in clinical populations such as those with ADHD, which could be due to a "ceiling effect" of the cognitive tasks in healthy individuals, Coghill noted.

To investigate further, the researchers conducted a randomized, double-blinded trial of standard adult doses of methylphenidate (30 mg), dexamphetamine (15 mg), and modafinil (200 mg) vs placebo. The healthy participants (n = 40), all of whom were aged 18 to 35 years, crossed to each of the other treatment groups over the course of four intervention sessions.

All were asked to solve eight instances of the knapsack task, the aim of which is to place theoretical objects in a knapsack to achieve the maximum value within a certain weight limit.

"This looks very simple but as the number of items increases, it becomes incredibly complex to compute, and actually is not computable using standard approaches. You have to deal with trial and error," Coghill said.

The participants also completed several CANTAB cognitive tasks.

"Surprising" Findings

Results showed that, overall, the drugs did not have a significant effect on task performance (slope = –0.16; P = .011).

Moreover, the drugs, both individually and collectively, had a significant negative effect on the value attained during any one attempt at the knapsack task (slope = –0.003; P = .02), an effect that extended "across the whole range" of task complexity, Coghill reported.

He went on to show that "participants actually looked as if they were working harder" when they took the three active drugs than when they were given a placebo. They also "spent more time solving each problem," he added

When taking the active drugs, participants also made more moves during each task than when taking placebo, and made their moves more quickly.

"So these medications increased motivation," Coghill said. "If you were sitting [and] watching this person, you would think that they were working harder."

Yet their productivity, defined as the average gain in value per move on the knapsack task, was lower. Regression analysis identified a "significant and sizeable drop in productivity" vs placebo, Coghill noted.

This was the case for methylphenidate (P < .001), dexamphetamine (P < .001), and modafinil (P < .05), "whether you looked at the mean or median performance," he said.

"Breaking it down a little bit more, when you looked at the individual participant level, you find substantial heterogeneity across participants," noted Coghill.

"More than that, we found a significant negative correlation between productivity under methylphenidate compared to productivity under placebo, and this suggests a regression to the mean," with participants who performed better under placebo performing worse with methylphenidate, he explained.

While the relationship was "exactly the same with modafinil," it was not found with dexamphetamine, with a strong negative correlation between the productivity effects between dexamphetamine and methylphenidate (slope = –0.29; P < .0001).

"This is surprising because we assume that methylphenidate and dexamphetamine are working in very similar ways," Coghill said.

Time to Rethink, Rewind?

Commenting for Medscape Medical News, session chair John F. Cryan, PhD, Department of Anatomy & Neuroscience, University College Cork, Ireland, said that, based on the current data, "we might need to rethink [how] 'smart' psychopharmacological agents are."

Cryan, who is also chair of the ECNP Scientific Program Committee, added that there may also be a need to revisit the difficulty of different types of cognitive tasks used in studies assessing the abilities of cognitive enhancing drugs and to "rewind conventional wisdom" around them.

Also commenting, Andrew Westbrook, PhD, Department of Cognitive Linguistics and Psychological Sciences, Brown University, Providence, Rhode Island, said the results seem "reasonable" and are "consistent with my own perspective."

However, he told Medscape Medical News that "some caveats are warranted, not least that the context of the task can have an impact on the results it obtains.

"We have hypothesized that pharmacologically-enhanced striatal dopamine signaling can boost a kind of cognitive impulsivity, leading to errors and diminished performance, especially for people who already have high striatal dopamine functioning."

He added that this impulsivity can also lead to errors "in situations where there are highly likely actions, thoughts, or behaviors" in a task, "which they would have to override to be successful" in performing it.

Westbrook gave the example of the "Stroop task where you are presented with words presented in some color ink and your job is to name the color of the ink but not read the word."

If the word 'green,' for example, was presented in green ink, "you may have no trouble naming the ink color," but if it was presented in red ink "then you may impulsively read the word, because that is what we normally do with words."

"Overriding this kind of habitual action can be particularly slippery business when striatal dopamine signaling is pharmacologically enhanced," Westbrook said.

No funding for the study was reported. Coghill reported relationships with Medice, Novartis, Servier, Takeda/Shire Cambridge University Press, and Oxford University Press.

35th European College of Neuropsychopharmacology (ECNP) Congress: Abstract OS02.04. Presented October 16, 2022.

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