‘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, Dr. 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 made more moves during each task than when taking placebo, and made their moves more quickly.
“So these medications increased motivation,” Dr. 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 sizable drop in productivity” vs. placebo, Dr. 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 Dr. 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,” Dr. Coghill said.
Time to rethink, rewind?
Commenting for this article, session chair John F. Cryan, PhD, department of anatomy and neuroscience, University College Cork, Ireland, said that, based on the current data, “we might need to rethink [how] ‘smart’ psychopharmacological agents are.”
Dr. Cryan, chair of the ECNP Scientific Program Committee, added that there may 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, of the department of cognitive linguistics and psychological sciences, Brown University, Providence, R.I., said the results seem “reasonable” and are “consistent with my own perspective.”
However, he told this news organization, “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.
Dr. 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,” Dr. Westbrook said.
No funding for the study was reported. Dr. Coghill reported relationships with Medice, Novartis, Servier, Takeda/Shire Cambridge University Press, and Oxford University Press.
A version of this article first appeared on Medscape.com.