Do smart drugs ACTUALLY make you smarter?

Do smart drugs ACTUALLY make you smarter?

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T’is the season of finals again, and with it, a surging interest in prescription “smart drugs” (see Fig 1). High school and college students are increasingly turning to ADHD medicine (Ritalin, Adderall) in hopes of enhancing school and test performance. Intuitively this makes sense: drugs that increase energy, attention and concentration should inevitably lead to better learning and memory, right? At the street price of $10 a pop (here in Vancouver at least), neuro-enhancement isn’t cheap. Which makes me wonder: aside from personal anecdotes, is there any scientific proof that smart drugs actually make people smarter?

…nerdy neurochemistry intro here, feel free to skip!

There are many types of “neuroenhancers”, but I’m going to focus on the two most popular ones, methylphenidate (MPH, Ritalin) and dl-amphetamine (Adderall, also known endearingly as “Addy”). A brief note on how they work first. Both drugs increase a class of neurotransmitters called monoamines in the brain, albeit through different mechanisms. These neurotransmitters – including dopamine, serotonin and norepinephrine – fine-tune the strength of excitatory vs inhibitory activity in different brain areas. Together, the monoamines control many parts of your psyche, such as motivation, attention, pleasure, mood, anxiety and alertness.

Screen Shot 2013-04-18 at 9.30.48 PMScreen Shot 2013-04-18 at 9.31.04 PMADHD meds preferentially increase dopamine and norepinephrine in the prefrontal cortex and basal ganglia, directly activating motivational circuits while suppressing background neuron firing. This essentially increases the signal-to-noise ratio of neurotransmission, allowing people to focus more on the task at hand. However, more is not always better. TOO much monoamines and you start suffering from cognitive inflexibility, the inability to switch between different concepts or process multiple concepts simultaneously. You focus so much it’s detrimental to your goal. People with ADHD don’t have enough monoamine transmission, and stimulants rectify this – that’s why they increase concentration and school/life performance. But do the drugs work for your average Joe?

From 1962 to 2005, roughly 40 studies have evaluated prescription stimulants as neuroenhancers in healthy adults. To thoroughly test the drugs’ effects on “smartness”, most studies focused on one of three types of cognition: learning/memory, working memory and cognitive control. Learning/memory tests reflect academic “booksmarts”; the latter two tests gauge a person’s higher cognitive functions, such as planning, attention, problem solving and mental flexibility. Most studies asked the participants afterwards if they felt “high”, and the majority reported no.

A learning task typically asks the volunteer to memorize a list of paired words, then sometime later, ask the volunteer to recall the word associated with a given word. Learning can either be visual (looking at words on a computer screen) or auditory (hearing the word pairs). In general, stimulants did not affect learning speed or short-term (minutes to hours) recall, but did enhance long-term (days to a week) memory. Small sample size aside (8 experiments on short-term and 2 on long-term recall), this suggests that stimulants may benefit memory retention in the long run. Unfortunately these data can’t be extrapolated to complex memory, which is more relevant to college learning and testing. Surveys already show students in pharmacy and medicine – areas that require a lot of memorization – use stimulants to improve academic performance. It would be really interesting to follow them and see if the drugs can boost learning in a lecture-like setting.

working-memory-3In contrast to factual memory, working memory is the ability to temporarily hold information in mind while manipulating it. Think of it as a mental white board. A common test for working memory is the spatial span task. Here’s how it goes: imagine looking at a bunch of white boxes scattered on a computer screen. The boxes start changing colors one by one randomly. Your task is to remember the order of the changes, and reproduce it either as shown originally or in the reverse order. Trust me, it’s really mentally taxing to do! One study in 1997 used this exact task to study Ritalin. People took either placebo or Ritalin first, did the task, then took the other pill and repeated the task. Surprisingly, while the placebo/Ritalin group performed better on Ritalin, the Ritalin/placebo group seemed to do better on the placebo (a non-significant trend)! Looking closer at their data, the baffled scientists realized the placebo/Ritalin group did worse overall than their counterparts. So maybe Ritalin does enhance working memory, but only in the “less able subjects”? A few studies in the early 2000s seems to support this idea: the lower a volunteer’s score on placebo, the greater the improvement on Ritalin. In stark contrast, a similar number of experiments showed no performance improvement on stimulants. So the jury’s still out there, but at the moment it seems stimulants work for people with low baseline working memory and do nothing for those already adept. While the results are a little disappointing, but on the plus side, no studies reported negative affects on working memory after stimulant use.

Speaking of negative effects, I’m going to go off on a tangent and talk about creativity. Stimulants have a bad rep of killing creativity. As the mathematician Poincare astutely noted, creativity is the discovery of “unsuspected kinship…between facts long known but wrongly believed to be strangers to one another”. Psychologists have long believed that creativity requires distraction and loosening of mental control; recent fMRI studies (e.g. rapper in the scanner, yo! ) support this idea, showing a relaxation of executive functions during the creative process.

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Here’s something you don’t see everyday: Jazz musician in an fMRI scanner. From: Limb CJ, Braun AR (2008) Neural Substrates of Spontaneous Musical Performance: An fMRI Study of Jazz Improvisation. PLoS ONE 3(2): e1679. doi:10.1371/journal.pone.0001679

Since Addy strengthens executive functions, it seems logical that cognitive enhancement comes at the price of butchered creativity. A 2009 study looked directly at this hypothesis… and shot it down. Fours tasks were used: two “divergent” ones with no wrong or right answers (e.g. coming up with as many functions as possible for an object) and two “convergent” ones – in the verbal and spatial domain – which have only one correct answer. In stark contrast to the hypothesis, Addy had no effect on either divergent tasks; it also didn’t enhance or impair the verbal association task. Instead, it enhanced some individuals’ performance on the spatial creativity task. Once again, low-performing individuals benefited more than high-performers. Note that only 10mg was used in this study – people tend to take double or triple that amount in a day, which may make a difference. But for now, the idea that stimulants wilt creativity is a myth.

Ok, going back to cognitive enhancement…the third type of “smarts” is punch_maincognitive control. In broad terms, it’s the ability to flexibly adapt your behavior 
in pursuit of a goal, especially in cases where your first response is not the right one. It’s the ability to stop yourself, re-evaluate the situation, and make the appropriate decision. It’s what makes us mature, responsible adults. Although cognitive control sounds vague, it correlates with important life outcomes such as academic or job success.

A barrage of tasks are available to assess cognitive control. One such is the stop signal task, where you have to click the mouse every time a symbol appears on a computer screen, except when a tone is also played. Since your first response is to click the mouse regardless, you’ll have to actively stop yourself at the tone to get the task right. Another example is the Wisconsin Card Sorting Task (shown below), where you have to sort cards according to rapidly changing rules.

Wisconsincardsort A recent fMRI study showed that Ritalin activates brain circuits that allow you to monitor behavior and detect performance errors. This error-detection process is central to higher cognitive functioning and intelligence. In studies that directly looked at task performance, both Ritalin and Addy boosted accuracy and decreased response time, although the effects were generally small. Once again, the drugs were more effective at correcting defects than upping performance. Nevertheless, these results do add some support for ADHD meds as cognitive enhancers, at least in the cognitive control domain.

The overall small effect size begs the question: is the small brain boost a reflection of the ceiling effect (subjects are so smart they can’t be made smarter) or a manifestation of the placebo effect?

A double-blind, placebo-controlled study in 2011 favors placebo effect: when participants expected to receive Ritalin instead of placebo, they reported better focus for longer periods of time regardless of what they actually took. Conversely, when they didn’t expect to get the drug, participants’ attention wavered and they performed worse on their given task, even when they got Ritalin. Even more interesting, the subjective feeling of getting high was also related to the expectation of getting Ritalin rather than actually taking Ritalin. These results argue strongly that cases of neuroenhancement in the literature are nothing but placebo effects.

Are “smart drugs” a false promise? At the moment it’s too early to tell, but the evidence seems to say “yes”. Research into the field of neuroenhancement is somewhat tempered by the surrounding ethics debate. Stimulants seem to improve some experimental task performances in a sub-population, but whether this translates to everyday cognitive function is questionable. The placebo study is especially worrisome: are everyday accounts of “feeling smarter” all in the user’s head?

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Pills won’t turn me into Einstein, but can’t I have a little brain boost?

I have to admit I am surprised and somewhat disappointed by the results. Experimental data directly contradicts the slew of anecdotal stories praising Ritalin and Addy as miracle study drugs. Is it all placebo? Are some people self-medicating undiagnosed ADHD and seeing results? Do prescription stimulant abusers have lower executive function than the average experiment subjects, and hence show larger improvement (I highly doubt this, an informal poll of 1400 Nature readers – most academics – showed ~20% have used cognitive enhancers for their perceived benefits)? Of course, learning, working memory and cognitive control represent just a few aspects of cognition and intelligence. To sing the old tune: more work needs to be done.

Have you ever taken prescription stimulants? Did they work for you? Do you think you were only experiencing a placebo effect? I’d love to hear your story!
ResearchBlogging.org
Lakhan SE, & Kirchgessner A (2012). Prescription stimulants in individuals with and without attention deficit hyperactivity disorder: misuse, cognitive impact, and adverse effects. Brain and behavior, 2 (5), 661-77 PMID: 23139911

ResearchBlogging.org
Smith ME, & Farah MJ (2011). Are prescription stimulants “smart pills”? The epidemiology and cognitive neuroscience of prescription stimulant use by normal healthy individuals. Psychological bulletin, 137 (5), 717-41 PMID: 21859174