#SfN13 Tackling depression from both ends

503.Mood Disorders: Preclinical Studies and Animal Models.

503.08. Characterization of CX614, an AMPAkine, as a fast onset antidepressant
HM JOURDI, M KABBAJ; Biomed. Sci., Florida State Univ., Tallahassee, FL

503.09. Vortioxetine improves a reversal learning deficit in rats induced by serotonin depletion or chronic stress. DA MORILAK, A WALLACE, A PEHRSON, C SANCHEZ-MORILLO; Pharmacol. and Ctr. for Biomed. Neurosci., Univ. of Texas Hlth. Sci. Ctr., SAN ANTONIO, TX; Lundbeck Res. USA, Paramus, NJ

            Source: http://www.rochetfamilychiro.com

People generally consider depression as something purely emotional – an inescapable distaste towards oneself, an unshakable apathy towards the world, a persistent slow, sticky feeling of exhaustion, as if walking the path of life with glue on both feet.

Yet depression has a strong cognitive component, one so powerful that some scientists believe it to be the root of emotional imbalance. Many sufferers describe their thought patterns as “stuck in a rut”, where they’re only capable of framing things in a negative light, thus seeing the world as pale and hopeless. This observation has prompted two groups of researchers to ask: can we treat depression by targeting cognitive inflexibility?

AMP-A(p) the synapse

Luckily for researchers from Florida State University, we already have a class of cognitive enhancers on the market. AMPAkines are known to enhance attention span and improve learning and memory in the elderly and those suffering from neurodegenerative diseases. These drugs get their name from strongly enhancing the function of the AMPA receptor as a positive modulator. Interestingly, ketamine, the club-drug-turned-fast-acting-anti-depressant requires AMPAR activation to work, suggesting that AMPAkines may not only alleviate depressive symptoms but also act more rapidly than traditional anti-depressants.

Researchers gave a group of young adult rats a single injection of either ketamine or CX614, one of the best-characterized AMPAkines. 24hrs later, they exposed the rats to water and measured how long they swam before giving up in despair. Compared to saline-injected control animals, both ketamine and CX614 reduced the amount of time they spent immobile, though ketamine was slightly more effective at the doses used.

In another cohort of rats, researchers used a stressor (they didn’t say what, but it could be anything from bullies to cats to robots) to acutely trigger depression-like symptoms. Rats have quite the sweet tooth; normally given the choice between sugar and plain water, they lap up the sweet stuff in earnest. However, once depressed, they seem to loose the ability to enjoy life’s pleasures and no longer prefer the treat. Once again, a single injection of either ketamine or CX614 restored their love for sugar within a day. Remarkably, the antidepressant-like effects of CX614 lasted up to 8 days, even longer than that of ketamine.

On the molecular level, many previous studies show that depression reduces the number of synapses, thus negatively affecting the way neurons communicate. In fact, ketamine is known to rapidly reverse this defect, which may be one of the reasons behind its anti-depressant effect. Does CX614 work in the same way?

Using brain tissue isolated from CX614-injected animals, researchers found that within 30min neurons in the hippocampus were actively making more proteins, as evidenced by increased activity of the protein translation machinery. At the same time, CX614 also triggered a cascade of molecular signalling to reconstruct and stabilize actin, a “skeletal” protein that helps a cell maintain or alter its structure.

Anatomy of a spine. Wikipedia

These two processes – protein translation and actin remodelling – allow neurons to form new spines, the little protrusions along dendrites that host synapses formed with (typically) another neuron. In other words, spines provide an anatomical structure for synaptic transmission. Although researchers did not directly prove their case with imaging techniques, these molecular changes certainly suggest that CX614 increases synapse formation.

Thus, like ketamine, AMPAKines may rapidly reduce depressive symptoms; unlike ketamine, they have very low potential for abuse. Whether their cognitive enhancing effects directly contribute to anti-depression though will have to be answered another day.

Flexible thoughts, sunny mind?

Researchers from the University of Texas and Lundbeck Research took the opposite approach – they picked an anti-depressant and investigated its cognitive enhancing effects. Vortioxetine is a selective serotonin reuptake inhibitor (SSRI) like Zoloft and Celexa. However, it also directly binds to and activates numerous types of serotonin receptors, giving it a unique pharmacological profile.

As mentioned above, patients with depression are often unable to flexibly reframe their thoughts. Neuroscientists can identify and measure a similar deficit in rats with a rather sneaky task. They first trained rats to dig for cheerios (yum!) from several pots, some of which smelled like cloves, others nutmeg; some filled with dry grainy sand, others with moist soft dirt. Unbeknownst to the rat, the digging material was just a distraction. Scent was the only clue they had to follow to find the treat.

After rats finally figured out the rules of the game, researchers suddenly switched the cheerios from the clove-sand pot to the nutmeg-sand pot, sat back, and watched how fast the rats updated their strategy as a measure of cognitive flexibility. In the first set of rats, researchers depleted ~90% of their serotonin levels with a chemical, thus coarsely mimicking the dearth of serotonin transmission seen in depressive patients. Unsurprisingly, they performed horribly, steadily going back to the original pot. However, when researchers gave them an injection of Vortioxetine 30min before testing, they rapidly ditched the old pot for the new.

Researchers then stressed a new group of rats with bouts of intense and unpredictable cold for 14 days straight. This treatment is often used to trigger deficits in reversal learning as well as depression-like behaviours (imagine being randomly thrown into a fridge for two weeks – you’d be constantly on edge and most likely depressed by the end too!). In the meantime, some rats received Vortioxetine in their food while others got placebo. In the end, those on placebo failed miserably on the cheerio-finding task, while those treated with Vortioxetine performed just as well as non-stressed controls.

These results suggest that Vortioxetine, an SSRI-type antidepressant, improves cognitive flexibility in stressed-out (and perhaps depressed) rats. However, the researchers did not show whether it also relived depressive-like symptoms at the doses used, how long the effect lasted, or whether the drug would perform in other (arguably more common) models of depression such as social defeat.

Taken together, these two studies complement each other beautifully, even though the results are still preliminary. Depression is a tough nut to crack, but the search for novel and fast-acting anti-depressants is in full swing. Among those presented at #SfN13 are the anesthetic gas isofluorane and the anti-cough medication dextromethorphan. Unfortunately as of now neither are ready for clinical use for depression.

The discovery of ketamine revolutionized the field of anti-depressant research in the last decade or so. Perhaps tackling depression on both cognitive and emotional ends – with cognitive enhancers or others – will prove to be even more effective at taming the beast.

Sappy little end-note: Back when I was studying pharmacy the best we could offer depressive patients were the atypical SSRIs, which takes weeks to months to start working. Many don’t respond to them at all and those who do built tolerance quickly. I’m so happy to have watched the story of ketamine unfold. If you’d like to know more, Gary Stix has a great 3-part series on Scientific American that’s well worth a read.

Check out my previous post on another potentially fast-acting anti-depressant L- acetyl-carnitine, a common fitness supplement.

“Cocaine addiction may be cured by Ritalin!” …Hmm, really?

I saw this headline from an r/science thread the other day, and had to look into it. As you’ve probably guessed, the answer is no, but the idea behind it is still a fascinating story.

Lots of people experiment with drugs; only some become addicted. Many addicts try to quit; only some succeed without relapse. Why?

Anatomy time!! Source: Baler R & Volkow ND. (2006) Drug addiction: the neurobiology of disrupted self-control. Trends in Molecular Medicine 12(12) 559

One idea is that people have a different baseline of self-control. The decision to take (“go”) or not take (“no go”) a drug comes from the orbitofrontal cortex (OFC – green in the graph above), a part of the frontal lobe in charge of thinking through a decision making process. The OFC gets its info from two regions: the nucleus accumbens (NAcc – red), which learns about rewards, and the prefrontal cortex (PFC) and Anterior Cingulate Cortex (ACC -blue), which inhibits impulse and restrains craving. (The hippocampus and amygdala, in purple, are important for drug-reward learning and memory.)

In a non-addict, the ACC-PFC (blue) usually wins out, telling the “judge” OFC to deny the motion. You don’t take the drug. However, in some vulnerable individuals the NAcc (red) wins out, and every time they take a drug – say, cocaine – it changes this pleasure-sensing, reward-predicting part of your brain, increasing its sensitivity to both the drug and its associated cues. At the same time, it also weakens inhibitory control, which skews the OFC towards a “go” decision. This breakdown of self-control clearly sets up the stage for unrestrained cycles that eventually results in compulsive drug taking.

So what if we can use a drug to bring back cognitive control and reset the circuitry? Would that treat addiction?

Here’s where Ritalin comes in. Like cocaine, Ritalin (methylphenidate) is a stimulant that increases dopamine level, just at a much slower pace with longer duration. Since there’s no spike in dopamine, there’s no rush. So, just like using the longer-lasting methadone to wean opiate addicts off heroin, it seems reasonable that Ritalin could be a used as a cocaine substitute on the route of recovery. However, Ritalin packs a one-two punch (otherwise it would be a “oh-duh!” story). As a medication for ADHD, one of its major effects is to strengthen cognitive control. It works especially well in this regard in people who have lower baselines of cognitive inhibition to begin with, like drug addicts. Put the two together, and Ritalin seems like the perfect candidate for battling cocaine addiction.

Problem is, on the behavioural level, it doesn’t work. Double-blind studies show that users didn’t report lower cravings in response to cocaine-associated cues, nor did they lower their drug use or relapse rates. However, these results are plagued by the curses of small sample size and high dropout rates, so researchers aren’t ready to throw Ritalin out the window just yet. Unfazed, they decided to directly peek into the brain with fMRI, to see if Ritalin has a more profound effect at the neural level.

In a 2010 study, researchers recruited 13 cocaine addicts (~18 years use) and 14 controls, stuck them in an fMRI while they completed a task. Here’s how it went: the volunteers were shown two types of words, either neutral or drug-related. All the words were in colour, and they had to press a button corresponding to the colour as fast as they could.

Under placebo (blue circle, left graph), the coke-abuser’s ACC (which controls inhibition) showed very low response to drug-related words; when given Ritalin (red circle), the ACC’s response shot up to that higher than controls’ (purple arrow). In a sense, Ritalin re-sensitized the coke addicts’ control center to drug-related cues. In terms of task performance, Ritalin also decreased impulsivity, evidenced by the lower number of errors they made (yellow arrow, right graph) – but the same also happed to healthy controls when given Ritalin. In fact, the addicts didn’t significantly perform worse than the controls, even with ACC hypo-activation. So under the hood, Ritalin seems to be strengthening cognitive control – it’s just not reflected in behaviour.

Now in a new study, the researchers wanted to know if Ritalin can change brain connectivity under a resting state. “Resting state” is quite the oxymoron, as the brain never shuts down completely. Instead, it exhibits spontaneous fluctuations in neural activity between brain regions, which also goes awry in cocaine addiction. Researchers recruited 18 volunteers who fit the criteria for cocaine addiction, but were otherwise healthy and not taking any medications. The volunteers when then given either placebo or Ritalin (20mg) and had their brain imaged. Here’re the findings: compared to placebo, Ritalin normalized the strength of 6 connectivity pathways related to emotional regulation, memory formation, craving suppression and inhibitory control. Ritalin had a similar degree of effect on all volunteers, regardless of how severe their cocaine addiction is. In this study, the researchers didn’t check for subjective feelings of craving after Ritalin administration.

So what’s the verdict? Can Ritalin help cocaine addiction? The evidence really isn’t strong. Nevertheless, it’s interesting that one dose of the “cognitive enhancer” can rectify some of the neural connectivity problems seen in addiction. In all honesty, I would be surprised if one dose of Ritalin can “treat” cocaine addiction, in terms of decreasing craving and drug-seeking. After all, the addiction to drugs of abuse doesn’t happen in a day with one dose either. In future studies, it would be interesting to see if multiple treatments with Ritalin, over a long period of time, can exert a behavioural effect in addition to the neural one. It would also be interesting to test the effects of Ritalin and cognitive-behavioural therapy (CBT), and see if this combo is stronger than CBT alone.

The idea of using cognitive enhancers for addiction therapy is gaining steam. Clinical trials with Adderall, Ritalin and Modafinil are all ongoing, and hopefully, larger studies with longer timeframes will give us a more conclusive result.

What do you guys think? Are scientists beating a dead horse, or is there actually something worth pursuing?

Konova AB, Moeller SJ, Tomasi D, Volkow ND, & Goldstein RZ (2013). Effects of Methylphenidate on Resting-State Functional Connectivity of the Mesocorticolimbic Dopamine Pathways in Cocaine Addiction. JAMA psychiatry (Chicago, Ill.), 1-11 PMID: 23803700

Goldstein RZ, & Volkow ND (2011). Oral methylphenidate normalizes cingulate activity and decreases impulsivity in cocaine addiction during an emotionally salient cognitive task. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 36 (1), 366-7 PMID: 21116260

Ladies: why Ritalin may not always be helpful. (Hint: sex, genes and dem hormones)

Little note: Since this post, I’ve been mulling over why Ritalin/Adderall doesn’t affect cognitive performance of healthy volunteers. Several reasons come to mind. I wasn’t reading the “right” literature (ie studies with positive results – any suggestions?). Stimulants may only influence brain activation patterns, but not performance. In this case, we can only detect differences by fMRI or other direct imagining techniques. Or individual differences confounded the results – especially differences in basal dopamine levels and how dopamine is processed after its release. I’m going to focus on the last bit here.  

As a fellow XX member of society, I know very well how much ladies are controlled by their monthly cycle. Thinking appetite and mood? That’s just the beginning. The rise and fall of estrogen and progesterone also influence sound processing, neurogenesis and vulnerability to drug addiction. And that’s not all.

Estrogen directly impacts how well you think.

Estrogen targets your brain. Source: cbc

Jabobs E and D’Esposito MD. 2011. Estrogen Shapes Dopamine-Dependent Cognitive Processes: Implications for Women’s Health. The Journal of Neuroscience. 31(14): 5286-5293.

Ok, I was being overdramatic. But based on results from this study, estrogen seems to impact one important aspect of cognition: working memory. Working memory is a fundamental cognitive ability to hold information in mind while manipulating it towards a goal. It supports a massive array of complex thinking, such as problem analyzing and updating your ideas/strategies when new information comes in. To some, working memory is a good surrogate marker (albeit not the only one) for intelligence.

The part of the brain supporting working memory is called the prefrontal cortex (PFC). For the PFC to function optimally, it needs to be in the Goldilocks’ zone of dopamine concentration: too low or too high, and PFC function deteriorates. Think of an inverted “U” (see the graph below).

This is where estrogen and genes come into play. Estrogen (or estradiol, to be more precise) enhances dopamine. Simple. Genes are slightly less straightforward. The concentration of PFC dopamine in the synaptic cleft (where it is released) is mostly determined by an enzyme called COMT. COMT comes in two flavors: the met/met variant, which has low activity and consequently higher dopamine, and it’s opposite, the val/val variant, which results in less dopamine. As of now, we think met/met individuals have near-optimal dopamine concentrations at baseline, while val/val carriers are a little short from optimum PFC function. Since estrogen enhances dopamine, the authors in this study asked: how will estrogen fluctuations influence a women’s working memory based on her genotype?

The authors recruited 24 healthy young women, rigorously tracked their cycles, and genotyped them for val/val or met/met alleles. The women were then invited back on two occasions – with estrogen levels at its highest and lowest – and performed a grueling task called the N-back while in an fMRI scanner.

Here’s how N-back works: for example, in the 2-back, subjects see a string of letters one-by-one, and need to pick out a letter that matched the one they saw 2 letters ago (“B”). To make things harder, researchers set up “lures”, where a letter matched a previously seen one, just not 2 letters ago (“R”). Although both 2 and 3-back trials depend on working memory, lure trails are exquisitely sensitive in differences in PFC function.

Not surprisingly, all women, regardless of cycle and genotype, performed worse as the load increased (needing to remember more letters), especially for lure trials. However, as seen below, in the 2-back, val/val women (less basal dopamine) performed much better when their estrogen was high (B) compared to low (A). Met/met women showed the opposite trend, with performance declining as estrogen went up. Dopamine levels seem to account for these observations: under high estrogen conditions (which boosts dopamine), increasing COMT enzyme activity (which degrades more dopamine) correlated with better accuracy. However, low estrogen (less dopamine) requires low COMT activity (slow degradation) for good performance.

A to C is significant. No info on anything else. Sad face.

These results suggest that estrogen is controlling working memory performance through dopamine. For met/met women, who already function well at baseline(C), increasing estrogen pushes them past the optimal dopamine peak, resulting in poorer function (D). For val/val women, who are slightly deficient in dopamine, estrogen is essentially a “smart drug”, boosting their performance by raising their dopamine levels to near optimum (A to B). Unfortunately, the authors only showed a significant difference between low dopamine (val/val, low estrogen, A) and high dopamine (met/met, low estrogen, C) conditions. I would love to know whether estrogen can boost val/val women’s performance to that comparable or above that of met/met women’s (C), and vice-versa, if the decreased met/met women’s performance is like that of val/val women’s at low estrogren (A) (confusing, I know).

Looking at the fRMI, the authors showed that the more the PFC (specifically, a part of the PFC called the middle frontal gyrus) activates, the better the women performs on lure trials, regardless of estrogen levels or gentotype. The activity level of PFC tightly correlated with COMT activity, with lower COMT activity (more dopamine) leading to higher PFC activation during the lure trials. Finally, the researchers found that women who had near-optimal dopamine levels (val/val high estrogen and met/met low estrogen) had the largest increase in PFC activity, and hence performed more accurately.

These results suggest that working memory, a key component of cognition, is dependent on the interplay between genes, neurotransmitters and hormones. If you’re a val/val, it may be beneficial to perform cognitively challenging tasks during the late follicular phase, when estrogen levels are high. If you’re a met/met, maybe save those tasks for the beginning of your cycle, when estrogen levels are low. Of course, this is heavy extrapolation, as the study only focused on dopamine and estrogen, without looking at the myriad of other neurotransmitter (especially norepinephrine, which also greatly influences PFC function) and sex hormones.

The study also hints that not every woman at every time will benefit from taking stimulants, such as Adderall or Ritalin. Stimulants enhance PFC function in ADHD individuals by increasing levels of dopamine. Hence, if you’re a val/val, stimulants may help improve working memory when estrogen levels are low (and possibly when high – we don’t have data to analyze this). On the other hand, if you’re a met/met already functioning at optimal dopamine concentrations, taking stimulants may instead decrease working memory performance, especially when your estrogen levels are high.

Linking back to the “smart drugs” post, since most studies didn’t screen for genotype and estrus cycle, could it be that different individual responses masked a net positive gain from stimulants? I’d love to know your thoughts.

Jacobs E, & D’Esposito M (2011). Estrogen shapes dopamine-dependent cognitive processes: implications for women’s health. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31 (14), 5286-93 PMID: 21471363

Do smart drugs ACTUALLY make you smarter?

Data from Google trends. Search is for Canada and may not be applicable to your area.

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, 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.

ADHD 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.

In 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.

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 cognitive 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.

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?

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!

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

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