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Sulbutiamine, mentioned earlier as a cholinergic smart drug, can also be classed a dopaminergic, although its mechanism is counterintuitive: by reducing the release of dopamine in the brain’s prefrontal cortex, the density of dopamine receptors actually increase after continued Sulbutiamine exposure, through a compensatory mechanism. (This provides an interesting example of how dividing smart drugs into sensible “classes” is a matter of taste as well as science, especially since many of them create their discernable neural effects through still undefined mechanisms.)
Many of the most popular “smart drugs” (Piracetam, Sulbutiamine, Ginkgo Biloba, etc.) have been around for decades or even millenia but are still known only in medical circles or among esoteric practicioners of herbal medicine. Why is this? If these compounds have proven cognitive benefits, why are they not ubiquitous? How come every grade-school child gets fluoride for the development of their teeth (despite fluoride’s being a known neurotoxin) but not, say, Piracetam for the development of their brains? Why does the nightly news slant stories to appeal more to a fear-of-change than the promise of a richer cognitive future?

“Who doesn’t want to maximize their cognitive ability? Who doesn’t want to maximize their muscle mass?” asks Murali Doraiswamy, who has led several trials of cognitive enhancers at Duke University Health System and has been an adviser to pharmaceutical and supplement manufacturers as well as the Food and Drug Administration. He attributes the demand to an increasingly knowledge-based society that values mental quickness and agility above all else.
Taurine (Examine.com) was another gamble on my part, based mostly on its inclusion in energy drinks. I didn’t do as much research as I should have: it came as a shock to me when I read in Wikipedia that taurine has been shown to prevent oxidative stress induced by exercise and was an antioxidant - oxidative stress is a key part of how exercise creates health benefits and antioxidants inhibit those benefits.
Exercise is also important, says Lebowitz. Studies have shown it sharpens focus, elevates your mood and improves concentration. Likewise, maintaining a healthy social life and getting enough sleep are vital, too. Studies have consistently shown that regularly skipping out on the recommended eight hours can drastically impair critical thinking skills and attention.
In August 2011, after winning the spaced repetition contest and finishing up the Adderall double-blind testing, I decided the time was right to try nicotine again. I had since learned that e-cigarettes use nicotine dissolved in water, and that nicotine-water was a vastly cheaper source of nicotine than either gum or patches. So I ordered 250ml of water at 12mg/ml (total cost: $18.20). A cigarette apparently delivers around 1mg of nicotine, so half a ml would be a solid dose of nicotine, making that ~500 doses. Plenty to experiment with. The question is, besides the stimulant effect, nicotine also causes habit formation; what habits should I reinforce with nicotine? Exercise, and spaced repetition seem like 2 good targets.

For illustration, consider amphetamines, Ritalin, and modafinil, all of which have been proposed as cognitive enhancers of attention. These drugs exhibit some positive effects on cognition, especially among individuals with lower baseline abilities. However, individuals of normal or above-average cognitive ability often show negligible improvements or even decrements in performance following drug treatment (for details, see de Jongh, Bolt, Schermer, & Olivier, 2008). For instance, Randall, Shneerson, and File (2005) found that modafinil improved performance only among individuals with lower IQ, not among those with higher IQ. [See also Finke et al 2010 on visual attention.] Farah, Haimm, Sankoorikal, & Chatterjee 2009 found a similar nonlinear relationship of dose to response for amphetamines in a remote-associates task, with low-performing individuals showing enhanced performance but high-performing individuals showing reduced performance. Such ∩-shaped dose-response curves are quite common (see Cools & Robbins, 2004)
…The first time I took supplemental potassium (50% US RDA in a lot of water), it was like a brain fog lifted that I never knew I had, and I felt profoundly energized in a way that made me feel exercise was reasonable and prudent, which resulted in me and the roommate that had just supplemented potassium going for an hour long walk at 2AM. Experiences since then have not been quite so profound (which probably was so stark for me as I was likely fixing an acute deficiency), but I can still count on a moderately large amount of potassium to give me a solid, nearly side effect free performance boost for a few hours…I had been doing Bikram yoga on and off, and I think I wasn’t keeping up the practice because I wasn’t able to properly rehydrate myself.
I take my piracetam in the form of capped pills consisting (in descending order) of piracetam, choline bitartrate, anhydrous caffeine, and l-tyrosine. On 8 December 2012, I happened to run out of them and couldn’t fetch more from my stock until 27 December. This forms a sort of (non-randomized, non-blind) short natural experiment: did my daily 1-5 mood/productivity ratings fall during 8-27 December compared to November 2012 & January 2013? The graphed data28 suggests to me a decline:
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A total of 14 studies surveyed reasons for using prescription stimulants nonmedically, all but one study confined to student respondents. The most common reasons were related to cognitive enhancement. Different studies worded the multiple-choice alternatives differently, but all of the following appeared among the top reasons for using the drugs: “concentration” or “attention” (Boyd et al., 2006; DeSantis et al., 2008, 2009; Rabiner et al., 2009; Teter et al., 2003, 2006; Teter, McCabe, Cranford, Boyd, & Guthrie, 2005; White et al., 2006); “help memorize,” “study,” “study habits,” or “academic assignments” (Arria et al., 2008; Barrett et al., 2005; Boyd et al., 2006; DeSantis et al., 2008, 2009; DuPont et al., 2008; Low & Gendaszek, 2002; Rabiner et al., 2009; Teter et al., 2005, 2006; White et al., 2006); “grades” or “intellectual performance” (Low & Gendaszek, 2002; White et al., 2006); “before tests” or “finals week” (Hall et al., 2005); “alertness” (Boyd et al., 2006; Hall et al., 2005; Teter et al., 2003, 2005, 2006); or “performance” (Novak et al., 2007). However, every survey found other motives mentioned as well. The pills were also taken to “stay awake,” “get high,” “be able to drink and party longer without feeling drunk,” “lose weight,” “experiment,” and for “recreational purposes.”
Turning to analyses related specifically to the drugs that are the subject of this article, reanalysis of the 2002 NSDUH data by Kroutil and colleagues (2006) found past-year nonmedical use of stimulants other than methamphetamine by 2% of individuals between the ages of 18 and 25 and by 0.3% of individuals 26 years of age and older. For ADHD medications in particular, these rates were 1.3% and 0.1%, respectively. Finally, Novak, Kroutil, Williams, and Van Brunt (2007) surveyed a sample of over four thousand individuals from the Harris Poll Online Panel and found that 4.3% of those surveyed between the ages of 18 and 25 had used prescription stimulants nonmedically in the past year, compared with only 1.3% between the ages of 26 and 49.
It’s not clear that there is much of an effect at all. This makes it hard to design a self-experiment - how big an effect on, say, dual n-back should I be expecting? Do I need an arduous long trial or an easy short one? This would principally determine the value of information too; chocolate seems like a net benefit even if it does not affect the mind, but it’s also fairly costly, especially if one likes (as I do) dark chocolate. Given the mixed research, I don’t think cocoa powder is worth investigating further as a nootropic.
Noopept is a Russian stimulant sometimes suggested for nootropics use as it may be more effective than piracetam or other -racetams, and its smaller doses make it more convenient & possibly safer. Following up on a pilot study, I ran a well-powered blind randomized self-experiment between September 2013 and August 2014 using doses of 12-60mg Noopept & pairs of 3-day blocks to investigate the impact of Noopept on self-ratings of daily functioning in addition to my existing supplementation regimen involving small-to-moderate doses of piracetam. A linear regression, which included other concurrent experiments as covariates & used multiple imputation for missing data, indicates a small benefit to the lower dose levels and harm from the highest 60mg dose level, but no dose nor Noopept as a whole was statistically-significant. It seems Noopept’s effects are too subtle to easily notice if they exist, but if one uses it, one should probably avoid 60mg+.
Many of the positive effects of cognitive enhancers have been seen in experiments using rats. For example, scientists can train rats on a specific test, such as maze running, and then see if the "smart drug" can improve the rats' performance. It is difficult to see how many of these data can be applied to human learning and memory. For example, what if the "smart drug" made the rat hungry? Wouldn't a hungry rat run faster in the maze to receive a food reward than a non-hungry rat? Maybe the rat did not get any "smarter" and did not have any improved memory. Perhaps the rat ran faster simply because it was hungrier. Therefore, it was the rat's motivation to run the maze, not its increased cognitive ability that affected the performance. Thus, it is important to be very careful when interpreting changes observed in these types of animal learning and memory experiments.
Companies already know a great deal about how their employees live their lives. With the help of wearable technologies and health screenings, companies can now analyze the relation between bodily activities — exercise, sleep, nutrition, etc. — and work performance. With the justification that healthy employees perform better, some companies have made exercise mandatory by using sanctions against those who refuse to perform. And according to The Kaiser Family Foundation, of the large U.S. companies that offer health screenings, nearly half of them use financial incentives to persuade employees to participate.
Potassium citrate powder is neither expensive nor cheap: I purchased 453g for $21. The powder is crystalline white, dissolves instantly in water, and largely tasteless (sort of saline & slightly unpleasant). The powder is 37% potassium by weight (the formula is C6H5K3O7) so 453g is actually 167g of potassium, so 80-160 days’ worth depending on dose.
These days, nootropics are beginning to take their rightful place as a particularly powerful tool in the Neurohacker’s toolbox. After all, biochemistry is deeply foundational to neural function. Whether you are trying to fix the damage that is done to your nervous system by a stressful and toxic environment or support and enhance your neural functioning, getting the chemistry right is table-stakes. And we are starting to get good at getting it right. What’s changed?
In addition, while the laboratory research reviewed here is of interest concerning the effects of stimulant drugs on specific cognitive processes, it does not tell us about the effects on cognition in the real world. How do these drugs affect academic performance when used by students? How do they affect the total knowledge and understanding that students take with them from a course? How do they affect various aspects of occupational performance? Similar questions have been addressed in relation to students and workers with ADHD (Barbaresi, Katusic, Colligan, Weaver, & Jacobsen, 2007; Halmøy, Fasmer, Gillberg, & Haavik, 2009; see also Advokat, 2010) but have yet to be addressed in the context of cognitive enhancement of normal individuals.
“We stumbled upon fasting as a way to optimize cognition and make yourself into a more efficient human being,” says Manuel Lam, an internal medicine physician who advises Nootrobox on clinical issues. He and members of the company’s executive team have implanted glucose monitors in their arms — not because they fear diabetes but because they wish to track the real-time effect of the foods they eat.
Brain-imaging studies are consistent with the existence of small effects that are not reliably captured by the behavioral paradigms of the literature reviewed here. Typically with executive function tasks, reduced activation of task-relevant areas is associated with better performance and is interpreted as an indication of higher neural efficiency (e.g., Haier, Siegel, Tang, Abel, & Buchsbaum, 1992). Several imaging studies showed effects of stimulants on task-related activation while failing to find effects on cognitive performance. Although changes in brain activation do not necessarily imply functional cognitive changes, they are certainly suggestive and may well be more sensitive than behavioral measures. Evidence of this comes from a study of COMT variation and executive function. Egan and colleagues (2001) found a genetic effect on executive function in an fMRI study with sample sizes as small as 11 but did not find behavioral effects in these samples. The genetic effect on behavior was demonstrated in a separate study with over a hundred participants. In sum, d-AMP and MPH measurably affect the activation of task-relevant brain regions when participants’ task performance does not differ. This is consistent with the hypothesis (although by no means positive proof) that stimulants exert a true cognitive-enhancing effect that is simply too small to be detected in many studies.
That first night, I had severe trouble sleeping, falling asleep in 30 minutes rather than my usual 19.6±11.9, waking up 12 times (5.9±3.4), and spending ~90 minutes awake (18.1±16.2), and naturally I felt unrested the next day; I initially assumed it was because I had left a fan on (moving air keeps me awake) but the new potassium is also a possible culprit. When I asked, Kevin said:
The U.S. Centers for Disease Control and Prevention estimates that gastrointestinal diseases affect between 60 and 70 million Americans every year. This translates into tens of millions of endoscopy procedures. Millions of colonoscopy procedures are also performed to diagnose or screen for colorectal cancers. Conventional, rigid scopes used for these procedures are uncomfortable for patients and may cause internal bruising or lead to infection because of reuse on different patients. Smart pills eliminate the need for invasive procedures: wireless communication allows the transmission of real-time information; advances in batteries and on-board memory make them useful for long-term sensing from within the body. The key application areas of smart pills are discussed below.

You have the highest density of mitochondria in your brain’s prefrontal cortex, which helps to explain why I feel Unfair Advantage in my head first. You have the second highest density in your heart, which is probably why I feel it in the center of my chest next. Mitochondrial energizers can have profound nootropic effects! At higher doses mitochondrial energizers also make for an excellent pre-workout supplements.
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