Another important epidemiological question about the use of prescription stimulants for cognitive enhancement concerns the risk of dependence. MPH and d-AMP both have high potential for abuse and addiction related to their effects on brain systems involved in motivation. On the basis of their reanalysis of NSDUH data sets from 2000 to 2002, Kroutil and colleagues (2006) estimated that almost one in 20 nonmedical users of prescription ADHD medications meets criteria for dependence or abuse. This sobering estimate is based on a survey of all nonmedical users. The immediate and long-term risks to individuals seeking cognitive enhancement remain unknown.
When you hear about nootropics, often called “smart drugs,” you probably picture something like the scene above from Limitless, where Bradley Cooper’s character becomes brilliant after downing a strange pill. The drugs and supplements currently available don’t pack that strong of a punch, but the concept is basically the same. Many nootropics have promising benefits, like boosting memory, focus, or motivation, and there’s research to support specific uses. But the most effective nootropics, like Modafinil, aren’t intended for use without a prescription to treat a specific condition. In fact, recreational use of nootropics is hotly-debated among doctors and medical researchers. Many have concerns about the possible adverse effects of long-term use, as well as the ethics of using cognitive enhancers to gain an advantage in school, sports, or even everyday work.
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.
Null results are generally less likely to be published. Consistent with the operation of such a bias in the present literature, the null results found in our survey were invariably included in articles reporting the results of multiple tasks or multiple measures of a single task; published single-task studies with exclusively behavioral measures all found enhancement. This suggests that some single-task studies with null results have gone unreported. The present mixed results are consistent with those of other recent reviews that included data from normal subjects, using more limited sets of tasks or medications (Advokat, 2010; Chamberlain et al., 2010; Repantis, Schlattmann, Laisney, & Heuser, 2010).
Remembering what Wedrifid told me, I decided to start with a quarter of a piece (~1mg). The gum was pretty tasteless, which ought to make blinding easier. The effects were noticeable around 10 minutes - greater energy verging on jitteriness, much faster typing, and apparent general quickening of thought. Like a more pleasant caffeine. While testing my typing speed in Amphetype, my speed seemed to go up >=5 WPM, even after the time penalties for correcting the increased mistakes; I also did twice the usual number without feeling especially tired. A second dose was similar, and the third dose was at 10 PM before playing Ninja Gaiden II seemed to stop the usual exhaustion I feel after playing through a level or so. (It’s a tough game, which I have yet to master like Ninja Gaiden Black.) Returning to the previous concern about sleep problems, though I went to bed at 11:45 PM, it still took 28 minutes to fall sleep (compared to my more usual 10-20 minute range); the next day I use 2mg from 7-8PM while driving, going to bed at midnight, where my sleep latency is a more reasonable 14 minutes. I then skipped for 3 days to see whether any cravings would pop up (they didn’t). I subsequently used 1mg every few days for driving or Ninja Gaiden II, and while there were no cravings or other side-effects, the stimulation definitely seemed to get weaker - benefits seemed to still exist, but I could no longer describe any considerable energy or jitteriness.
There is a similar substance which can be purchased legally almost anywhere in the world called adrafinil. This is a prodrug for modafinil. You can take it, and then the body will metabolize it into modafinil, providing similar beneficial effects. Unfortunately, it takes longer for adrafinil to kick in—about an hour—rather than a matter of minutes. In addition, there are more potential side-effects to taking the prodrug as compared to the actual drug.
Several studies have assessed the effect of MPH and d-AMP on tasks tapping various other aspects of spatial working memory. Three used the spatial working memory task from the CANTAB battery of neuropsychological tests (Sahakian & Owen, 1992). In this task, subjects search for a target at different locations on a screen. Subjects are told that locations containing a target in previous trials will not contain a target in future trials. Efficient performance therefore requires remembering and avoiding these locations in addition to remembering and avoiding locations already searched within a trial. Mehta et al. (2000) found evidence of greater accuracy with MPH, and Elliott et al. (1997) found a trend for the same. In Mehta et al.’s study, this effect depended on subjects’ working memory ability: the lower a subject’s score on placebo, the greater the improvement on MPH. In Elliott et al.’s study, MPH enhanced performance for the group of subjects who received the placebo first and made little difference for the other group. The reason for this difference is unclear, but as mentioned above, this may reflect ability differences between the groups. More recently, Clatworthy et al. (2009) undertook a positron emission tomography (PET) study of MPH effects on two tasks, one of which was the CANTAB spatial working memory task. They failed to find consistent effects of MPH on working memory performance but did find a systematic relation between the performance effect of the drug in each individual and its effect on individuals’ dopamine activity in the ventral striatum.

Similarly, Mehta et al 2000 noted that the positive effects of methylphenidate (40 mg) on spatial working memory performance were greatest in those volunteers with lower baseline working memory capacity. In a study of the effects of ginkgo biloba in healthy young adults, Stough et al 2001 found improved performance in the Trail-Making Test A only in the half with the lower verbal IQ.
There are seven primary classes used to categorize smart drugs: Racetams, Stimulants, Adaptogens, Cholinergics, Serotonergics, Dopaminergics, and Metabolic Function Smart Drugs. Despite considerable overlap and no clear border in the brain and body’s responses to these substances, each class manifests its effects through a different chemical pathway within the body.

ADHD medication sales are growing rapidly, with annual revenues of $12.9 billion in 2015. These drugs can be obtained legally by those who have a prescription, which also includes those who have deliberately faked the symptoms in order to acquire the desired medication. (According to an experiment published in 2010, it is difficult for medical practitioners to separate those who feign the symptoms from those who actually have them.) That said, faking might not be necessary if a doctor deems your desired productivity level or your stress around a big project as reason enough to prescribe medication.
Nootropics. You might have heard of them. The “limitless pill” that keeps Billionaires rich. The ‘smart drugs’ that students are taking to help boost their hyperfocus. The cognitive enhancers that give corporate executives an advantage. All very exciting. But as always, the media are way behind the curve. Yes, for the past few decades, cognitive enhancers were largely sketchy substances that people used to grasp at a short term edge at the expense of their health and well being. But the days of taking prescription pills to pull an all-nighter are so 2010. The better, safer path isn’t with these stimulants but with nootropics. Nootropics consist of dietary supplements and substances which enhance your cognition, in particular when it comes to motivation, creativity, memory, and other executive functions. They play an important role in supporting memory and promoting optimal brain function. 
Nor am I sure how important the results are - partway through, I haven’t noticed anything bad, at least, from taking Noopept. And any effect is going to be subtle: people seem to think that 10mg is too small for an ingested rather than sublingual dose and I should be taking twice as much, and Noopept’s claimed to be a chronic gradual sort of thing, with less of an acute effect. If the effect size is positive, regardless of statistical-significance, I’ll probably think about doing a bigger real self-experiment (more days blocked into weeks or months & 20mg dose)
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.)
I bought 500g of piracetam (Examine.com; FDA adverse events) from Smart Powders (piracetam is one of the cheapest nootropics and SP was one of the cheapest suppliers; the others were much more expensive as of October 2010), and I’ve tried it out for several days (started on 7 September 2009, and used it steadily up to mid-December). I’ve varied my dose from 3 grams to 12 grams (at least, I think the little scoop measures in grams), taking them in my tea or bitter fruit juice. Cranberry worked the best, although orange juice masks the taste pretty well; I also accidentally learned that piracetam stings horribly when I got some on a cat scratch. 3 grams (alone) didn’t seem to do much of anything while 12 grams gave me a nasty headache. I also ate 2 or 3 eggs a day.
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When comparing supplements, consider products with a score above 90% to get the greatest benefit from smart pills to improve memory. Additionally, we consider the reviews that users send to us when scoring supplements, so you can determine how well products work for others and use this information to make an informed decision. Every month, our editor puts her name on that month’s best smart bill, in terms of results and value offered to users.
An additional complexity, related to individual differences, concerns dosage. This factor, which varies across studies and may be fixed or determined by participant body weight within a study, undoubtedly influences the cognitive effects of stimulant drugs. Furthermore, single-unit recordings with animals and, more recently, imaging of humans indicate that the effects of stimulant dose are nonmonotonic; increases enhance prefrontal function only up to a point, with further increases impairing function (e.g., Arnsten, 1998; Mattay et al., 2003; Robbins & Arnsten, 2009). Yet additional complexity comes from the fact that the optimal dosage depends on the same kinds of individual characteristics just discussed and on the task (Mattay et al., 2003).
One symptom of Alzheimer's disease is a reduced brain level of the neurotransmitter called acetylcholine. It is thought that an effective treatment for Alzheimer's disease might be to increase brain levels of acetylcholine. Another possible treatment would be to slow the death of neurons that contain acetylcholine. Two drugs, Tacrine and Donepezil, are both inhibitors of the enzyme (acetylcholinesterase) that breaks down acetylcholine. These drugs are approved in the US for treatment of Alzheimer's disease.
Theanine can also be combined with caffeine as both of them work in synergy to increase memory, reaction time, mental endurance, and memory. The best part about Theanine is that it is one of the safest nootropics and is readily available in the form of capsules.  A natural option would be to use an excellent green tea brand which constitutes of tea grown in the shade because then Theanine would be abundantly present in it.
How much of the nonmedical use of prescription stimulants documented by these studies was for cognitive enhancement? Prescription stimulants could be used for purposes other than cognitive enhancement, including for feelings of euphoria or energy, to stay awake, or to curb appetite. Were they being used by students as smart pills or as “fun pills,” “awake pills,” or “diet pills”? Of course, some of these categories are not entirely distinct. For example, by increasing the wakefulness of a sleep-deprived person or by lifting the mood or boosting the motivation of an apathetic person, stimulants are likely to have the secondary effect of improving cognitive performance. Whether and when such effects should be classified as cognitive enhancement is a question to which different answers are possible, and none of the studies reviewed here presupposed an answer. Instead, they show how the respondents themselves classified their reasons for nonmedical stimulant use.
I took 1.5mg of melatonin, and went to bed at ~1:30AM; I woke up around 6:30, took a modafinil pill/200mg, and felt pretty reasonable. By noon my mind started to feel a bit fuzzy, and lunch didn’t make much of it go away. I’ve been looking at studies, and users seem to degrade after 30 hours; I started on mid-Thursday, so call that 10 hours, then 24 (Friday), 24 (Saturday), and 14 (Sunday), totaling 72hrs with <20hrs sleep; this might be equivalent to 52hrs with no sleep, and Wikipedia writes:
Since my experiment had a number of flaws (non-blind, varying doses at varying times of day), I wound up doing a second better experiment using blind standardized smaller doses in the morning. The negative effect was much smaller, but there was still no mood/productivity benefit. Having used up my first batch of potassium citrate in these 2 experiments, I will not be ordering again since it clearly doesn’t work for me.

Cognitive control is a broad concept that refers to guidance of cognitive processes in situations where the most natural, automatic, or available action is not necessarily the correct one. Such situations typically evoke a strong inclination to respond but require people to resist responding, or they evoke a strong inclination to carry out one type of action but require a different type of action. The sources of these inclinations that must be overridden are various and include overlearning (e.g., the overlearned tendency to read printed words in the Stroop task), priming by recent practice (e.g., the tendency to respond in the go/no-go task when the majority of the trials are go trials, or the tendency to continue sorting cards according to the previously correct dimension in the Wisconsin Card Sorting Test [WCST]; Grant & Berg, 1948) and perceptual salience (e.g., the tendency to respond to the numerous flanker stimuli as opposed to the single target stimulus in the flanker task). For the sake of inclusiveness, we also consider the results of studies of reward processing in this section, in which the response tendency to be overridden comes from the desire to have the reward immediately.
Cognitive control is a broad concept that refers to guidance of cognitive processes in situations where the most natural, automatic, or available action is not necessarily the correct one. Such situations typically evoke a strong inclination to respond but require people to resist responding, or they evoke a strong inclination to carry out one type of action but require a different type of action. The sources of these inclinations that must be overridden are various and include overlearning (e.g., the overlearned tendency to read printed words in the Stroop task), priming by recent practice (e.g., the tendency to respond in the go/no-go task when the majority of the trials are go trials, or the tendency to continue sorting cards according to the previously correct dimension in the Wisconsin Card Sorting Test [WCST]; Grant & Berg, 1948) and perceptual salience (e.g., the tendency to respond to the numerous flanker stimuli as opposed to the single target stimulus in the flanker task). For the sake of inclusiveness, we also consider the results of studies of reward processing in this section, in which the response tendency to be overridden comes from the desire to have the reward immediately.
Since coffee drinking may lead to a worsening of calcium balance in humans, we studied the serial changes of serum calcium, PTH, 1,25-dihydroxyvitamin D (1,25(OH)2D) vitamin D and calcium balance in young and adult rats after daily administration of caffeine for 4 weeks. In the young rats, there was an increase in urinary calcium and endogenous fecal calcium excretion after four days of caffeine administration that persisted for the duration of the experiment. Serum calcium decreased on the fourth day of caffeine administration and then returned to control levels. In contrast, the serum PTH and 1,25(OH)2D remained unchanged initially, but increased after 2 weeks of caffeine administration…In the adult rat group, an increase in the urinary calcium and endogenous fecal calcium excretion and serum levels of PTH was found after caffeine administration. However, the serum 1,25(OH)2D levels and intestinal absorption coefficient of calcium remained the same as in the adult control group.
Finally, a workforce high on stimulants wouldn’t necessarily be more productive overall. “One thinks ‘are these things dangerous?’ – and that’s important to consider in the short term,” says Huberman. “But there’s also a different question, which is: ‘How do you feel the day afterwards?’ Maybe you’re hyper-focused for four hours, 12 hours, but then you’re below baseline for 24 or 48.”
The evidence? Ritalin is FDA-approved to treat ADHD. It has also been shown to help patients with traumatic brain injury concentrate for longer periods, but does not improve memory in those patients, according to a 2016 meta-analysis of several trials. A study published in 2012 found that low doses of methylphenidate improved cognitive performance, including working memory, in healthy adult volunteers, but high doses impaired cognitive performance and a person’s ability to focus. (Since the brains of teens have been found to be more sensitive to the drug’s effect, it’s possible that methylphenidate in lower doses could have adverse effects on working memory and cognitive functions.)
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Fortunately for me, the FDA decided Smart Powder’s advertising was too explicit and ordered its piracetam sales stopped; I was equivocal at the previous price point, but then I saw that between the bulk discount and the fire-sale coupon, 3kg was only $99.99 (shipping was amortized over that, the choline, caffeine, and tryptophan). So I ordered in September 2010. As well, I had decided to cap my own pills, eliminating the inconvenience and bad taste. 3kg goes a very long way so I am nowhere close to running out of my pills; there is nothing to report since, as the pills are simply part of my daily routine.
Nicotine’s stimulant effects are general and do not come with the same tweakiness and aggression associated with the amphetamines, and subjectively are much cleaner with less of a crash. I would say that its stimulant effects are fairly strong, around that of modafinil. Another advantage is that nicotine operates through nicotinic receptors and so doesn’t cross-tolerate with dopaminergic stimulants (hence one could hypothetically cycle through nicotine, modafinil, amphetamines, and caffeine, hitting different receptors each time).

Actually, researchers are studying substances that may improve mental abilities. These substances are called "cognitive enhancers" or "smart drugs" or "nootropics." ("Nootropic" comes from Greek - "noos" = mind and "tropos" = changed, toward, turn). The supposed effects of cognitive enhancement can be several things. For example, it could mean improvement of memory, learning, attention, concentration, problem solving, reasoning, social skills, decision making and planning.


Four of the studies focused on middle and high school students, with varied results. Boyd, McCabe, Cranford, and Young (2006) found a 2.3% lifetime prevalence of nonmedical stimulant use in their sample, and McCabe, Teter, and Boyd (2004) found a 4.1% lifetime prevalence in public school students from a single American public school district. Poulin (2001) found an 8.5% past-year prevalence in public school students from four provinces in the Atlantic region of Canada. A more recent study of the same provinces found a 6.6% and 8.7% past-year prevalence for MPH and AMP use, respectively (Poulin, 2007).
But there would also be significant downsides. Amphetamines are structurally similar to crystal meth – a potent, highly addictive recreational drug which has ruined countless lives and can be fatal. Both Adderall and Ritalin are known to be addictive, and there are already numerous reports of workers who struggled to give them up. There are also side effects, such as nervousness, anxiety, insomnia, stomach pains, and even hair loss, among others.
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At this point I began to get bored with it and the lack of apparent effects, so I began a pilot trial: I’d use the LED set for 10 minutes every few days before 2PM, record, and in a few months look for a correlation with my daily self-ratings of mood/productivity (for 2.5 years I’ve asked myself at the end of each day whether I did more, the usual, or less work done that day than average, so 2=below-average, 3=average, 4=above-average; it’s ad hoc, but in some factor analyses I’ve been playing with, it seems to load on a lot of other variables I’ve measured, so I think it’s meaningful).

Upon examining the photographs, I noticed no difference in eye color, but it seems that my move had changed the ambient lighting in the morning and so there was a clear difference between the two sets of photographs! The before photographs had brighter lighting than the after photographs. Regardless, I decided to run a small survey on QuickSurveys/Toluna to confirm my diagnosis of no-change; the survey was 11 forced-choice pairs of photographs (before-after), with the instructions as follows:
A large review published in 2011 found that the drug aids with the type of memory that allows us to explicitly remember past events (called long-term conscious memory), as opposed to the type that helps us remember how to do things like riding a bicycle without thinking about it (known as procedural or implicit memory.) The evidence is mixed on its effect on other types of executive function, such as planning or ability on fluency tests, which measure a person’s ability to generate sets of data—for example, words that begin with the same letter. 
When you drink tea, you’re getting some caffeine (less than the amount in coffee), plus an amino acid called L-theanine that has been shown in studies to increase activity in the brain’s alpha frequency band, which can lead to relaxation without drowsiness. These calming-but-stimulating effects might contribute to tea’s status as the most popular beverage aside from water. People have been drinking it for more than 4,000 years, after all, but modern brain hackers try to distill and enhance the benefits by taking just L-theanine as a nootropic supplement. Unfortunately, that means they’re missing out on the other health effects that tea offers. It’s packed with flavonoids, which are associated with longevity, reduced inflammation, weight loss, cardiovascular health, and cancer prevention.

One should note the serious caveats here: it is a small in vitro study of a single category of human cells with an effect size that is not clear on a protein which feeds into who-knows-what pathways. It is not a result in a whole organism on any clinically meaningful endpoint, even if we take it at face-value (many results never replicate). A look at followup work citing Rapuri et al 2007 is not encouraging: Google Scholar lists no human studies of any kind, much less high-quality studies like RCTs; just some rat followups on the calcium effect. This is not to say Rapuri et al 2007 is a bad study, just that it doesn’t bear the weight people are putting on it: if you enjoy caffeine, this is close to zero evidence that you should reduce or drop caffeine consumption; if you’re taking too much caffeine, you already have plenty of reasons to reduce; if you’re drinking lots of coffee, you already have plenty of reasons to switch to tea; etc.


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?
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