Caffeine metabolism is primarily determined by the cytochrome enzyme P-450 1A2 (CYP1A2), and studies have shown that different ethnic populations exhibit widely varying expressions of the gene responsible for CYP1A2. Evidence suggests that a particular CYP1A2 impacts caffeine consumption by modifying the risks of certain diseases that are associated with caffeine consumption. It has also been shown that variations in the expression of genes that code for adenosine and dopamine receptors play a role in mediating your response to caffeine. For example, in Caucasians, the presence of certain genetic expressions for both adenosine and dopamine receptors is associated with caffeine-induced anxiety. Variations in CYP1A2 are also responsible for the speed at which different people metabolize caffeine.
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 data29 suggests to me a decline:
purpose of this research study titled ‘Nootropics Market – Growth, Future Prospects, and Competitive Analysis, 2016 – 2024’ is to provide investors, developers, company executives and industry participants with in-depth analysis to allow them to take strategic initiatives and decisions related to the prospects in the global nootropics products market.
One idea I’ve been musing about is the connections between IQ, Conscientiousness, and testosterone. IQ and Conscientiousness do not correlate to a remarkable degree - even though one would expect IQ to at least somewhat enable a long-term perspective, self-discipline, metacognition, etc! There are indications in studies of gifted youth that they have lower testosterone levels. The studies I’ve read on testosterone indicate no improvements to raw ability. So, could there be a self-sabotaging aspect to human intelligence whereby greater intelligence depends on lack of testosterone, but this same lack also holds back Conscientiousness (despite one’s expectation that intelligence would produce greater self-discipline and planning), undermining the utility of greater intelligence? Could cases of high IQ types who suddenly stop slacking and accomplish great things sometimes be due to changes in testosterone? Studies on the correlations between IQ, testosterone, Conscientiousness, and various measures of accomplishment are confusing and don’t always support this theory, but it’s an idea to keep in mind.
Eliminating foggy-headedness seems to be the goal of many users of neuroenhancers. But can today's drugs actually accomplish this? I recently posed this question to Chatterjee's colleague Martha Farah, who is a psychologist at Penn and the director of its Center for Cognitive Neuroscience. She is deeply fascinated by, and mildly critical of, neuroenhancers, but basically in favour - with the important caveat that we need to know much more about how these drugs work. While Farah does not take neuroenhancers, she had just finished a paper in which she reviewed the evidence on prescription stimulants as neuroenhancers from 40 laboratory studies involving healthy subjects. Most of the studies looked at one of three types of cognition: learning, working memory, and cognitive control. A typical learning test asks subjects to memorise a list of paired words; an hour, a few days, or a week later, they are presented with the first words in the pairs and asked to come up with the second. Neuroenhancers did improve retention, especially where subjects had been asked to remember information for several days or longer.
I was contacted by the Longecity user lostfalco, and read through some of his writings on the topic. I had never heard of LLLT before, but the mitochondria mechanism didn’t sound impossible (although I wondered whether it made sense at a quantity level14151617), and there was at least some research backing it; more importantly, lostfalco had discovered that devices for LLLT could be obtained as cheap as $15. (Clearly no one will be getting rich off LLLT or affiliate revenue any time soon.) Nor could I think of any way the LLLT could be easily harmful: there were no drugs involved, physical contact was unnecessary, power output was too low to directly damage through heating, and if it had no LLLT-style effect but some sort of circadian effect through hitting photoreceptors, using it in the morning wouldn’t seem to interfere with sleep.
Last April the scientific journal Nature published the results of an informal online poll asking whether readers attempted to sharpen "their focus, concentration, or memory" by taking drugs such as Ritalin and Provigil, a newer kind of stimulant, known generically as modafinil, which was developed to treat narcolepsy. One in five respondents said they did. A majority of the 1,400 readers who responded said that healthy adults should be permitted to take brain boosters for non-medical reasons, and 69% said that mild side-effects were an acceptable risk. Though a majority said that such drugs should not be made available to children who had no diagnosed medical condition, a third admitted that they would feel pressure to give "smart drugs" to their kids if they learned that other parents were doing so.

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Similarly, we could try applying Nick Bostrom’s reversal test and ask ourselves, how would we react to a virus which had no effect but to eliminate sleep from alternating nights and double sleep in the intervening nights? We would probably grouch about it for a while and then adapt to our new hedonistic lifestyle of partying or working hard. On the other hand, imagine the virus had the effect of eliminating normal sleep but instead, every 2 minutes, a person would fall asleep for a minute. This would be disastrous! Besides the most immediate problems like safely driving vehicles, how would anything get done? You would hold a meeting and at any point, a third of the participants would be asleep. If the virus made it instead 2 hours on, one hour off, that would be better but still problematic: there would be constant interruptions. And so on, until we reach our present state of 16 hours on, 8 hours off. Given that we rejected all the earlier buffer sizes, one wonders if 16:8 can be defended as uniquely suited to circumstances. Is that optimal? It may be, given the synchronization with the night-day cycle, but I wonder; rush hour alone stands as an argument against synchronized sleep - wouldn’t our infrastructure would be much cheaper if it only had to handle the average daily load rather than cope with the projected peak loads? Might not a longer cycle be better? The longer the day, the less we are interrupted by sleep; it’s a hoary cliche about programmers that they prefer to work in long sustained marathons during long nights rather than sprint occasionally during a distraction-filled day, to the point where some famously adopt a 28 hour day (which evenly divides a week into 6 days). Are there other occupations which would benefit from a 20 hour waking period? Or 24 hour waking period? We might not know because without chemical assistance, circadian rhythms would overpower anyone attempting such schedules. It certainly would be nice if one had long time chunks in which could read a challenging book in one sitting, without heroic arrangements.↩
10:30 AM; no major effect that I notice throughout the day - it’s neither good nor bad. This smells like placebo (and part of my mind is going how unlikely is it to get placebo 3 times in a row!, which is just the Gambler’s fallacy talking inasmuch as this is sampling with replacement). I give it 60% placebo; I check the next day right before taking, and it is. Man!

I have been taking these supplements for almost three weeks now. What I have noticed is there is a marked difference in the decrease of my daily brain fog. This was huge for me! However, I gave the product 4 stars because of my concern about the high count of vitamin B6. I think this should have been addressed in a disclaimer for concerned consumers
For the moment, people looking for that particular quick fix have a limited choice of meds. But given the amount of money and research hours being spent on developing drugs to treat cognitive decline, Provigil and Adderall are likely to be joined by a bigger pharmacopoeia. Among the drugs in the pipeline are ampakines, which target a type of glutamate receptor in the brain; it is hoped that they may stem the memory loss associated with diseases like Alzheimer's. But ampakines may also give healthy people a palpable cognitive boost. A 2007 study of 16 healthy elderly volunteers found that 500mg of one particular ampakine "unequivocally" improved short-term memory, though it appeared to detract from episodic memory - the recall of past events. Another class of drugs, cholinesterase inhibitors, which are already being used with some success to treat Alzheimer's patients, have also shown promise as neuroenhancers. In one study the drug donepezil strengthened the performance of pilots on flight simulators; in another, of 30 healthy young male volunteers, it improved verbal and visual episodic memory. Several pharmaceutical companies are working on drugs that target nicotine receptors in the brain in the hope that they can replicate the cognitive uptick that smokers get from cigarettes.
There are many books about nutrition and cognitive functions. The authors ground their nutrition protocol on what humans ate during the paleolithic era. Often these authors contradict each other. For some, we were better hunters than gatherers so we ate mostly meat. For others, we were better gatherers and ate primarily nuts, plants, fruits. Others advance our digestive system can’t tolerate grains because it was a modern invention of the first agricultural revolution (about 10,000 years ago).

On the other hand, sometimes you’ll feel a great cognitive boost as soon as you take a pill. That can be a good thing or a bad thing. I find, for example, that modafinil makes you more of what you already are. That means if you are already kind of a dick and you take modafinil, you might act like a really big dick and regret it. It certainly happened to me! I like to think that I’ve done enough hacking of my brain that I’ve gotten over that programming… and that when I use nootropics they help me help people.


Its high levels of collagen help reduce intestinal inflammation, and healing amino acids like proline and glycine keep your immune system functioning properly and help improve memory. Bone broth is what I prescribe most frequently to my patients because it truly helps heal your body from the inside out. You’ll also be surprised at how simple and economical it is to make at home with my Beef Bone Broth Recipe.
Paul Phillips was unusual for a professional poker player. When he joined the circuit in the late 1990s he was already a millionaire: a twentysomething tech guy who helped found an internet portal called go2net and cashed in at the right moment. He was cerebral and at times brusque. On the international poker scene Phillips cultivated a geeky New Wave style. He wore vintage shirts in wild geometric patterns; his hair was dyed orange or silver one week, shaved off the next. Most unusual of all, Phillips talked freely about taking prescription drugs - Adderall and, especially, Provigil - in order to play better cards.
Last winter, I spoke again with Alex, the Harvard graduate, and found that, after a break of several months, he had gone back to taking Adderall - a small dose every day. He felt that he was learning to use the drug in a more "disciplined" manner. Now, he said, it was less about staying up late to finish work he should have done earlier, and more "about staying focused on work, which makes me want to work longer hours". What employer would object to that?
I asked Marcus which nootropic he would want if he were stranded on a desert island. "I guess it would depend on the challenges I was facing on the island. If staying healthy was the biggest challenge, then I'd choose AC-11," he said. "If I needed to stay motivated to rebuild the village, I would choose Mucuna [pruriens]. If I was hunting, I'd choose Huperzia serrata, for mental acuity and speed."
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-Caviar contains a unique blend of nutrients that are perfect for the brain, including omega-3 fats (a brain-must), choline (a B vitamin needed to make memories), vitamin B6 and B12 (needed to support the nervous system), minerals like iron and magnesium (needed for healthy blood and tissues) and a good amount of protein combined with potent antioxidants like vitamin A, vitamin C, and selenium. [Because] caviar [can be] expensive, fatty fish would be my recommended alternative, especially Alaskan salmon [and] mackerel, bluefish, sardines [and] anchovies [to get the] omega-3’s your brain needs.
Or in other words, since the standard deviation of my previous self-ratings is 0.75 (see the Weather and my productivity data), a mean rating increase of >0.39 on the self-rating. This is, unfortunately, implying an extreme shift in my self-assessments (for example, 3s are ~50% of the self-ratings and 4s ~25%; to cause an increase of 0.25 while leaving 2s alone in a sample of 23 days, one would have to push 3s down to ~25% and 4s up to ~47%). So in advance, we can see that the weak plausible effects for Noopept are not going to be detected here at our usual statistical levels with just the sample I have (a more plausible experiment might use 178 pairs over a year, detecting down to d>=0.18). But if the sign is right, it might make Noopept worthwhile to investigate further. And the hardest part of this was just making the pills, so it’s not a waste of effort.
When taken regularly, Vitacern Brain Focus Supplement can help your mind function at its best for noticeable improvements in brain power. Our brain supplement promotes better concentration and improved focus to help you excel at work or school. In addition, our focus supplement aids in brain health throughout life for clearer thinking and memory support.

Nicotine absorption through the stomach is variable and relatively reduced in comparison with absorption via the buccal cavity and the small intestine. Drinking, eating, and swallowing of tobacco smoke by South American Indians have frequently been reported. Tenetehara shamans reach a state of tobacco narcosis through large swallows of smoke, and Tapirape shams are said to eat smoke by forcing down large gulps of smoke only to expel it again in a rapid sequence of belches. In general, swallowing of tobacco smoke is quite frequently likened to drinking. However, although the amounts of nicotine swallowed in this way - or in the form of saturated saliva or pipe juice - may be large enough to be behaviorally significant at normal levels of gastric pH, nicotine, like other weak bases, is not significantly absorbed.
Powders are good for experimenting with (easy to vary doses and mix), but not so good for regular taking. I use OO gel capsules with a Capsule Machine: it’s hard to beat $20, it works, it’s not that messy after practice, and it’s not too bad to do 100 pills. However, I once did 3kg of piracetam + my other powders, and doing that nearly burned me out on ever using capsules again. If you’re going to do that much, something more automated is a serious question! (What actually wound up infuriating me the most was when capsules would stick in either the bottom or top try - requiring you to very gingerly pull and twist them out, lest the two halves slip and spill powder - or when the two halves wouldn’t lock and you had to join them by hand. In contrast: loading the gel caps could be done automatically without looking, after some experience.)
Last spring, 100 people showed up at a Peak Performance event where psychedelic psychologist James Fadiman said the key to unleashing the cognition-enhancing effects of LSD — which he listed as less anxiety, better focus, improved sleep, greater creativity — was all in the dosage. He recommended a tenth of a “party dose” — enough to give you “the glow” and enhance your cognitive powers without “the trip.”
I am sort of a health nut. I only use natural medicines- never prescriptions. Lately I have been experiencing some brain fog in spite of my detoxing, so I tried this product. I LOVE IT! I really can tell a difference. I have tried many memory and brain support supplements before, but this one seems quite different. I love the daytime and separate night time formulas. I have never slept so soundly in my life. In fact, I've always had a lot of trouble sleeping, but I sleep like a baby and wake feeling refreshed and full of energy.
This product is a miracle! I have purchased it TWICE because it is so helpful with my memory and cognition. I bought this product because I needed to strengthen my memory and focus, and I wanted to be awake when I did it! I had just switched to a job that is second shift (2PM-11PM) and it was very difficult to adjust to those hours AND learn all of the new technical systems required for my new job. But after taking this supplement, I noticed a HUGE difference in a few days! I was awake and alert like it was 11AM everyday. But it wasn’t like the jolt you sometimes get from caffeine, more like an alertness after a good night’s sleep. No jitters, no headaches, no stomach upset. Just energy and the feeling of being AWAKE. I am now telling all of my co-workers about it!
Farah has also been considering the ethical complications resulting from the rise of smart drugs. Don't neuroenhancers confer yet another advantage on the kind of people who already can afford private tutors? Writing last year in the Cavalier Daily, the student newspaper of the University of Virginia, a columnist named Greg Crapanzano argued that neuroenhancers "create an unfair advantage for the users who are willing to break the law in order to gain an edge. These students create work that is dependent on the use of a pill rather than their own work ethic." Of course, it's hard to imagine a university administration that would require students to pee in a cup before entering an exam hall. And even with the aid of a neuroenhancer, you still have to write the essay, conceive the screenplay or finish the grant proposal. Moreover, if you can take credit for work you've done on caffeine or nicotine, then you can take credit for work produced on Provigil.
The evidence? A 2012 study in Greece found it can boost cognitive function in adults with mild cognitive impairment (MCI), a type of disorder marked by forgetfulness and problems with language, judgement, or planning that are more severe than average “senior moments,” but are not serious enough to be diagnosed as dementia. In some people, MCI will progress into dementia.
There are a number of treatments for the last. I already use melatonin. I sort of have light therapy from a full-spectrum fluorescent desk lamp. But I get very little sunlight; the surprising thing would be if I didn’t have a vitamin D deficiency. And vitamin D deficiencies have been linked with all sorts of interesting things like near-sightedness, with time outdoors inversely correlating with myopia and not reading or near-work time. (It has been claimed that caffeine interferes with vitamin D absorption and so people like me especially need to take vitamin D, on top of the deficits caused by our vampiric habits, but I don’t think this is true35.) Unfortunately, there’s not very good evidence that vitamin D supplementation helps with mood/SAD/depression: there’s ~6 small RCTs with some findings of benefits, with their respective meta-analysis turning in a positive but currently non-statistically-significant result. Better confirmed is reducing all-cause mortality in elderly people (see, in order of increasing comprehensiveness: Evidence Syntheses 2013, Chung et al 2009, Autier & Gandini 2007, Bolland et al 2014).

Integrity & Reputation: Go with a company that sells more than just a brain formula. If a company is just selling this one item,buyer-beware!!! It is an indication that it is just trying to capitalize on a trend and make a quick buck. Also, if a website selling a brain health formula does not have a highly visible 800# for customer service, you should walk away.
Took random pill at 2:02 PM. Went to lunch half an hour afterwards, talked until 4 - more outgoing than my usual self. I continued to be pretty energetic despite not taking my caffeine+piracetam pills, and though it’s now 12:30 AM and I listened to TAM YouTube videos all day while reading, I feel pretty energetic and am reviewing Mnemosyne cards. I am pretty confident the pill today was Adderall. Hard to believe placebo effect could do this much for this long or that normal variation would account for this. I’d say 90% confidence it was Adderall. I do some more Mnemosyne, typing practice, and reading in a Montaigne book, and finally get tired and go to bed around 1:30 AM or so. I check the baggie when I wake up the next morning, and sure enough, it had been an Adderall pill. That makes me 1 for 2.
The abuse liability of caffeine has been evaluated.147,148 Tolerance development to the subjective effects of caffeine was shown in a study in which caffeine was administered at 300 mg twice each day for 18 days.148 Tolerance to the daytime alerting effects of caffeine, as measured by the MSLT, was shown over 2 days on which 250 g of caffeine was given twice each day48 and to the sleep-disruptive effects (but not REM percentage) over 7 days of 400 mg of caffeine given 3 times each day.7 In humans, placebo-controlled caffeine-discontinuation studies have shown physical dependence on caffeine, as evidenced by a withdrawal syndrome.147 The most frequently observed withdrawal symptom is headache, but daytime sleepiness and fatigue are also often reported. The withdrawal-syndrome severity is a function of the dose and duration of prior caffeine use…At higher doses, negative effects such as dysphoria, anxiety, and nervousness are experienced. The subjective-effect profile of caffeine is similar to that of amphetamine,147 with the exception that dysphoria/anxiety is more likely to occur with higher caffeine doses than with higher amphetamine doses. Caffeine can be discriminated from placebo by the majority of participants, and correct caffeine identification increases with dose.147 Caffeine is self-administered by about 50% of normal subjects who report moderate to heavy caffeine use. In post-hoc analyses of the subjective effects reported by caffeine choosers versus nonchoosers, the choosers report positive effects and the nonchoosers report negative effects. Interestingly, choosers also report negative effects such as headache and fatigue with placebo, and this suggests that caffeine-withdrawal syndrome, secondary to placebo choice, contributes to the likelihood of caffeine self-administration. This implies that physical dependence potentiates behavioral dependence to caffeine.
A key area that has been widely researched is the link between the microbiome (bacteria) in the gut and the brain. The hypothesis is that alterations in bacteria due to changes in our environment such as increased hygiene, increased exposure to antibiotics, refined and processed foods and stress have led to disturbances in short-chain fatty acids (SFCAs), which are byproducts of fermentation in the gut when bacteria come into contact with indigestible fibre found in food.

-Water [is also important]. Over 80% of the brain’s content is water. Every chemical reaction that takes place in the brain needs water, especially energy production. The brain is so sensitive to dehydration that even a minimal loss of water can cause symptoms like brain fog, fatigue, dizziness, confusion and, more importantly, brain shrinkage. The longevity and well-being of your brain are critically dependent upon consuming hard water. This refers to plain water that is high in minerals and natural electrolytes. Most people don’t realize that the water they’re drinking is not actually “water”.
…The Fate of Nicotine in the Body also describes Battelle’s animal work on nicotine absorption. Using C14-labeled nicotine in rabbits, the Battelle scientists compared gastric absorption with pulmonary absorption. Gastric absorption was slow, and first pass removal of nicotine by the liver (which transforms nicotine into inactive metabolites) was demonstrated following gastric administration, with consequently low systemic nicotine levels. In contrast, absorption from the lungs was rapid and led to widespread distribution. These results show that nicotine absorbed from the stomach is largely metabolized by the liver before it has a chance to get to the brain. That is why tobacco products have to be puffed, smoked or sucked on, or absorbed directly into the bloodstream (i.e., via a nicotine patch). A nicotine pill would not work because the nicotine would be inactivated before it reached the brain.
There are over a thousand websites and hundreds of reference guides chock full of complicated methods for combining many of the compounds you’ve just discovered. There’s a reason for this: the practice of “stacking” nootropics and smart drugs into specific combinations can be far more powerful and efficacious than consuming a single, lonely compound in isolation. For example, dosing choline sources with your morning coffee can make your brain feel fresh for hours or mixing curcumin with black pepper can dramatically amp up the neural anti-inflammatory effects of both compounds. Ultimately, a teaspoon of lion’s mane extract just isn’t as titillating as lion’s mane blended with caffeine, theanine, nicotine and a touch of vinpocetine.
A record of nootropics I have tried, with thoughts about which ones worked and did not work for me. These anecdotes should be considered only as anecdotes, and one’s efforts with nootropics a hobby to put only limited amounts of time into due to the inherent limits of drugs as a force-multiplier compared to other things like programming1; for an ironic counterpoint, I suggest the reader listen to a video of Jonathan Coulton’s I Feel Fantastic while reading.

"More and more of our young people are using these drugs to help them work. They've got their laptop, their iPhone, and their Adderall. This rising generation of workers and leaders may have a subtly different style of thinking and working, because they're using these drugs or because they learned to work using these drugs, so that even if you take the drugs away they'll still have a certain approach. I'm a little concerned that we could be raising a generation of very focused accountants."
I tried taking whole pills at 1 and 3 AM. I felt kind of bushed at 9 AM after all the reading, and the 50 minute nap didn’t help much - I was sleep only around 10 minutes and spent most of it thinking or meditation. Just as well the 3D driver is still broken; I doubt the scores would be reasonable. Began to perk up again past 10 AM, then felt more bushed at 1 PM, and so on throughout the day; kind of gave up and began watching & finishing anime (Amagami and Voices of a Distant Star) for the rest of the day with occasional reading breaks (eg. to start James C. Scotts Seeing Like A State, which is as described so far). As expected from the low quality of the day, the recovery sleep was bigger than before: a full 10 hours rather than 9:40; the next day, I slept a normal 8:50, and the following day ~8:20 (woken up early); 10:20 (slept in); 8:44; 8:18 (▁▇▁▁). It will be interesting to see whether my excess sleep remains in the hour range for ’good modafinil nights and two hours for bad modafinil nights.
It looks like the overall picture is that nicotine is absorbed well in the intestines and the colon, but not so well in the stomach; this might be the explanation for the lack of effect, except on the other hand, the specific estimates I see are that 10-20% of the nicotine will be bioavailable in the stomach (as compared to 50%+ for mouth or lungs)… so any of my doses of >5ml should have overcome the poorer bioavailability! But on the gripping hand, these papers are mentioning something about the liver metabolizing nicotine when absorbed through the stomach, so…
And if you obtain your vitamin C from a multivitamin, you receive other key nutrients that many studies over the years have linked to healthy brain function, including beta carotene, iron, zinc, B12 and folic acid. In the June 1999 issue of the Journal of Biology and Psychiatry, for instance, researchers at Sweden's Gotenborg University reported that older people were more likely to score poorly on word memory tests if they had low levels of folic acid.
Attention Deficit and Hyperactivity Disorder (ADHD) is a condition that relates to a collection of behavioural symptoms such as hyperactivity, impulsiveness and inattentiveness. It is most commonly diagnosed in childhood between the ages of 6 and 12 when disruptive behaviour begins to show, however, due to a growing awareness of the condition, it is also becoming common among adults. According to the thinktank Demos, the cost of undiagnosed ADHD in adults in the UK who are unable to work or hold down a full-time job are estimated to cost billions of pounds to the nation. They warn that too many may be going through life struggling, unable to access the support ot diagnosis they need, which means there could be a huge amount of wasted talent.
Research does not support that drugs like Ritalin help students do well in school. Studies show that prescription stimulants do not help to improve learning or thinking in those who do not actually have ADHD. Further, research reveals that students who abuse prescription stimulants have lower GPAs than students who do not abuse the drugs.[14] Although Ritalin improves concentration, this effect is largely misunderstood among non-prescribed users. These illicit users mistakenly believe that they can use a drug out of its prescribed context, thinking they can reap the benefits intended for legitimate users.
Nootropics are classically defined as something that a) improves brain health, and b) does no harm. So, while many treatments being advertised online and on TV can be classified as nootropics, some of them don’t fit the bill because of the dangerous and damaging side effects they also confer upon the unwary consumer. In fact, most of the results you might get from searching ‘best brain pills’ are similarly not that great, let alone the best.

Nootropics (/noʊ.əˈtrɒpɪks/ noh-ə-TROP-iks) (colloquial: smart drugs and cognitive enhancers) are drugs, supplements, and other substances that may improve cognitive function, particularly executive functions, memory, creativity, or motivation, in healthy individuals.[1] While many substances are purported to improve cognition, research is at a preliminary stage as of 2018, and the effects of the majority of these agents are not fully determined.
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