Speaking of addictive substances, some people might have considered cocaine a nootropic (think: the finance industry in Wall Street in the 1980s). The incredible damage this drug can do is clear, but the plant from which it comes has been used to make people feel more energetic and less hungry, and to counteract altitude sickness in Andean South American cultures for 5,000 years, according to an opinion piece that Bolivia’s president, Evo Morales Ayma, wrote for the New York Times.
Caffeine dose dependently decreased the 1,25(OH)(2)D(3) induced VDR expression and at concentrations of 1 and 10mM, VDR expression was decreased by about 50-70%, respectively. In addition, the 1,25(OH)(2)D(3) induced alkaline phosphatase activity was also reduced at similar doses thus affecting the osteoblastic function. The basal ALP activity was not affected with increasing doses of caffeine. Overall, our results suggest that caffeine affects 1,25(OH)(2)D(3) stimulated VDR protein expression and 1,25(OH)(2)D(3) mediated actions in human osteoblast cells.
Intrigued by old scientific results & many positive anecdotes since, I experimented with microdosing LSD - taking doses ~10μg, far below the level at which it causes its famous effects. At this level, the anecdotes claim the usual broad spectrum of positive effects on mood, depression, ability to do work, etc. After researching the matter a bit, I discovered that as far as I could tell, since the original experiment in the 1960s, no one had ever done a blind or even a randomized self-experiment on it.
A “smart pill” is a drug that increases the cognitive ability of anyone taking it, whether the user is cognitively impaired or normal. The Romanian neuroscientist Corneliu Giurgea is often credited with first proposing, in the 1960s, that smart pills should be developed to increase the intelligence of the general population (see Giurgea, 1984). He is quoted as saying, “Man is not going to wait passively for millions of years before evolution offers him a better brain” (Gazzaniga, 2005, p. 71). In their best-selling book, Smart Drugs and Nutrients, Dean and Morgenthaler (1990) reviewed a large number of substances that have been used by healthy individuals with the goal of increasing cognitive ability. These include synthetic and natural products that affect neurotransmitter levels, neurogenesis, and blood flow to the brain. Although many of these substances have their adherents, none have become widely used. Caffeine and nicotine may be exceptions to this generalization, as one motivation among many for their use is cognitive enhancement (Julien, 2001).
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.
When I worked on the Bulletproof Diet book, I wanted to verify that the effects I was getting from Bulletproof Coffee were not coming from modafinil, so I stopped using it and measured my cognitive performance while I was off of it. What I found was that on Bulletproof Coffee and the Bulletproof Diet, my mental performance was almost identical to my performance on modafinil. I still travel with modafinil, and I’ll take it on occasion, but while living a Bulletproof lifestyle I rarely feel the need.
Analyzing the results is a little tricky because I was simultaneously running the first magnesium citrate self-experiment, which turned out to cause a quite complex result which looks like a gradually-accumulating overdose negating an initial benefit for net harm, and also toying with LLLT, which turned out to have a strong correlation with benefits. So for the potential small Noopept effect to not be swamped, I need to include those in the analysis. I designed the experiment to try to find the best dose level, so I want to look at an average Noopept effect but also the estimated effect at each dose size in case some are negative (especially in the case of 5-pills/60mg); I included the pilot experiment data as 10mg doses since they were also blind & randomized. Finally, missingness affects analysis: because not every variable is recorded for each date (what was the value of the variable for the blind randomized magnesium citrate before and after I finished that experiment? what value do you assign the Magtein variable before I bought it and after I used it all up?), just running a linear regression may not work exactly as one expects as various days get omitted because part of the data was missing.
Yet some researchers point out these drugs may not be enhancing cognition directly, but simply improving the user’s state of mind – making work more pleasurable and enhancing focus. “I’m just not seeing the evidence that indicates these are clear cognition enhancers,” says Martin Sarter, a professor at the University of Michigan, who thinks they may be achieving their effects by relieving tiredness and boredom. “What most of these are actually doing is enabling the person who’s taking them to focus,” says Steven Rose, emeritus professor of life sciences at the Open University. “It’s peripheral to the learning process itself.”
I have also tried to get in contact with senior executives who have experience with these drugs (either themselves or in their firms), but without success. I have to wonder: Are they completely unaware of the drugs’ existence? Or are they actively suppressing the issue? For now, companies can ignore the use of smart drugs. And executives can pretend as if these drugs don’t exist in their workplaces. But they can’t do it forever.
Two additional studies used other spatial working memory tasks. Barch and Carter (2005) required subjects to maintain one of 18 locations on the perimeter of a circle in working memory and then report the name of the letter that appeared there in a similarly arranged circle of letters. d-AMP caused a speeding of responses but no change in accuracy. Fleming et al. (1995) referred to a spatial delay response task, with no further description or citation. They reported no effect of d-AMP in the task except in the zero-delay condition (which presumably places minimal demand on working memory).

Most people I talk to about modafinil seem to use it for daytime usage; for me that has not ever worked out well, but I had nothing in particular to show against it. So, as I was capping the last of my piracetam-caffeine mix and clearing off my desk, I put the 4 remaining Modalerts pills into capsules with the last of my creatine powder and then mixed them with 4 of the theanine-creatine pills. Like the previous Adderall trial, I will pick one pill blindly each day and guess at the end which it was. If it was active (modafinil-creatine), take a break the next day; if placebo (theanine-creatine), replace the placebo and try again the next day. We’ll see if I notice anything on DNB or possibly gwern.net edits.
The miniaturization of electronic components has been crucial to smart pill design. As cloud computing and wireless communication platforms are integrated into the health care system, the use of smart pills for monitoring vital signs and medication compliance is likely to increase. In the long term, smart pills are expected to be an integral component of remote patient monitoring and telemedicine. As the call for noninvasive point-of-care testing increases, smart pills will become mainstream devices.
Modafinil is a prescription smart drug most commonly given to narcolepsy patients, as it promotes wakefulness. In addition, users indicate that this smart pill helps them concentrate and boosts their motivation. Owing to Modafinil, the feeling of fatigue is reduced, and people report that their everyday functions improve because they can manage their time and resources better, as a result reaching their goals easier.
Kratom (Erowid, Reddit) is a tree leaf from Southeast Asia; it’s addictive to some degree (like caffeine and nicotine), and so it is regulated/banned in Thailand, Malaysia, Myanmar, and Bhutan among others - but not the USA. (One might think that kratom’s common use there indicates how very addictive it must be, except it literally grows on trees so it can’t be too hard to get.) Kratom is not particularly well-studied (and what has been studied is not necessarily relevant - I’m not addicted to any opiates!), and it suffers the usual herbal problem of being an endlessly variable food product and not a specific chemical with the fun risks of perhaps being poisonous, but in my reading it doesn’t seem to be particularly dangerous or have serious side-effects.
Power times prior times benefit minus cost of experimentation: (0.20 \times 0.30 \times 540) - 41 = -9. So the VoI is negative: because my default is that fish oil works and I am taking it, weak information that it doesn’t work isn’t enough. If the power calculation were giving us 40% reliable information, then the chance of learning I should drop fish oil is improved enough to make the experiment worthwhile (going from 20% to 40% switches the value from -$9 to +$23.8).

So is there a future in smart drugs? Some scientists are more optimistic than others. Gary Lynch, a professor in the School of Medicine at the University of California, Irvine argues that recent advances in neuroscience have opened the way for the smart design of drugs, configured for specific biological targets in the brain. “Memory enhancement is not very far off,” he says, although the prospects for other kinds of mental enhancement are “very difficult to know… To me, there’s an inevitability to the thing, but a timeline is difficult.”
All clear? Try one (not dozens) of nootropics for a few weeks and keep track of how you feel, Kerl suggests. It’s also important to begin with as low a dose as possible; when Cyr didn’t ease into his nootropic regimen, his digestion took the blow, he admits. If you don’t notice improvements, consider nixing the product altogether and focusing on what is known to boost cognitive function – eating a healthy diet, getting enough sleep regularly and exercising. "Some of those lifestyle modifications," Kerl says, "may improve memory over a supplement."
And there are other uses that may make us uncomfortable. The military is interested in modafinil as a drug to maintain combat alertness. A drug such as propranolol could be used to protect soldiers from the horrors of war. That could be considered a good thing – post-traumatic stress disorder is common in soldiers. But the notion of troops being unaffected by their experiences makes many feel uneasy.
Core body temperature, local pH and internal pressure are important indicators of patient well-being. While a thermometer can give an accurate reading during regular checkups, the monitoring of professionals in high-intensity situations requires a more accurate inner body temperature sensor. An ingestible chemical sensor can record acidity and pH levels along the gastrointestinal tract to screen for ulcers or tumors. Sensors also can be built into medications to track compliance.
Metabolic function smart drugs provide mental benefits by generally facilitating the body’s metabolic processes related to the production of new tissues and the release of energy from food and fat stores. Creatine, a long-time favorite performance-enhancement drug for competitive athletes, was in the news recently when it was found in a double-blind, placebo-controlled crossover trial to have significant cognitive benefits – including both general speed of cognition and improvements in working memory. Ginkgo Biloba is another metabolic function smart drug used to increase memory and improve circulation – however, news from recent studies raises questions about these purported effects.
For obvious reasons, it’s difficult for researchers to know just how common the “smart drug” or “neuro-enhancing” lifestyle is. However, a few recent studies suggest cognition hacking is appealing to a growing number of people. A survey conducted in 2016 found that 15% of University of Oxford students were popping pills to stay competitive, a rate that mirrored findings from other national surveys of UK university students. In the US, a 2014 study found that 18% of sophomores, juniors, and seniors at Ivy League colleges had knowingly used a stimulant at least once during their academic career, and among those who had ever used uppers, 24% said they had popped a little helper on eight or more occasions. Anecdotal evidence suggests that pharmacological enhancement is also on the rise within the workplace, where modafinil, which treats sleep disorders, has become particularly popular.
Methylphenidate, commonly known as Ritalin, is a stimulant first synthesised in the 1940s. More accurately, it’s a psychostimulant - often prescribed for ADHD - that is intended as a drug to help focus and concentration. It also reduces fatigue and (potentially) enhances cognition. Similar to Modafinil, Ritalin is believed to reduce dissipation of dopamine to help focus. Ritalin is a Class B drug in the UK, and possession without a prescription can result in a 5 year prison sentence. Please note: Side Effects Possible. See this article for more on Ritalin.
The ethics of cognitive enhancement have been extensively debated in the academic literature (e.g., Bostrom & Sandberg, 2009; Farah et al., 2004; Greely et al., 2008; Mehlman, 2004; Sahakian & Morein-Zamir, 2007). We do not attempt to review this aspect of the problem here. Rather, we attempt to provide a firmer empirical basis for these discussions. Despite the widespread interest in the topic and its growing public health implications, there remains much researchers do not know about the use of prescription stimulants for cognitive enhancement.
Certain pharmaceuticals could also qualify as nootropics. For at least the past 20 years, a lot of people—students, especially—have turned to attention deficit hyperactivity disorder (ADHD) drugs like Ritalin and Adderall for their supposed concentration-strengthening effects. While there’s some evidence that these stimulants can improve focus in people without ADHD, they have also been linked, in both people with and without an ADHD diagnosis, to insomnia, hallucinations, seizures, heart trouble and sudden death, according to a 2012 review of the research in the journal Brain and Behavior. They’re also addictive.
Blinding stymied me for a few months since the nasty taste was unmistakable and I couldn’t think of any gums with a similar flavor to serve as placebo. (The nasty taste does not seem to be due to the nicotine despite what one might expect; Vaniver plausibly suggested the bad taste might be intended to prevent over-consumption, but nothing in the Habitrol ingredient list seemed to be noted for its bad taste, and a number of ingredients were sweetening sugars of various sorts. So I couldn’t simply flavor some gum.)

Googling, you sometimes see correlational studies like Intake of Flavonoid-Rich Wine, Tea, and Chocolate by Elderly Men and Women Is Associated with Better Cognitive Test Performance; in this one, the correlated performance increase from eating chocolate was generally fairly modest (say, <10%), and the maximum effects were at 10g/day of what was probably milk chocolate, which generally has 10-40% chocolate liquor in it, suggesting any experiment use 1-4g. More interesting is the blind RCT experiment Consumption of cocoa flavanols results in acute improvements in mood and cognitive performance during sustained mental effort11, which found improvements at ~1g; the most dramatic improvement of the 4 tasks (on the Threes correct) saw a difference of 2 to 6 at the end of the hour of testing, while several of the other tests converged by the end or saw the controls winning (Sevens correct). Crews et al 2008 found no cognitive benefit, and an fMRI experiment found the change in brain oxygen levels it wanted but no improvement to reaction times.
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.↩

Before you try nootropics, I suggest you start with the basics: get rid of the things in your diet and life that reduce cognitive performance first. That is easiest. Then, add in energizers like Brain Octane and clean up your diet. Then, go for the herbals and the natural nootropics. Use the pharmaceuticals selectively only after you’ve figured out your basics.

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