Frustrated by the lack of results, pharmaceutical companies have been shutting down their psychiatric drug research programmes. Traditional methods, such as synthesising new molecules and seeing what effect they have on symptoms, seem to have run their course. A shift of strategy is looming, towards research that focuses on genes and brain circuitry rather than chemicals. The shift will prolong the wait for new blockbuster drugs further, as the new systems are developed, and offers no guarantees of results.


That it is somewhat valuable is clear if we consider it under another guise. Imagine you received the same salary you do, but paid every day. Accounting systems would incur considerable costs handling daily payments, since they would be making so many more and so much smaller payments, and they would have to know instantly whether you showed up to work that day and all sorts of other details, and the recipients themselves would waste time dealing with all these checks or looking through all the deposits to their account, and any errors would be that much harder to track down. (And conversely, expensive payday loans are strong evidence that for poor people, a bi-weekly payment is much too infrequent.) One might draw a comparison to batching or buffers in computers: by letting data pile up in buffers, the computer can then deal with them in one batch, amortizing overhead over many items rather than incurring the overhead again and again. The downside, of course, is that latency will suffer and performance may drop based on that or the items becoming outdated & useless. The right trade-off will depend on the specifics; one would not expect random buffer-sizes to be optimal, but one would have to test and see what works best.
One of the other suggested benefits is for boosting serotonin levels; low levels of serotonin are implicated in a number of issues like depression. I’m not yet sure whether tryptophan has helped with motivation or happiness. Trial and error has taught me that it’s a bad idea to take tryptophan in the morning or afternoon, however, even smaller quantities like 0.25g. Like melatonin, the dose-response curve is a U: ~1g is great and induces multiple vivid dreams for me, but ~1.5g leads to an awful night and a headache the next day that was worse, if anything, than melatonin. (One morning I woke up with traces of at least 7 dreams, although I managed to write down only 2. No lucid dreams, though.)
The smart pill that FDA approved is called Abilify MyCite. This tiny pill has a drug and an ingestible sensor. The sensor gets activated when it comes into contact with stomach fluid to detect when the pill has been taken. The data is then transmitted to a wearable patch that eventually conveys the information to a paired smartphone app. Doctors and caregivers, with the patient’s consent, can then access the data via a web portal.
And yet aside from anecdotal evidence, we know very little about the use of these drugs in professional settings. The Financial Times has claimed that they are “becoming popular among city lawyers, bankers, and other professionals keen to gain a competitive advantage over colleagues.” Back in 2008 the narcolepsy medication Modafinil was labeled the “entrepreneur’s drug of choice” by TechCrunch. That same year, the magazine Nature asked its readers whether they use cognitive-enhancing drugs; of the 1,400 respondents, one in five responded in the affirmative.
The surveys just reviewed indicate that many healthy, normal students use prescription stimulants to enhance their cognitive performance, based in part on the belief that stimulants enhance cognitive abilities such as attention and memorization. Of course, it is possible that these users are mistaken. One possibility is that the perceived cognitive benefits are placebo effects. Another is that the drugs alter students’ perceptions of the amount or quality of work accomplished, rather than affecting the work itself (Hurst, Weidner, & Radlow, 1967). A third possibility is that stimulants enhance energy, wakefulness, or motivation, which improves the quality and quantity of work that students can produce with a given, unchanged, level of cognitive ability. To determine whether these drugs enhance cognition in normal individuals, their effects on cognitive task performance must be assessed in relation to placebo in a masked study design.
At dose #9, I’ve decided to give up on kratom. It is possible that it is helping me in some way that careful testing (eg. dual n-back over weeks) would reveal, but I don’t have a strong belief that kratom would help me (I seem to benefit more from stimulants, and I’m not clear on how an opiate-bearer like kratom could stimulate me). So I have no reason to do careful testing. Oh well.
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.
Clarke and Sokoloff (1998) remarked that although [a] common view equates concentrated mental effort with mental work…there appears to be no increased energy utilization by the brain during such processes (p. 664), and …the areas that participate in the processes of such reasoning represent too small a fraction of the brain for changes in their functional and metabolic activities to be reflected in the energy metabolism of the brain… (p. 675).
As mentioned earlier, cognitive control is needed not only for inhibiting actions, but also for shifting from one kind of action or mental set to another. The WCST taxes cognitive control by requiring the subject to shift from sorting cards by one dimension (e.g., shape) to another (e.g., color); failures of cognitive control in this task are manifest as perseverative errors in which subjects continue sorting by the previously successful dimension. Three studies included the WCST in their investigations of the effects of d-AMP on cognition (Fleming et al., 1995; Mattay et al., 1996, 2003), and none revealed overall effects of facilitation. However, Mattay et al. (2003) subdivided their subjects according to COMT genotype and found differences in both placebo performance and effects of the drug. Subjects who were homozygous for the val allele (associated with lower prefrontal dopamine activity) made more perseverative errors on placebo than other subjects and improved significantly with d-AMP. Subjects who were homozygous for the met allele performed best on placebo and made more errors on d-AMP.
The experiment then is straightforward: cut up a fresh piece of gum, randomly select from it and an equivalent dry piece of gum, and do 5 rounds of dual n-back to test attention/energy & WM. (If it turns out to be placebo, I’ll immediately use the remaining active dose: no sense in wasting gum, and this will test whether nigh-daily use renders nicotine gum useless, similar to how caffeine may be useless if taken daily. If there’s 3 pieces of active gum left, then I wrap it very tightly in Saran wrap which is sticky and air-tight.) The dose will be 1mg or 1/4 a gum. I cut up a dozen pieces into 4 pieces for 48 doses and set them out to dry. Per the previous power analyses, 48 groups of DNB rounds likely will be enough for detecting small-medium effects (partly since we will be only looking at one metric - average % right per 5 rounds - with no need for multiple correction). Analysis will be one-tailed, since we’re looking for whether there is a clear performance improvement and hence a reason to keep using nicotine gum (rather than whether nicotine gum might be harmful).

The majority of nonmedical users reported obtaining prescription stimulants from a peer with a prescription (Barrett et al., 2005; Carroll et al., 2006; DeSantis et al., 2008, 2009; DuPont et al., 2008; McCabe & Boyd, 2005; Novak et al., 2007; Rabiner et al., 2009; White et al., 2006). Consistent with nonmedical user reports, McCabe, Teter, and Boyd (2006) found 54% of prescribed college students had been approached to divert (sell, exchange, or give) their medication. Studies of secondary school students supported a similar conclusion (McCabe et al., 2004; Poulin, 2001, 2007). In Poulin’s (2007) sample, 26% of students with prescribed stimulants reported giving or selling some of their medication to other students in the past month. She also found that the number of students in a class with medically prescribed stimulants was predictive of the prevalence of nonmedical stimulant use in the class (Poulin, 2001). In McCabe et al.’s (2004) middle and high school sample, 23% of students with prescriptions reported being asked to sell or trade or give away their pills over their lifetime.
3 days later, I’m fairly miserable (slept poorly, had a hair-raising incident, and a big project was not received as well as I had hoped), so well before dinner (and after a nap) I brew up 2 wooden-spoons of Malaysia Green (olive-color dust). I drank it down; tasted slightly better than the first. I was feeling better after the nap, and the kratom didn’t seem to change that.
Vitamin B12 is also known as Cobalamin and is a water-soluble essential vitamin.  A (large) deficiency of Vitamin B12 will ultimately lead to cognitive impairment [52]. Older people and people who don’t eat meat are at a higher risk than young people who eat more meat. And people with depression have less Vitamin B12 than the average population [53].
But, if we find in 10 or 20 years that the drugs don't do damage, what are the benefits? These are stimulants that help with concentration. College students take such drugs to pass tests; graduates take them to gain professional licenses. They are akin to using a calculator to solve an equation. Do you really want a doctor who passed his boards as a result of taking speed — and continues to depend on that for his practice?
A study mentioned in Neuropsychopharmacology as of August 2002, revealed that Bacopa Monnieri decreases the rate of forgetting newly acquired information, memory consolidations, and verbal learning rate. It also helps in enhancing the nerve impulse transmission, which leads to increased alertness. It is also known to relieve the effects of anxiety and depression. All these benefits happen as Bacopa Monnieri dosage helps in activating choline acetyltransferase and inhibiting acetylcholinesterase which enhances the levels of acetylcholine in the brain, a chemical that is also associated in improving memory and attention.
Two increasingly popular options are amphetamines and methylphenidate, which are prescription drugs sold under the brand names Adderall and Ritalin. In the United States, both are approved as treatments for people with ADHD, a behavioural disorder which makes it hard to sit still or concentrate. Now they’re also widely abused by people in highly competitive environments, looking for a way to remain focused on specific tasks.
So what about the flip side: a drug to erase bad memories? It may have failed Jim Carrey in Eternal Sunshine of the Spotless Mind, but neuroscientists have now discovered an amnesia drug that can dull the pain of traumatic events. The drug, propranolol, was originally used to treat high blood pressure and heart disease. Doctors noticed that patients given the drug suffered fewer signs of stress when recalling a trauma.
Since the discovery of the effect of nootropics on memory and focus, the number of products on the market has increased exponentially. The ingredients used in a supplement can tell you about the effectiveness of the product. Brain enhancement pills that produce the greatest benefit are formulated with natural vitamins and substances, rather than caffeine and synthetic ingredients. In addition to better results, natural supplements are less likely to produce side effects, compared with drugs formulated with chemical ingredients.
Probably most significantly, use of the term “drug” has a significant negative connotation in our culture. “Drugs” are bad: So proclaimed Richard Nixon in the War on Drugs, and Nancy “No to Drugs” Reagan decades later, and other leaders continuing to present day. The legitimate demonization of the worst forms of recreational drugs has resulted in a general bias against the elective use of any chemical to alter the body’s processes. Drug enhancement of athletes is considered cheating – despite the fact that many of these physiological shortcuts obviously work. University students and professionals seeking mental enhancements by taking smart drugs are now facing similar scrutiny.

Somewhat ironically given the stereotypes, while I was in college I dabbled very little in nootropics, sticking to melatonin and tea. Since then I have come to find nootropics useful, and intellectually interesting: they shed light on issues in philosophy of biology & evolution, argue against naive psychological dualism and for materialism, offer cases in point on the history of technology & civilization or recent psychology theories about addiction & willpower, challenge our understanding of the validity of statistics and psychology - where they don’t offer nifty little problems in statistics and economics themselves, and are excellent fodder for the young Quantified Self movement4; modafinil itself demonstrates the little-known fact that sleep has no accepted evolutionary explanation. (The hard drugs also have more ramifications than one might expect: how can one understand the history of Southeast Asia and the Vietnamese War without reference to heroin, or more contemporaneously, how can one understand the lasting appeal of the Taliban in Afghanistan and the unpopularity & corruption of the central government without reference to the Taliban’s frequent anti-drug campaigns or the drug-funded warlords of the Northern Alliance?)
The hormone testosterone (Examine.com; FDA adverse events) needs no introduction. This is one of the scariest substances I have considered using: it affects so many bodily systems in so many ways that it seems almost impossible to come up with a net summary, either positive or negative. With testosterone, the problem is not the usual nootropics problem that that there is a lack of human research, the problem is that the summary constitutes a textbook - or two. That said, the 2011 review The role of testosterone in social interaction (excerpts) gives me the impression that testosterone does indeed play into risk-taking, motivation, and social status-seeking; some useful links and a representative anecdote:

Began double-blind trial. Today I took one pill blindly at 1:53 PM. at the end of the day when I have written down my impressions and guess whether it was one of the Adderall pills, then I can look in the baggy and count and see whether it was. there are many other procedures one can take to blind oneself (have an accomplice mix up a sequence of pills and record what the sequence was; don’t count & see but blindly take a photograph of the pill each day, etc.) Around 3, I begin to wonder whether it was Adderall because I am arguing more than usual on IRC and my heart rate seems a bit high just sitting down. 6 PM: I’ve started to think it was a placebo. My heart rate is back to normal, I am having difficulty concentrating on long text, and my appetite has shown up for dinner (although I didn’t have lunch, I don’t think I had lunch yesterday and yesterday the hunger didn’t show up until past 7). Productivity wise, it has been a normal day. All in all, I’m not too sure, but I think I’d guess it was Adderall with 40% confidence (another way of saying placebo with 60% confidence). When I go to examine the baggie at 8:20 PM, I find out… it was an Adderall pill after all. Oh dear. One little strike against Adderall that I guessed wrong. It may be that the problem is that I am intrinsically a little worse today (normal variation? come down from Adderall?).


COGNITUNE is for informational purposes only, and should not be considered medical advice, diagnosis or treatment recommendations. Always consult with your doctor or primary care physician before using any nutraceuticals, dietary supplements, or prescription medications. Seeking a proper diagnosis from a certified medical professional is vital for your health.

AMP was first investigated as an asthma medication in the 1920s, but its psychological effects were soon noticed. These included increased feelings of energy, positive mood, and prolonged physical endurance and mental concentration. These effects have been exploited in a variety of medical and nonmedical applications in the years since they were discovered, including to treat depression, to enhance alertness in military personnel, and to provide a competitive edge in athletic competition (Rasmussen, 2008). Today, AMP remains a widely used and effective treatment for ADHD (Wilens, 2006).
Another ingredient used in this formula is GABA or Gamma-Aminobutyric acid; it’s the second most common neurotransmitter found in the human brain. Being an inhibitory neurotransmitter it helps calm and reduce neuronal activity; this calming effect makes GABA an excellent ingredient in anti-anxiety medication. Lecithin is another ingredient found in Smart Pill and is a basic compound found in every cell of the body, with cardiovascular benefits it can also help restore the liver. Another effect is that it works with neurological functions such as memory or attention, thus improving brain Effectiveness.
Phenotropil is an over-the-counter supplement similar in structure to Piracetam (and Noopept). This synthetic smart drug has been used to treat stroke, epilepsy and trauma recovery. A 2005 research paper also demonstrated that patients diagnosed with natural lesions or brain tumours see improvements in cognition. Phenylpiracetam intake can also result in minimised feelings of anxiety and depression. This is one of the more powerful unscheduled Nootropics available.
Some data suggest that cognitive enhancers do improve some types of learning and memory, but many other data say these substances have no effect. The strongest evidence for these substances is for the improvement of cognitive function in people with brain injury or disease (for example, Alzheimer's disease and traumatic brain injury). Although "popular" books and companies that sell smart drugs will try to convince you that these drugs work, the evidence for any significant effects of these substances in normal people is weak. There are also important side-effects that must be considered. Many of these substances affect neurotransmitter systems in the central nervous system. The effects of these chemicals on neurological function and behavior is unknown. Moreover, the long-term safety of these substances has not been adequately tested. Also, some substances will interact with other substances. A substance such as the herb ma-huang may be dangerous if a person stops taking it suddenly; it can also cause heart attacks, stroke, and sudden death. Finally, it is important to remember that products labeled as "natural" do not make them "safe."

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.)


This doesn’t fit the U-curve so well: while 60mg is substantially negative as one would extrapolate from 30mg being ~0, 48mg is actually better than 15mg. But we bought the estimates of 48mg/60mg at a steep price - we ignore the influence of magnesium which we know influences the data a great deal. And the higher doses were added towards the end, so may be influenced by the magnesium starting/stopping. Another fix for the missingness is to impute the missing data. In this case, we might argue that the placebo days of the magnesium experiment were identical to taking no magnesium at all and so we can classify each NA as a placebo day, and rerun the desired analysis:
Legal issues aside, this wouldn’t be very difficult to achieve. Many companies already have in-house doctors who give regular health check-ups — including drug tests — which could be employed to control and regulate usage. Organizations could integrate these drugs into already existing wellness programs, alongside healthy eating, exercise, and good sleep.
The pill delivers an intestinal injection without exposing the drug to digestive enzymes. The patient takes what seems to be an ordinary capsule, but the “robotic” pill is a sophisticated device which incorporates a number of innovations, enabling it to navigate through the stomach and enter the small intestine. The Rani Pill™ goes through a transformation and positions itself to inject the drug into the intestinal wall.
A study mentioned in Neuropsychopharmacology as of August 2002, revealed that Bacopa Monnieri decreases the rate of forgetting newly acquired information, memory consolidations, and verbal learning rate. It also helps in enhancing the nerve impulse transmission, which leads to increased alertness. It is also known to relieve the effects of anxiety and depression. All these benefits happen as Bacopa Monnieri dosage helps in activating choline acetyltransferase and inhibiting acetylcholinesterase which enhances the levels of acetylcholine in the brain, a chemical that is also associated in improving memory and attention.
I can test fish oil for mood, since the other claimed benefits like anti-schizophrenia are too hard to test. The medical student trial (Kiecolt-Glaser et al 2011) did not see changes until visit 3, after 3 weeks of supplementation. (Visit 1, 3 weeks, visit 2, supplementation started for 3 weeks, visit 3, supplementation continued 3 weeks, visit 4 etc.) There were no tests in between the test starting week 1 and starting week 3, so I can’t pin it down any further. This suggests randomizing in 2 or 3 week blocks. (For an explanation of blocking, see the footnote in the Zeo page.)
For 2 weeks, upon awakening I took close-up photographs of my right eye. Then I ordered two jars of Life-Extension Sea-Iodine (60x1mg) (1mg being an apparently safe dose), and when it arrived on 10 September 2012, I stopped the photography and began taking 1 iodine pill every other day. I noticed no ill effects (or benefits) after a few weeks and upped the dose to 1 pill daily. After the first jar of 60 pills was used up, I switched to the second jar, and began photography as before for 2 weeks. The photographs were uploaded, cropped by hand in Gimp, and shrunk to more reasonable dimensions; both sets are available in a Zip file.
The Nature commentary is ivory tower intellectualism at its best. The authors state that society must prepare for the growing demand of such drugs; that healthy adults should be allowed drugs to enhance cognitive ability; that this is "morally equivalent" and no more unnatural than diet, sleep, or the use of computers; that we need an evidence-based approach to evaluate the risks; and that we need legal and ethical policies to ensure fair and equitable use.
In contrast to the types of memory discussed in the previous section, which are long-lasting and formed as a result of learning, working memory is a temporary store of information. Working memory has been studied extensively by cognitive psychologists and cognitive neuroscientists because of its role in executive function. It has been likened to an internal scratch pad; by holding information in working memory, one keeps it available to consult and manipulate in the service of performing tasks as diverse as parsing a sentence and planning a route through the environment. Presumably for this reason, working memory ability correlates with measures of general intelligence (Friedman et al., 2006). The possibility of enhancing working memory ability is therefore of potential real-world interest.
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.
After I ran out of creatine, I noticed the increased difficulty, and resolved to buy it again at some point; many months later, there was a Smart Powders sale so bought it in my batch order, $12 for 1000g. As before, it made Taekwondo classes a bit easier. I paid closer attention this second time around and noticed that as one would expect, it only helped with muscular fatigue and did nothing for my aerobic issues. (I hate aerobic exercise, so it’s always been a weak point.) I eventually capped it as part of a sulbutiamine-DMAE-creatine-theanine mix. This ran out 1 May 2013. In March 2014, I spent $19 for 1kg of micronized creatine monohydrate to resume creatine use and also to use it as a placebo in a honey-sleep experiment testing Seth Roberts’s claim that a few grams of honey before bedtime would improve sleep quality: my usual flour placebo being unusable because the mechanism might be through simple sugars, which flour would digest into. (I did not do the experiment: it was going to be a fair amount of messy work capping the honey and creatine, and I didn’t believe Roberts’s claims for a second - my only reason to do it would be to prove the claim wrong but he’d just ignore me and no one else cares.) I didn’t try measuring out exact doses but just put a spoonful in my tea each morning (creatine is tasteless). The 1kg lasted from 25 March to 18 September or 178 days, so ~5.6g & $0.11 per day.
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.
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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