After 7 days, I ordered a kg of choline bitartrate from Bulk Powders. Choline is standard among piracetam-users because it is pretty universally supported by anecdotes about piracetam headaches, has support in rat/mice experiments27, and also some human-related research. So I figured I couldn’t fairly test piracetam without some regular choline - the eggs might not be enough, might be the wrong kind, etc. It has a quite distinctly fishy smell, but the actual taste is more citrus-y, and it seems to neutralize the piracetam taste in tea (which makes things much easier for me).
One last note on tolerance; after the first few days of using smart drugs, just like with other drugs, you may not get the same effects as before. You’ve just experienced the honeymoon period. This is where you feel a large effect the first few times, but after that, you can’t replicate it. Be careful not to exceed recommended doses, and try cycling to get the desired effects again.
This research is in contrast to the other substances I like, such as piracetam or fish oil. I knew about withdrawal of course, but it was not so bad when I was drinking only tea. And the side-effects like jitteriness are worse on caffeine without tea; I chalk this up to the lack of theanine. (My later experiences with theanine seems to confirm this.) These negative effects mean that caffeine doesn’t satisfy the strictest definition of nootropic (having no negative effects), but is merely a cognitive enhancer (with both benefits & costs). One might wonder why I use caffeine anyway if I am so concerned with mental ability.
I posted a link to the survey on my Google+ account, and inserted the link at the top of all gwern.net pages; 51 people completed all 11 binary choices (most of them coming from North America & Europe), which seems adequate since the 11 questions are all asking the same question, and 561 responses to one question is quite a few. A few different statistical tests seem applicable: a chi-squared test whether there’s a difference between all the answers, a two-sample test on the averages, and most meaningfully, summing up the responses as a single pair of numbers and doing a binomial test:
Federal law classifies most nootropics as dietary supplements, which means that the Food and Drug Administration does not regulate manufacturers’ statements about their benefits (as the giant “This product is not intended to diagnose, treat, cure, or prevent any disease” disclaimer on the label indicates). And the types of claims that the feds do allow supplement companies to make are often vague and/or supported by less-than-compelling scientific evidence. “If you find a study that says that an ingredient caused neurons to fire on rat brain cells in a petri dish,” says Pieter Cohen, an assistant professor at Harvard Medical School, “you can probably get away with saying that it ‘enhances memory’ or ‘promotes brain health.’”
Schroeder, Mann-Koepke, Gualtieri, Eckerman, and Breese (1987) assessed the performance of subjects on placebo and MPH in a game that allowed subjects to switch between two different sectors seeking targets to shoot. They did not observe an effect of the drug on overall level of performance, but they did find fewer switches between sectors among subjects who took MPH, and perhaps because of this, these subjects did not develop a preference for the more fruitful sector.
That study is also interesting for finding benefits to chronic piracetam+choline supplementation in the mice, which seems connected to a Russian study which reportedly found that piracetam (among other more obscure nootropics) increased secretion of BDNF in mice. See also Drug heuristics on a study involving choline supplementation in pregnant rats.↩
According to clinical psychiatrist and Harvard Medical School Professor, Emily Deans, “there's probably nothing dangerous about the occasional course of nootropics...beyond that, it's possible to build up a tolerance if you use them often enough." Her recommendation is to seek pharmaceutical-grade products which she says are more accurate regarding dosage and less likely to be contaminated.
Cocoa flavanols (CF) positively influence physiological processes in ways which suggest that their consumption may improve aspects of cognitive function. This study investigated the acute cognitive and subjective effects of CF consumption during sustained mental demand. In this randomized, controlled, double-blinded, balanced, three period crossover trial 30 healthy adults consumed drinks containing 520 mg, 994 mg CF and a matched control, with a 3-day washout between drinks. Assessments included the state anxiety inventory and repeated 10-min cycles of a Cognitive Demand Battery comprising of two serial subtraction tasks (Serial Threes and Serial Sevens), a Rapid Visual Information Processing (RVIP) task and a mental fatigue scale, over the course of 1 h. Consumption of both 520 mg and 994 mg CF significantly improved Serial Threes performance. The 994 mg CF beverage significantly speeded RVIP responses but also resulted in more errors during Serial Sevens. Increases in self-reported mental fatigue were significantly attenuated by the consumption of the 520 mg CF beverage only. This is the first report of acute cognitive improvements following CF consumption in healthy adults. While the mechanisms underlying the effects are unknown they may be related to known effects of CF on endothelial function and blood flow.
the larger size of the community enables economies of scale and increases the peak sophistication possible. In a small nootropics community, there is likely to be no one knowledgeable about statistics/experimentation/biochemistry/neuroscience/whatever-you-need-for-a-particular-discussion, and the available funds increase: consider /r/Nootropics’s testing program, which is doable only because it’s a large lucrative community to sell to so the sellers are willing to donate funds for independent lab tests/Certificates of Analysis (COAs) to be done. If there were 1000 readers rather than 23,295, how could this ever happen short of one of those 1000 readers being very altruistic?
Instead, I urge the military to examine the use of smart drugs and the potential benefits they bring to the military. If they are safe, and pride cognitive enhancement to servicemembers, then we should discuss their use in the military. Imagine the potential benefits on the battlefield. They could potentially lead to an increase in the speed and tempo of our individual and collective OODA loop. They could improve our ability to become aware and make observations. Improve the speed of orientation and decision-making. Lastly, smart drugs could improve our ability to act and adapt to rapidly changing situations.
We’ve talk about how caffeine affects the body in great detail, but the basic idea is that it can improve your motivation and focus by increasing catecholamine signaling. Its effects can be dampened over time, however, as you start to build a caffeine tolerance. Research on L-theanine, a common amino acid, suggests it promotes neuronal health and can decrease the incidence of cold and flu symptoms by strengthening the immune system. And one study, published in the journal Biological Psychology, found that L-theanine reduces psychological and physiological stress responses—which is why it’s often taken with caffeine. In fact, in a 2014 systematic review of 11 different studies, published in the journal Nutrition Review, researchers found that use of caffeine in combination with L-theanine promoted alertness, task switching, and attention. The reviewers note the effects are most pronounced during the first two hours post-dose, and they also point out that caffeine is the major player here, since larger caffeine doses were found to have more of an effect than larger doses of L-theanine.
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.)
Took pill around 6 PM; I had a very long drive to and from an airport ahead of me, ideal for Adderall. In case it was Adderall, I chewed up the pill - by making it absorb faster, more of the effect would be there when I needed it, during driving, and not lingering in my system past midnight. Was it? I didn’t notice any change in my pulse, I yawned several times on the way back, my conversation was not more voluminous than usual. I did stay up later than usual, but that’s fully explained by walking to get ice cream. All in all, my best guess was that the pill was placebo, and I feel fairly confident but not hugely confident that it was placebo. I’d give it ~70%. And checking the next morning… I was right! Finally.
The above are all reasons to expect that even if I do excellent single-subject design self-experiments, there will still be the old problem of internal validity versus external validity: an experiment may be wrong or erroneous or unlucky in some way (lack of internal validity) or be right but not matter to anyone else (lack of external validity). For example, alcohol makes me sad & depressed; I could run the perfect blind randomized experiment for hundreds of trials and be extremely sure that alcohol makes me less happy, but would that prove that alcohol makes everyone sad or unhappy? Of course not, and as far as I know, for a lot of people alcohol has the opposite effect. So my hypothetical alcohol experiment might have tremendous internal validity (it does prove that I am sadder after inebriating), and zero external validity (someone who has never tried alcohol learns nothing about whether they will be depressed after imbibing). Keep this in mind if you are minded to take the experiments too seriously.
Many people find that they experience increased “brain fog” as they age, some of which could be attributed to early degeneration of synapses and neural pathways. Some drugs have been found to be useful for providing cognitive improvements in these individuals. It’s possible that these supplements could provide value by improving brain plasticity and supporting the regeneration of cells.10
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:
One reason I like modafinil is that it enhances dopamine release, but it binds to your dopamine receptors differently than addictive substances like cocaine and amphetamines do, which may be part of the reason modafinil shares many of the benefits of other stimulants but doesn’t cause addiction or withdrawal symptoms.   It does increase focus, problem-solving abilities, and wakefulness, but it is not in the same class of drugs as Adderall, and it is not a classical stimulant. Modafinil is off of patent, so you can get it generically, or order it from India. It’s a prescription drug, so you need to talk to a physician.