These brain enhancers allow users to go without sleep for extended periods of time. But in the long-term, insomnia is a hazardous side effect, not a so-called benefit. Lack of sleep is extremely detrimental to your brain health and function. It’s during sleep that your brain consolidates memories, cleans away toxins, repairs itself, and creates new brain cells. (52, 53, 54, 55)
This continued up to 1 AM, at which point I decided not to take a second armodafinil (why spend a second pill to gain what would likely be an unproductive set of 8 hours?) and finish up the experiment with some n-backing. My 5 rounds: 60/38/62/44/5024. This was surprising. Compare those scores with scores from several previous days: 39/42/44/40/20/28/36. I had estimated before the n-backing that my scores would be in the low-end of my usual performance (20-30%) since I had not slept for the past 41 hours, and instead, the lowest score was 38%. If one did not know the context, one might think I had discovered a good nootropic! Interesting evidence that armodafinil preserves at least one kind of mental performance.
The original magnesium l-threonate caused me no apparent problems by the time I finished off the powder and usage correlated with better days, further supporting the hypothesis that magnesium helps it. But l-threonate would be difficult to cap (and hence blind self-experiment) and is ruinously expensive on a per-dose basis. So I looked around for alternatives for the followup; one of the most common compounds suggested was the citrate form because it is reasonably well-absorbed and causes fewer digestive problems, so I could just take that. Magnesium oxide is widely available it looks cheap, but the absorption/bioavailability problem makes it unattractive: at a 3:5 ratio, an estimate of 4% absorption, a ZMA formulation of an impressive-sounding 500mg would be 500 \times \frac{3}{5} \times 0.04 = 12mg or a small fraction of RDAs for male adults like 400mg elemental. (Calcium shouldn’t be a problem since I get 220mg of calcium from my multivitamin and I enjoy dairy products daily.)
Perhaps the most well-known natural nootropic stimulant and neuroenhancer is caffeine. Caffeine has been shown to prevent memory deficits in experimental models of Alzheimer’s disease and may even restore memory following impairment. In studies performed with college students, caffeine was shown to have particularly potent effects on memory improvement during students’ non-optimal time of day, in this case, early in the morning. Caffeine’s benefits go even further because it’s never found in an isolated vacuum in nature, meaning that it’s always located in some kind of plant such as green tea or bean such as coffee that carry additional beneficial compounds which often enhance the effects of caffeine, including, most notably, certain cholesterols, polyphenols and antioxidants. In fact, one study determined that caffeine alone does not account for the benefits caused by coffee consumption. Rather, the phytochemical content of coffee (coffee contains over 1,000 different natural chemicals!) gives it potent antioxidant and anti-inflammatory properties that complement the neuroprotective effects of caffeine on the central nervous system.

As discussed in my iodine essay (FDA adverse events), iodine is a powerful health intervention as it eliminates cretinism and improves average IQ by a shocking magnitude. If this effect were possible for non-fetuses in general, it would be the best nootropic ever discovered, and so I looked at it very closely. Unfortunately, after going through ~20 experiments looking for ones which intervened with iodine post-birth and took measures of cognitive function, my meta-analysis concludes that: the effect is small and driven mostly by one outlier study. Once you are born, it’s too late. But the results could be wrong, and iodine might be cheap enough to take anyway, or take for non-IQ reasons. (This possibility was further weakened for me by an August 2013 blood test of TSH which put me at 3.71 uIU/ml, comfortably within the reference range of 0.27-4.20.)
So, I have started a randomized experiment; should take 2 months, given the size of the correlation. If that turns out to be successful too, I’ll have to look into methods of blinding - for example, some sort of electronic doohickey which turns on randomly half the time and which records whether it’s on somewhere one can’t see. (Then for the experiment, one hooks up the LED, turns the doohickey on, and applies directly to forehead, checking the next morning to see whether it was really on or off).
The magnesium was neither randomized nor blinded and included mostly as a covariate to avoid confounding (the Noopept coefficient & t-value increase somewhat without the Magtein variable), so an OR of 1.9 is likely too high; in any case, this experiment was too small to reliably detect any effect (~26% power, see bootstrap power simulation in the magnesium section) so we can’t say too much.
The Nootroo arrives in a shiny gold envelope with the words “proprietary blend” and “intended for use only in neuroscience research” written on the tin. It has been designed, says Matzner, for “hours of enhanced learning and memory”. The capsules contain either Phenylpiracetam or Noopept (a peptide with similar effects and similarly uncategorised) and are distinguished by real flakes of either edible silver or gold. They are to be alternated between daily, allowing about two weeks for the full effect to be felt. Also in the capsules are L-Theanine, a form of choline, and a types of caffeine which it is claimed has longer lasting effects.
Green tea is widely drunk in many cultures, especially in Asia, and is known to have potent health benefits. These benefits are attributed to its polyphenol content (particularly the flavanols and flavonols). In cell cultures and animal studies, the polyphenols have been proven to prevent neurotoxin-induced cell injury. Green tea also has anti-inflammatory properties and, according to a study performed on aged mice, may delay memory regression. It’s safe to drink several cups of green tea per day, though it may be more efficacious to take a green tea extract supplement to reach a daily dose of 400 to 500 mg of EGCG, one of the main active components of green tea.
…The first time I took supplemental potassium (50% US RDA in a lot of water), it was like a brain fog lifted that I never knew I had, and I felt profoundly energized in a way that made me feel exercise was reasonable and prudent, which resulted in me and the roommate that had just supplemented potassium going for an hour long walk at 2AM. Experiences since then have not been quite so profound (which probably was so stark for me as I was likely fixing an acute deficiency), but I can still count on a moderately large amount of potassium to give me a solid, nearly side effect free performance boost for a few hours…I had been doing Bikram yoga on and off, and I think I wasn’t keeping up the practice because I wasn’t able to properly rehydrate myself.
Takao Hensch, a Harvard professor of cellular biology and part of a Boston Children’s Hospital team, found that the drug encouraged the brain to learn new skills as quickly as the sponge-like brain of an infant in her patient Shannon, an otherwise normal 14-year-old girl who suffers from extremely poor eyesight brought on by amblyopia, commonly known as lazy eye. In a matter of months, the drug helped Shannon’s brain relearn how to use her eye which resulted in markedly improved vision.
During pregnancy and after pregnancy there is often a concern for the potential depletion of the maternal nutrient reservoir due to the needs of the growing foetus. A nutrient that is particularly important for mental wellbeing and is also essential for the growth of the foetus’s brain, is DHA. This is an omega 3 fatty acid that is found in oily fish and is the primary structural component of brain tissue, as well as playing a crucial role in the maintenance of brain cells and neurotransmitter metabolism (our body can also convert plant sources of omegas 3’s into DHA, such as those found in flaxseeds or chia seeds into DHA, but the conversion can often very poor). Deficiency in this nutrient during pregnancy is common, namely because of lack of seafood intake (the most bioavailable source of DHA) due to poor eating habits and concerns of mercury levels in fish during pregnancy, as well as higher requirements during foetal growth, which can lead to depletion. Due to the role that DHA plays in neurotransmitter metabolism, deficiency in this nutrient has been correlated to symptoms of depression during pregnancy (7). In order, to support your intake of omega 3, aim to have 3 portions of oily fish a week from sources that are low in mercury. These are mainly small fish that have a short life-span such as sardines, mackerel and herring. If you are vegetarian or vegan, although omega 3 is less readily available, it is still possible to get this nutrient from your diet through flax seeds, chia seeds, walnuts and seaweed. If you feel you may not be getting enough through your diet, you may want to consider using a good quality fish oil supplement (or algae based supplement if vegan) as an option. With fish oils, aim to choose a supplement that has been filtered for heavy metals and other pollutants to make sure you're getting the full benefits of the omega 3 oils.
As you may or may not know, curcumin has become a darling of the nutrition world in the last several years, thanks to a flurry of research that indicates the turmeric derivative can do everything from support the brain to reduce painful body-wide inflammation to even support positive mood. You can learn more about the research behind curcumin here:
The nootropics I’m taking are called RISE, and they're made by a company called Nootrobox, which was started by Geoffrey Woo, a young Stanford computer science graduate. There's no one common ingredient in nootropics; what unites them is the intent to improve brain performance. The RISE stack, which costs $29 plus shipping for 30 pills, contains 350 mg of bacopa monnieri powder (an herb that is commonly used medicinally in South Asia), 100 mg of L-theanine (an amino acid found in green tea), and 50 mg of caffeine (about the amount in a can of Diet Coke). Like most nootropics, the RISE stack itself isn't FDA-approved for use as a cognitive enhancer, but Nootrobox says that the compounds within it are approved as dietary supplements. "We use the precise ingredients at the right dosages and the right ratios as supported by double-blind, peer-reviewed clinicals," Nootrobox's site claims.
Similar delicacies from around the world include Mexican tacos de sesos.[1] The Anyang tribe of Cameroon practiced a tradition in which a new tribal chief would consume the brain of a hunted gorilla, while another senior member of the tribe would eat the heart.[2] Indonesian cuisine specialty in Minangkabau cuisine also served beef brain in a coconut-milk gravy named gulai otak (beef brain curry).[3][4] In Cuban cuisine, "brain fritters" are made by coating pieces of brain with bread crumbs and then frying them.[5]
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.
We’d want 53 pairs, but Fitzgerald 2012’s experimental design called for 32 weeks of supplementation for a single pair of before-after tests - so that’d be 1664 weeks or ~54 months or ~4.5 years! We can try to adjust it downwards with shorter blocks allowing more frequent testing; but problematically, iodine is stored in the thyroid and can apparently linger elsewhere - many of the cited studies used intramuscular injections of iodized oil (as opposed to iodized salt or kelp supplements) because this ensured an adequate supply for months or years with no further compliance by the subjects. If the effects are that long-lasting, it may be worthless to try shorter blocks than ~32 weeks.
"Herbs will have several different compounds in them, as opposed to, let's say, a drug like amphetamine, which is basically one compound, one molecule," Sahelian says. "Herbs will have a set of several or several dozen compounds in them. It's difficult to pinpoint which one of them is the most active or whether it's the combination of many of them that are producing the result."
In fact, when combined into a variety of different supplement “stacks” and taken in the correct dosage, these compounds – usually referred to as either smart drugs or nootropics (but now also including the category of psychedelics) – can completely change how your brain performs, including impacting receptor sites for neurotransmitters, altering levels of enzymes that break down specific neurotransmitters, changing cell membrane structures and thus controlling the movement of molecules inside and outside of the cell, increasing cerebral perfusion, which improves blood flow to the brain, affecting what are called “biogenic processes”, including neuronal cell creation or “neurogenesis”, and neuroendocrine regulation, regulating hormonal processes of the body specifically related to cognition (See additional studies here, here, here and here.).
Nootropics – sometimes called smart drugs – are compounds that enhance brain function. They’re becoming a popular way to give your mind an extra boost. According to one Telegraph report, up to 25% of students at leading UK universities have taken the prescription smart drug modafinil [1], and California tech startup employees are trying everything from Adderall to LSD to push their brains into a higher gear [2].

Mosconi holds a dual PhD in neuroscience and nuclear medicine. She is the associate director of the Alzheimer’s Prevention Clinic at Weill Cornell Medical College/New York-Presbyterian Hospital, and the founder of the Nutrition and Brain Fitness Lab at New York University School of Medicine. With her training and experience, she ought to understand and practice rigorous science. She makes all the right noises about scientific literacy and recognizing pseudoscience, but she seems unable to look in the mirror and see her own errors.
You have the highest density of mitochondria in your brain’s prefrontal cortex, which helps to explain why I feel Unfair Advantage in my head first. You have the second highest density in your heart, which is probably why I feel it in the center of my chest next. Mitochondrial energizers can have profound nootropic effects! At higher doses mitochondrial energizers also make for an excellent pre-workout supplements.
Creatine is stored as phosphocreatine, which acts as a high-energy reserve. Phosphocreatine decreases rapidly during brain activity. Supplementing with creatine (2 grams per day for 1 month) increased average brain creatine by 9.7%. It acts as an energy source for the brain to focus on learning tasks, as well as an energy source for storing memories.
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.

Absorption of nicotine across biological membranes depends on pH. Nicotine is a weak base with a pKa of 8.0 (Fowler, 1954). In its ionized state, such as in acidic environments, nicotine does not rapidly cross membranes…About 80 to 90% of inhaled nicotine is absorbed during smoking as assessed using C14-nicotine (Armitage et al., 1975). The efficacy of absorption of nicotine from environmental smoke in nonsmoking women has been measured to be 60 to 80% (Iwase et al., 1991)…The various formulations of nicotine replacement therapy (NRT), such as nicotine gum, transdermal patch, nasal spray, inhaler, sublingual tablets, and lozenges, are buffered to alkaline pH to facilitate the absorption of nicotine through cell membranes. Absorption of nicotine from all NRTs is slower and the increase in nicotine blood levels more gradual than from smoking (Table 1). This slow increase in blood and especially brain levels results in low abuse liability of NRTs (Henningfield and Keenan, 1993; West et al., 2000). Only nasal spray provides a rapid delivery of nicotine that is closer to the rate of nicotine delivery achieved with smoking (Sutherland et al., 1992; Gourlay and Benowitz, 1997; Guthrie et al., 1999). The absolute dose of nicotine absorbed systemically from nicotine gum is much less than the nicotine content of the gum, in part, because considerable nicotine is swallowed with subsequent first-pass metabolism (Benowitz et al., 1987). Some nicotine is also retained in chewed gum. A portion of the nicotine dose is swallowed and subjected to first-pass metabolism when using other NRTs, inhaler, sublingual tablets, nasal spray, and lozenges (Johansson et al., 1991; Bergstrom et al., 1995; Lunell et al., 1996; Molander and Lunell, 2001; Choi et al., 2003). Bioavailability for these products with absorption mainly through the mucosa of the oral cavity and a considerable swallowed portion is about 50 to 80% (Table 1)…Nicotine is poorly absorbed from the stomach because it is protonated (ionized) in the acidic gastric fluid, but is well absorbed in the small intestine, which has a more alkaline pH and a large surface area. Following the administration of nicotine capsules or nicotine in solution, peak concentrations are reached in about 1 h (Benowitz et al., 1991; Zins et al., 1997; Dempsey et al., 2004). The oral bioavailability of nicotine is about 20 to 45% (Benowitz et al., 1991; Compton et al., 1997; Zins et al., 1997). Oral bioavailability is incomplete because of the hepatic first-pass metabolism. Also the bioavailability after colonic (enema) administration of nicotine (examined as a potential therapy for ulcerative colitis) is low, around 15 to 25%, presumably due to hepatic first-pass metabolism (Zins et al., 1997). Cotinine is much more polar than nicotine, is metabolized more slowly, and undergoes little, if any, first-pass metabolism after oral dosing (Benowitz et al., 1983b; De Schepper et al., 1987; Zevin et al., 1997).
A common dose for this combination is 500 milligrams per day of Lion’s Mane, 240 milligrams per day of Ginkgo Biloba, and 100 milligrams twice per day of Bacopa Monnieri. Consider buying each ingredient in bulk to have stock and experiment with. If you are not experiencing positive results after 12 weeks, try adjusting the dosages in small increments. For example, you can start by adjusting Bacopa Monnieri to 150 milligrams twice per day for a couple weeks. Be patient: the end result is worth the trial and error.
The next cheap proposition to test is that the 2ml dose is so large that the sedation/depressive effect of nicotine has begun to kick in. This is easy to test: take much less, like half a ml. I do so two or three times over the next day, and subjectively the feeling seems to be the same - which seems to support that proposition (although perhaps I’ve been placebo effecting myself this whole time, in which case the exact amount doesn’t matter). If this theory is true, my previous sleep results don’t show anything; one would expect nicotine-as-sedative to not hurt sleep or improve it. I skip the day (no cravings or addiction noticed), and take half a ml right before bed at 11:30; I fall asleep in 12 minutes and have a ZQ of ~105. The next few days I try putting one or two drops into the tea kettle, which seems to work as well (or poorly) as before. At that point, I was warned that there were some results that nicotine withdrawal can kick in with delays as long as a week, so I shouldn’t be confident that a few days off proved an absence of addiction; I immediately quit to see what the week would bring. 4 or 7 days in, I didn’t notice anything. I’m still using it, but I’m definitely a little nonplussed and disgruntled - I need some independent source of nicotine to compare with!
One of the most obscure -racetams around, coluracetam (Smarter Nootropics, Ceretropic, Isochroma) acts in a different way from piracetam - piracetam apparently attacks the breakdown of acetylcholine while coluracetam instead increases how much choline can be turned into useful acetylcholine. This apparently is a unique mechanism. A crazy Longecity user, ScienceGuy ponied up $16,000 (!) for a custom synthesis of 500g; he was experimenting with 10-80mg sublingual doses (the ranges in the original anti-depressive trials) and reported a laundry list of effects (as does Isochroma): primarily that it was anxiolytic and increased work stamina. Unfortunately for my stack, he claims it combines poorly with piracetam. He offered free 2g samples for regulars to test his claims. I asked & received some.
I find this very troubling. The magnesium supplementation was harmful enough to do a lot of cumulative damage over the months involved (I could have done a lot of writing September 2013 - June 2014), but not so blatantly harmful enough as to be noticeable without a randomized blind self-experiment or at least systematic data collection - neither of which are common among people who would be supplementing magnesium I would much prefer it if my magnesium overdose had come with visible harm (such as waking up in the middle of the night after a nightmare soaked in sweat), since then I’d know quickly and surely, as would anyone else taking magnesium. But the harm I observed in my data? For all I know, that could be affecting every user of magnesium supplements! How would we know otherwise?

Working memory has been likened to a mental scratch pad: you use it to keep relevant data in mind while you're completing a task. (Imagine a cross-examination, in which a lawyer has to keep track of the answers a witness has given and formulate new questions based on them.) In one common test subjects are shown a series of items - usually letters or numbers - and then presented with challenges: was this number or letter in the series? Was this one? In the working-memory tests, subjects performed better on neuroenhancers, though several of the studies suggested that the effect depended on how good a subject's working memory was to begin with: the better it was, the less benefit the drugs provided.


Alex remains enthusiastic about Adderall, but he also has a slightly jaundiced critique of it. "It only works as a cognitive enhancer insofar as you are dedicated to accomplishing the task at hand," he said. "The number of times I've taken Adderall late at night and decided that, rather than starting my paper, hey, I'll organise my entire music library! I've seen people obsessively cleaning their rooms on it." Alex thought that generally the drug helped him to bear down on his work, but it also tended to produce writing with a characteristic flaw. "Often I've looked back at papers I've written on Adderall, and they're verbose. They're labouring a point, trying to create this airtight argument. I'd produce two pages on something that could be said in a couple of sentences." Nevertheless, his Adderall-assisted papers usually earned him at least a B. They got the job done. As Alex put it: "Productivity is a good thing."

Thursday: 3g piracetam/4g choline bitartrate at 1; 1 200mg modafinil at 2:20; noticed a leveling of fatigue by 3:30; dry eyes? no bad after taste or anything. a little light-headed by 4:30, but mentally clear and focused. wonder if light-headedness is due simply to missing lunch and not modafinil. 5:43: noticed my foot jiggling - doesn’t usually jiggle while in piracetam/choline. 7:30: starting feeling a bit jittery & manic - not much or to a problematic level but definitely noticeable; but then, that often happens when I miss lunch & dinner. 12:30: bedtime. Can’t sleep even with 3mg of melatonin! Subjectively, I toss & turn (in part thanks to my cat) until 4:30, when I really wake up. I hang around bed for another hour & then give up & get up. After a shower, I feel fairly normal, strangely, though not as good as if I had truly slept 8 hours. The lesson here is to pay attention to wikipedia when it says the half-life is 12-15 hours! About 6AM I take 200mg; all the way up to 2pm I feel increasingly less energetic and unfocused, though when I do apply myself I think as well as ever. Not fixed by food or tea or piracetam/choline. I want to be up until midnight, so I take half a pill of 100mg and chew it (since I’m not planning on staying up all night and I want it to work relatively soon). From 4-12PM, I notice that today as well my heart rate is elevated; I measure it a few times and it seems to average to ~70BPM, which is higher than normal, but not high enough to concern me. I stay up to midnight fine, take 3mg of melatonin at 12:30, and have no trouble sleeping; I think I fall asleep around 1. Alarm goes off at 6, I get up at 7:15 and take the other 100mg. Only 100mg/half-a-pill because I don’t want to leave the half laying around in the open, and I’m curious whether 100mg + ~5 hours of sleep will be enough after the last 2 days. Maybe next weekend I’ll just go without sleep entirely to see what my limits are.


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Cost-wise, the gum itself (~$5) is an irrelevant sunk cost and the DNB something I ought to be doing anyway. If the results are negative (which I’ll define as d<0.2), I may well drop nicotine entirely since I have no reason to expect other forms (patches) or higher doses (2mg+) to create new benefits. This would save me an annual expense of ~$40 with a net present value of <820 ($); even if we count the time-value of the 20 minutes for the 5 DNB rounds over 48 days (0.2 \times 48 \times 7.25 = 70), it’s still a clear profit to run a convincing experiment.
Such competitive anxieties are already being felt in the workplace. Recently an advice column in Wired featured a question from a reader worried about "a rising star at the firm" who was "using unprescribed modafinil to work crazy hours. Our boss has started getting on my case for not being as productive." And on internet forums such as ImmInst (Immortality Institute), whose members share a nerdy passion for tweaking their cognitive function through drugs and supplements, people trade advice about dosages and "stacks" - improvised combinations - of neuroenhancers ("Cut a tablet into fourths and took 25mg every four hours, four times today, and had a great and productive day - with no side-effects"). In one recent post a 52-year-old - who was working full time, studying for an advanced degree at night and "married, etc" - wrote that after experimenting with modafinil he had settled on two daily doses of 100mg each. He believed that he was "performing a little better", adding: "I also feel slightly more animated when in discussion."
"Instead of messing it up, we should be appreciating something that nature has taken years to optimize," Dr. Lisa mentions. But, we aren't messing it up voluntarily or, at the very least, on any conscious or malicious level. She attributes our disregard for neuro-nutrition to a series of factors, which include the portion size of meals, how parents don't have the time to cook or teach children how to eat healthily, the big influence of cafeteria food, and our "always on the go" culture. According to her, this leads us to unconsciously choose meals which are poor quality and high in sugars, a deathly combination for our brains.
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.
Panax ginseng – A review by the Cochrane Collaboration concluded that "there is a lack of convincing evidence to show a cognitive enhancing effect of Panax ginseng in healthy participants and no high quality evidence about its efficacy in patients with dementia."[36] According to the National Center for Complementary and Integrative Health, "[a]lthough Asian ginseng has been widely studied for a variety of uses, research results to date do not conclusively support health claims associated with the herb."[37]
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