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.
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:
As mentioned above, eating foods that are rich in indigestible fibre such as vegetables and fruits, as well as eating good fats that are found in grass-fed butter, nuts and seeds, olive oil, coconut oil and avocado, provide bacteria with prebiotics that help to produce the ‘friendly’ short-chain fatty acids such as butyrate. Avoiding processed foods that contain calcium propionate, which lead to higher levels of propionic acid - the not so friendly short-chain fatty acid - is also another key strategy to support the gut-brain link.
It’s 3 p.m., and I am crushing my e-mail inbox. At this time of day, I’m typically struggling to stave off the post-lunch slowdown by downing another cup of coffee or two. But today, message after message is flying off my fingertips effortlessly—work e-mail, personal e-mail, digital errands I’d been meaning to run for months. I’m in the zone, as they say, and for this burst of late afternoon productivity, I might have nootropics to thank.
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.
It is incredibly easy to abuse and become addicted to methylphenidate, and misuse is shockingly prevalent, even among so-called “non-affected” users: with students, biohackers, soccer moms and busy executives popping it – and many of the other smart drugs below – like candy. It’s also not all it’s cracked up to be. Side effects include insomnia, stomach ache, headache and anorexia. Overdoses (which may occur easily as it can be difficult to estimate and regulate dosage) can lead to agitation, hallucinations, psychosis, lethargy, seizures, tachycardia (rapid heart rate), dysrhythmia (irregular heart rhythms), hypertension and hyperthermia. Methylphenidate is particularly hazardous to developing brains, especially those of younger students who are frequently prescribed the drug or who – often in high school and college – use it without a prescription. The prefrontal cortex, located behind the forehead, is responsible for cognition, personality-expression and decision-making, and develops well into the mid-20s, at which point it takes over as the “rational” part of the brain. In the central nervous system, and particularly in the prefrontal cortex, dopamine levels must have a natural rise and fall in order for healthy rational processes (executive control) to develop. By influencing dopamine levels, methylphenidate can negatively impact this healthy cognitive development, especially when it is abused or used too frequently.
I noticed on SR something I had never seen before, an offer for 150mgx10 of Waklert for ฿13.47 (then, ฿1 = $3.14). I searched and it seemed Sun was somehow manufacturing armodafinil! Interesting. Maybe not cost-effective, but I tried out of curiosity. They look and are packaged the same as the Modalert, but at a higher price-point: 150 rather than 81 rupees. Not entirely sure how to use them: assuming quality is the same, 150mg Waklert is still 100mg less armodafinil than the 250mg Nuvigil pills.
The nootropics community is surprisingly large and involved. When I wade into forums and the nootropics subreddit, I find members trading stack recipes and notifying each other of newly synthesized compounds. Some of these “psychonauts” seem like they’ve studied neuroscience; others appear to be novices dipping their toes into the world of cognitive enhancement. But all of them have the same goal: amplifying the brain’s existing capabilities without screwing anything up too badly. It’s the same impulse that grips bodybuilders—the feeling that with small chemical tweaks and some training, we can squeeze more utility out of the body parts we have. As Taylor Hatmaker of the Daily Dot recently wrote, “Together, these faceless armchair scientists seek a common truth—a clean, unharmful way to make their brains better—enforcing their own self-imposed safety parameters and painstakingly precise methods, all while publishing their knowledge for free, in plain text, to relatively crude, shared databases."
Starting from the studies in my meta-analysis, we can try to estimate an upper bound on how big any effect would be, if it actually existed. One of the most promising null results, Southon et al 1994, turns out to be not very informative: if we punch in the number of kids, we find that they needed a large effect size (d=0.81) before they could see anything:
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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.
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.↩
Upon examining the photographs, I noticed no difference in eye color, but it seems that my move had changed the ambient lighting in the morning and so there was a clear difference between the two sets of photographs! The before photographs had brighter lighting than the after photographs. Regardless, I decided to run a small survey on QuickSurveys/Toluna to confirm my diagnosis of no-change; the survey was 11 forced-choice pairs of photographs (before-after), with the instructions as follows:
Take quarter at midnight, another quarter at 2 AM. Night runs reasonably well once I remember to eat a lot of food (I finish a big editing task I had put off for weeks), but the apathy kicks in early around 4 AM so I gave up and watched Scott Pilgrim vs. the World, finishing around 6 AM. I then read until it’s time to go to a big shotgun club function, which occupies the rest of the morning and afternoon; I had nothing to do much of the time and napped very poorly on occasion. By the time we got back at 4 PM, the apathy was completely gone and I started some modafinil research with gusto (interrupted by going to see Puss in Boots). That night: Zeo recorded 8:30 of sleep, gap of about 1:50 in the recording, figure 10:10 total sleep; following night, 8:33; third night, 8:47; fourth, 8:20 (▇▁▁▁).
It makes no sense to ban the use of neuroenhancers. Too many people are already taking them, and the users tend to be educated and privileged people who proceed with just enough caution to avoid getting into trouble. Besides, Anjan Chatterjee is right that there is an apt analogy with plastic surgery. In a consumer society like ours, if people are properly informed about the risks and benefits of neuroenhancers, they can make their own choices about how to alter their minds, just as they can make their own decisions about shaping their bodies.
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.
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.
Dr. Mosconi: I love apples. When I’m at the office though, I’ll bring homemade trail mix [made with] higher quality dried fruit, nuts and seeds. [It's] packed with brain-essential nutrients that come from goji berries, Brazil nuts, walnuts, cacao nibs, pistachios, hemp hearts and more. Plus, I drink plenty of rose water throughout the day, which is very anti-inflammatory.
One might suggest just going to the gym or doing other activities which may increase endogenous testosterone secretion. This would be unsatisfying to me as it introduces confounds: the exercise may be doing all the work in any observed effect, and certainly can’t be blinded. And blinding is especially important because the 2011 review discusses how some studies report that the famed influence of testosterone on aggression (eg. Wedrifid’s anecdote above) is a placebo effect caused by the folk wisdom that testosterone causes aggression & rage!
Caveats aside, if you do want to try a nootropic, consider starting with something simple and pretty much risk-free, like aromatherapy with lemon essential oil or frankincense, which can help activate your brain, Barbour says. You could also sip on "golden milk," a sweet and anti-inflammatory beverage made with turmeric, or rosemary-infused water, she adds.
But before you go lock yourself in a dark, quiet room in order to prevent this overburden on your brain, you should know that there are scientifically researched compounds designed to amplify cognitive function and help your brain deal with this excess load, or simply get you through a period of sleep deprivation, increased creativity or work demands, the need to pull an all-nighter or an intense bout of work or study.
The realm of natural nootropics is also accompanied by a family of synthetic nootropics called racetams, most notably piracetam and aniracetam. Piracetam is known to directly enhance learning, memory and attention and, with no observed adverse side effects, can restore cognitive performance in patients who have suffered cranial trauma, inflammation, strokes and ischemic complications following coronary bypass surgery. It can also improve symptoms of delirium and reduce depression and anxiety. In adults, the standard dose of piracetam ranges from 1,200 to 4,800 mg, often broken up into three smaller doses throughout the day. Aniracetam has been shown to concentration-dependently counteract cell death induced by excitotoxicity caused by glutamate, resulting in an overall neuroprotective effect. While you may not be shoveling mouthfuls of glutamate down your hatch or eating cartonsful of MSG-containing Chinese food each night, the same mechanism of action can help protect your brain from excitotoxicity or inflammation caused by other central nervous system irritants, such as toxins, chemicals, herbicides, pesticides, rancid oils, etc. Effective doses of aniracetam range from a single 400 mg dose to two doses per day between 500 and 750 mg, taken with meals.
Some supplement blends, meanwhile, claim to work by combining ingredients – bacopa, cat's claw, huperzia serrata and oat straw in the case of Alpha Brain, for example – that have some support for boosting cognition and other areas of nervous system health. One 2014 study in Frontiers in Aging Neuroscience, suggested that huperzia serrata, which is used in China to fight Alzheimer's disease, may help slow cell death and protect against (or slow the progression of) neurodegenerative diseases. The Alpha Brain product itself has also been studied in a company-funded small randomized controlled trial, which found Alpha Brain significantly improved verbal memory when compared to adults who took a placebo.
Brain enhancing drug – the steroids of the mental world, these are compounds that can be both artificial or natural that are not recommended for casual consumption. If taken over a long period of time, they can and will result in permanent and debilitating damage, and if taken wrongly, they can and will result in injury, illness, and death. So far from being the best brain pill that they loop around and punch the actual best brain pill in the face.
By analyzing the brain images, the team found that these patients, compared with people who weren’t susceptible to the placebo, had a difference in volume between the right and left sides of the limbic system in the brain, which is involved in instinct and mood. There were also differences in the number of nerve cell connections between the prefrontal cortex and other brain areas. Personality questionnaires revealed that these people had a higher self-awareness and openness than nonresponders.
On the nutritional naughty list for years, egg yolks are finally experiencing their well-deserved day in the sun. If you’ve been eating only egg whites, the yolk’s on you. Yolks contain large amounts of choline, which helps in fetal brain development for pregnant women. It also breaks down bethane, a chemical that produces hormones related to happiness. That’s right, eggs can make you happy! (6)
(As I was doing this, I reflected how modafinil is such a pure example of the money-time tradeoff. It’s not that you pay someone else to do something for you, which necessarily they will do in a way different from you; nor is it that you have exchanged money to free yourself of a burden of some future time-investment; nor have you paid money for a speculative return of time later in life like with many medical expenses or supplements. Rather, you have paid for 8 hours today of your own time.)
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.
A big part is that we are finally starting to apply complex systems science to psycho-neuro-pharmacology and a nootropic approach. The neural system is awesomely complex and old-fashioned reductionist science has a really hard time with complexity. Big companies spends hundreds of millions of dollars trying to separate the effects of just a single molecule from placebo – and nootropics invariably show up as “stacks” of many different ingredients (ours, Qualia , currently has 42 separate synergistic nootropics ingredients from alpha GPC to bacopa monnieri and L-theanine). That kind of complex, multi pathway input requires a different methodology to understand well that goes beyond simply what’s put in capsules.