Adrafinil is Modafinil’s predecessor, because the scientists tested it as a potential narcolepsy drug. It was first produced in 1974 and immediately showed potential as a wakefulness-promoting compound. Further research showed that Adrafinil is metabolized into its component parts in the liver, that is into inactive modafinil acid. Ultimately, Modafinil has been proclaimed the primary active compound in Adrafinil.
Flow diagram of epidemiology literature search completed July 1, 2010. Search terms were nonmedical use, nonmedical use, misuse, or illicit use, and prescription stimulants, dextroamphetamine, methylphenidate, Ritalin, or Adderall. Stages of subsequent review used the information contained in the titles, abstracts, and articles to determine whether articles reported studies of the extent of nonmedical prescription stimulant use by students and related questions addressed in the present article including students’ motives and frequency of use.
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." 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."
That doesn’t necessarily mean all smart drugs – now and in the future – will be harmless, however. The brain is complicated. In trying to upgrade it, you risk upsetting its intricate balance. “It’s not just about more, it’s about having to be exquisitely and exactly right. And that’s very hard to do,” says Arnstein. “What’s good for one system may be bad for another system,” adds Trevor Robbins, Professor of Cognitive Neuroscience at the University of Cambridge. “It’s clear from the experimental literature that you can affect memory with pharmacological agents, but the problem is keeping them safe.”
Ethical issues also arise with the use of drugs to boost brain power. Their use as cognitive enhancers isn’t currently regulated. But should it be, just as the use of certain performance-enhancing drugs is regulated for professional athletes? Should universities consider dope testing to check that students aren’t gaining an unfair advantage through drug use?
With this experiment, I broke from the previous methodology, taking the remaining and final half Nuvigil at midnight. I am behind on work and could use a full night to catch up. By 8 AM, I am as usual impressed by the Nuvigil - with Modalert or something, I generally start to feel down by mid-morning, but with Nuvigil, I feel pretty much as I did at 1 AM. Sleep: 9:51/9:15/8:27
Cytisine is not known as a stimulant and I’m not addicted to nicotine, so why give it a try? Nicotine is one of the more effective stimulants available, and it’s odd how few nicotine analogues or nicotinic agonists there are available; nicotine has a few flaws like short half-life and increasing blood pressure, so I would be interested in a replacement. The nicotine metabolite cotinine, in the human studies available, looks intriguing and potentially better, but I have been unable to find a source for it. One of the few relevant drugs which I can obtain is cytisine, from Ceretropic, at 2x1.5mg doses. There are not many anecdotal reports on cytisine, but at least a few suggest somewhat comparable effects with nicotine, so I gave it a try.
Didn't seem very important to me. Trump's ability to discern importance in military projects, sure, why not. Shanahan may be the first honest cabinet head; it could happen. With the record this administration has I'd need some long odds to bet that way. Does anyone doubt he got the loyalty spiel and then the wink and nod that anything he could get away with was fine. monies
I noticed what may have been an effect on my dual n-back scores; the difference is not large (▃▆▃▃▂▂▂▂▄▅▂▄▂▃▅▃▄ vs ▃▄▂▂▃▅▂▂▄▁▄▃▅▂▃▂▄▂▁▇▃▂▂▄▄▃▃▂▃▂▂▂▃▄▄▃▆▄▄▂▃▄▃▁▂▂▂▃▂▄▂▁▁▂▄▁▃▂▄) and appears mostly in the averages - Toomim’s quick two-sample t-test gave p=0.23, although a another analysis gives p=0.138112. One issue with this before-after quasi-experiment is that one would expect my scores to slowly rise over time and hence a fish oil after would yield a score increase - the 3.2 point difference could be attributable to that, placebo effect, or random variation etc. But an accidentally noticed effect (d=0.28) is a promising start. An experiment may be worth doing given that fish oil does cost a fair bit each year: randomized blocks permitting an fish-oil-then-placebo comparison would take care of the first issue, and then blinding (olive oil capsules versus fish oil capsules?) would take care of the placebo worry.
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.”
The Defense Department reports rely on data collected by the private real estate firms that operate base housing in partnership with military branches. The companies' compensation is partly determined by the results of resident satisfaction surveys. I had to re-read this sentence like 5 times to make sure I understood it correctly. I just can't even. Seriously, in what universe did anyone think that this would be a good idea?
Of course, there are drugs out there with more transformative powers. “I think it’s very clear that some do work,” says Andrew Huberman, a neuroscientist based at Stanford University. In fact, there’s one category of smart drugs which has received more attention from scientists and biohackers – those looking to alter their own biology and abilities – than any other. These are the stimulants.
My first time was relatively short: 10 minutes around the F3/F4 points, with another 5 minutes to the forehead. Awkward holding it up against one’s head, and I see why people talk of LED helmets, it’s boring waiting. No initial impressions except maybe feeling a bit mentally cloudy, but that goes away within 20 minutes of finishing when I took a nap outside in the sunlight. Lostfalco says Expectations: You will be tired after the first time for 2 to 24 hours. It’s perfectly normal., but I’m not sure - my dog woke me up very early and disturbed my sleep, so maybe that’s why I felt suddenly tired. On the second day, I escalated to 30 minutes on the forehead, and tried an hour on my finger joints. No particular observations except less tiredness than before and perhaps less joint ache. Third day: skipped forehead stimulation, exclusively knee & ankle. Fourth day: forehead at various spots for 30 minutes; tiredness 5/6/7/8th day (11/12/13/4): skipped. Ninth: forehead, 20 minutes. No noticeable effects.
Take at 10 AM; seem a bit more active but that could just be the pressure of the holiday season combined with my nice clean desk. I do the chores without too much issue and make progress on other things, but nothing major; I survive going to The Sitter without too much tiredness, so ultimately I decide to give the palm to it being active, but only with 60% confidence. I check the next day, and it was placebo. Oops.
Piracetam is a reliable supplement for improving creativity. It is an entry level racetam due to its lack of severe side effects and relative subtlety. Piracetam’s effects take hold over time through continual use. There is less instant gratification compared to other brain enhancers. Additionally, this nootropic can enhance holistic thinking, verbal memory, and mental energy levels.
Competitors of importance in the smart pills market have been recorded and analyzed in MRFR's report. These market players include RF Co., Ltd., CapsoVision, Inc., JINSHAN Science & Technology, BDD Limited, MEDTRONIC, Check-Cap, PENTAX Medical, INTROMEDIC, Olympus Corporation, FUJIFILM Holdings Corporation, MEDISAFE, and Proteus Digital Health, Inc.
Some of the newest substances being used as ‘smart drugs’ are medically prescribed for other conditions. For example, methylphenidate, commonly known as Ritalin, is used to treat attention deficit hyperactivity disorder (ADHD). So is Adderall, a combination drug containing two forms of amphetamine. These are among a suite of pharmaceuticals now being used by healthy people, particularly university students, to enhance their capabilities for learning or working.
“I bought this book because I didn’t want a weightloss diet, but I wanted the most optimal gut/brain food I could find to help with an autoimmune. I subscribe to Cavin’s podcast and another newsletter for gut health which also recommended this book. Also, he’s a personal friend of mine who’s recovery I have witnessed firsthand. Thank you so much for all of the research and your continued dedication to not only help yourself, but for also helping others!”
There is an ancient precedent to humans using natural compounds to elevate cognitive performance. Incan warriors in the 15th century would ingest coca leaves (the basis for cocaine) before battle. Ethiopian hunters in the 10th century developed coffee bean paste to improve hunting stamina. Modern athletes ubiquitously consume protein powders and hormones to enhance their training, recovery, and performance. The most widely consumed psychoactive compound today is caffeine. Millions of people use coffee and tea to be more alert and focused.
That first night, I had severe trouble sleeping, falling asleep in 30 minutes rather than my usual 19.6±11.9, waking up 12 times (5.9±3.4), and spending ~90 minutes awake (18.1±16.2), and naturally I felt unrested the next day; I initially assumed it was because I had left a fan on (moving air keeps me awake) but the new potassium is also a possible culprit. When I asked, Kevin said:
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.
Ongoing studies are looking into the possible pathways by which nootropic substances function. Researchers have postulated that the mental health advantages derived from these substances can be attributed to their effects on the cholinergic and dopaminergic systems of the brain. These systems regulate two important neurotransmitters, acetylcholine and dopamine.
I don’t believe there’s any need to control for training with repeated within-subject sampling, since there will be as many samples on both control and active days drawn from the later trained period as with the initial untrained period. But yes, my D5B scores seem to have plateaued pretty much and only very slowly increase; you can look at the stats file yourself.
Historically used to help people with epilepsy, piracetam is used in some cases of myoclonus, or muscle twitching. Its actual mechanism of action is unclear: It doesn’t act exactly as a sedative or stimulant, but still influences cognitive function, and is believed to act on receptors for acetylcholine in the brain. Piracetam is used off-label as a 'smart drug' to help focus and concentration or sometimes as a way to allegedly boost your mood. Again, piracetam is a prescription-only drug - any supply to people without a prescription is illegal, and supplying it may result in a fine or prison sentence.
Scientists found that the drug can disrupt the way memories are stored. This ability could be invaluable in treating trauma victims to prevent associated stress disorders. The research has also triggered suggestions that licensing these memory-blocking drugs may lead to healthy people using them to erase memories of awkward conversations, embarrassing blunders and any feelings for that devious ex-girlfriend.
Smart Pill is formulated with herbs, amino acids, vitamins and co-factors to provide nourishment for the brain, which may enhance memory, cognitive function, and clarity. , which may enhance memory, cognitive function, and clarity. In a natural base containing potent standardized extract 24% flavonoid glycosides. Fast acting super potent formula. A unique formulation containing a blend of essential nutrients, herbs and co-factors.
And in his followup work, An opportunity cost model of subjective effort and task performance (discussion). Kurzban seems to have successfully refuted the blood-glucose theory, with few dissenters from commenting researchers. The more recent opinion seems to be that the sugar interventions serve more as a reward-signal indicating more effort is a good idea, not refueling the engine of the brain (which would seem to fit well with research on procrastination).↩
With all these studies pointing to the nootropic benefits of some essential oils, it can logically be concluded then that some essential oils can be considered “smart drugs.” However, since essential oils have so much variety and only a small fraction of this wide range has been studied, it cannot be definitively concluded that absolutely all essential oils have brain-boosting benefits. The connection between the two is strong, however.
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.
Took pill #6 at 12:35 PM. Hard to be sure. I ultimately decided that it was Adderall because I didn’t have as much trouble as I normally would in focusing on reading and then finishing my novel (Surface Detail) despite my family watching a movie, though I didn’t notice any lack of appetite. Call this one 60-70% Adderall. I check the next evening and it was Adderall.
The concept of neuroenhancement and the use of substances to improve cognitive functioning in healthy individuals, is certainly not a new one. In fact, one of the first cognitive enhancement drugs, Piracetam, was developed over fifty years ago by psychologist and chemist C.C. Giurgea. Although he did not know the exact mechanism, Giurgia believed the drug boosted brain power and so began his exploration into "smart pills", or nootropics, a term he coined from the Greek nous, meaning "mind," and trepein, meaning "to bend.
Theanine can also be combined with caffeine as both of them work in synergy to increase memory, reaction time, mental endurance, and memory. The best part about Theanine is that it is one of the safest nootropics and is readily available in the form of capsules. A natural option would be to use an excellent green tea brand which constitutes of tea grown in the shade because then Theanine would be abundantly present in it.
In the United States, people consume more coffee than fizzy drink, tea and juice combined. Alas, no one has ever estimated its impact on economic growth – but plenty of studies have found myriad other benefits. Somewhat embarrassingly, caffeine has been proven to be better than the caffeine-based commercial supplement that Woo’s company came up with, which is currently marketed at $17.95 for 60 pills.
And as before, around 9 AM I began to feel the peculiar feeling that I was mentally able and apathetic (in a sort of aboulia way); so I decided to try what helped last time, a short nap. But this time, though I took a full hour, I slept not a wink and my Zeo recorded only 2 transient episodes of light sleep! A back-handed sort of proof of alertness, I suppose. I didn’t bother trying again. The rest of the day was mediocre, and I wound up spending much of it on chores and whatnot out of my control. Mentally, I felt better past 3 PM.
None of that has kept entrepreneurs and their customers from experimenting and buying into the business of magic pills, however. In 2015 alone, the nootropics business raked in over $1 billion dollars, and web sites like the nootropics subreddit, the Bluelight forums, and Bulletproof Exec are popular and packed with people looking for easy ways to boost their mental performance. Still, this bizarre, Philip K. Dick-esque world of smart drugs is a tough pill to swallow. To dive into the topic and explain, I spoke to Kamal Patel, Director of evidence-based medical database Examine.com, and even tried a few commercially-available nootropics myself.
Smart drug, also called nootropic or cognitive enhancer, any of a group of pharmaceutical agents used to improve the intellectual capacity of persons suffering from neurological diseases and psychological disorders. The use of such drugs by healthy individuals in order to improve concentration, to study longer, and to better manage stress is a subject of controversy.
As opposed to what it might lead you to believe, Ginkgo Smart is not simply a Ginkgo Biloba supplement. In all actuality, it’s much more than that – a nootropic (Well duh, we wouldn’t be reviewing it otherwise). Ginkgo Smart has actually been seeing quite some popularity lately, possibly riding on the popularity of Ginkgo Biloba as a supplement, which has been storming through the US lately, and becoming one of the highest selling supplement in the US. We were pleasantly pleased at the fact that it wasn’t too hard to find Ginkgo Smart’s ingredients… Learn More...
An additional complexity, related to individual differences, concerns dosage. This factor, which varies across studies and may be fixed or determined by participant body weight within a study, undoubtedly influences the cognitive effects of stimulant drugs. Furthermore, single-unit recordings with animals and, more recently, imaging of humans indicate that the effects of stimulant dose are nonmonotonic; increases enhance prefrontal function only up to a point, with further increases impairing function (e.g., Arnsten, 1998; Mattay et al., 2003; Robbins & Arnsten, 2009). Yet additional complexity comes from the fact that the optimal dosage depends on the same kinds of individual characteristics just discussed and on the task (Mattay et al., 2003).
If you have spent any time shopping for memory enhancer pills, you have noticed dozens of products on the market. Each product is advertised to improve memory, concentration, and focus. However, choosing the first product promising results may not produce the desired improvements. Taking the time to research your options and compare products will improve your chances of finding a supplement that works.
I have elsewhere remarked on the apparent lack of benefit to taking multivitamins and the possible harm; so one might well wonder about a specific vitamin like vitamin D. However, a multivitamin is not vitamin D, so it’s no surprise that they might do different things. If a multivitamin had no vitamin D in it, or if it had vitamin D in different doses, or if it had substances which interacted with vitamin D (such as calcium), or if it had substances which had negative effects which outweigh the positive (such as vitamin A?), we could well expect differing results. In this case, all of those are true to varying extents. Some multivitamins I’ve had contained no vitamin D. The last multivitamin I was taking both contains vitamins used in the negative trials and also some calcium; the listed vitamin D dosage was a trivial ~400IU, while I take >10x as much now (5000IU).
Ginsenoside Rg1, a molecule found in the plant genus panax (ginseng), is being increasingly researched as an effect nootropic. Its cognitive benefits including increasing learning ability and memory acquisition, and accelerating neural development. It targets mainly the NMDA receptors and nitric oxide synthase, which both play important roles in personal and emotional intelligence. The authors of the study cited above, say that their research findings thus far have boosted their confidence in a "bright future of cognitive drug development."
My first impression of ~1g around 12:30PM was that while I do not feel like running around, within an hour I did feel like the brain fog was lighter than before. The effect wasn’t dramatic, so I can’t be very confident. Operationalizing brain fog for an experiment might be hard: it doesn’t necessarily feel like I would do better on dual n-back. I took 2 smaller doses 3 and 6 hours later, to no further effect. Over the following weeks and months, I continued to randomly alternate between potassium & non-potassium days. I noticed no effects other than sleep problems.
In sum, the evidence concerning stimulant effects of working memory is mixed, with some findings of enhancement and some null results, although no findings of overall performance impairment. A few studies showed greater enhancement for less able participants, including two studies reporting overall null results. When significant effects have been found, their sizes vary from small to large, as shown in Table 4. Taken together, these results suggest that stimulants probably do enhance working memory, at least for some individuals in some task contexts, although the effects are not so large or reliable as to be observable in all or even most working memory studies.
A related task is the B–X version of the CPT, in which subjects must respond when an X appears only if it was preceded by a B. As in the 1-back task, the subject must retain the previous trial’s letter in working memory because it determines the subject’s response to the current letter. In this case, when the current letter is an X, then the subject should respond only if the previous letter was a B. Two studies examined stimulant effects in this task. Rapoport et al. (1980) found that d-AMP reduced errors of omission in the longer of two test sessions, and Klorman et al. (1984) found that MPH reduced errors of omission and response time.
An entirely different set of questions concerns cognitive enhancement in younger students, including elementary school and even preschool children. Some children can function adequately in school without stimulants but perform better with them; medicating such children could be considered a form of cognitive enhancement. How often does this occur? What are the roles and motives of parents, teachers, and pediatricians in these cases? These questions have been discussed elsewhere and deserve continued attention (Diller, 1996; Singh & Keller, 2010).
If I stop tonight and do nothing Monday (and I sleep the normal eight hours and do not pay any penalty), then that’ll be 4 out of 5 days on modafinil, each saving 3 or 4 hours. Each day took one pill which cost me $1.20, but each pill saved let’s call it 3.5 hours; if I value my time at minimum wage, or 7.25/hr (federal minimum wage), then that 3.5 hours is worth $25.37, which is much more than $1.20, ~21x more.
“Certain people might benefit from certain combinations of certain things,” he told me. “But across populations, there is still no conclusive proof that substances of this class improve cognitive functions.” And with no way to reliably measure the impact of a given substance on one’s mental acuity, one’s sincere beliefs about “what works” probably have a lot to do with, say, how demanding their day was, or whether they ate breakfast, or how susceptible they are to the placebo effect.
The use of cognitive enhancers by healthy individuals sparked debate about ethics and safety. Cognitive enhancement by pharmaceutical means was considered a form of illicit drug use in some places, even while other cognitive enhancers, such as caffeine and nicotine, were freely available. The conflict therein raised the possibility for further acceptance of smart drugs in the future. However, the long-term effects of smart drugs on otherwise healthy brains were unknown, delaying safety assessments.
I largely ignored this since the discussions were of sub-RDA doses, and my experience has usually been that RDAs are a poor benchmark and frequently far too low (consider the RDA for vitamin D). This time, I checked the actual RDA - and was immediately shocked and sure I was looking at a bad reference: there was no way the RDA for potassium was seriously 3700-4700mg or 4-5 grams daily, was there? Just as an American, that implied that I was getting less than half my RDA. (How would I get 4g of potassium in the first place? Eat a dozen bananas a day⸮) I am not a vegetarian, nor is my diet that fantastic: I figured I was getting some potassium from the ~2 fresh tomatoes I was eating daily, but otherwise my diet was not rich in potassium sources. I have no blood tests demonstrating deficiency, but given the figures, I cannot see how I could not be deficient.
Two additional studies assessed the effects of d-AMP on visual–motor sequence learning, a form of nondeclarative, procedural learning, and found no effect (Kumari et al., 1997; Makris, Rush, Frederich, Taylor, & Kelly, 2007). In a related experimental paradigm, Ward, Kelly, Foltin, and Fischman (1997) assessed the effect of d-AMP on the learning of motor sequences from immediate feedback and also failed to find an effect.
…The Fate of Nicotine in the Body also describes Battelle’s animal work on nicotine absorption. Using C14-labeled nicotine in rabbits, the Battelle scientists compared gastric absorption with pulmonary absorption. Gastric absorption was slow, and first pass removal of nicotine by the liver (which transforms nicotine into inactive metabolites) was demonstrated following gastric administration, with consequently low systemic nicotine levels. In contrast, absorption from the lungs was rapid and led to widespread distribution. These results show that nicotine absorbed from the stomach is largely metabolized by the liver before it has a chance to get to the brain. That is why tobacco products have to be puffed, smoked or sucked on, or absorbed directly into the bloodstream (i.e., via a nicotine patch). A nicotine pill would not work because the nicotine would be inactivated before it reached the brain.
A provisional conclusion about the effects of stimulants on learning is that they do help with the consolidation of declarative learning, with effect sizes varying widely from small to large depending on the task and individual study. Indeed, as a practical matter, stimulants may be more helpful than many of the laboratory tasks indicate, given the apparent dependence of enhancement on length of delay before testing. Although, as a matter of convenience, experimenters tend to test memory for learned material soon after the learning, this method has not generally demonstrated stimulant-enhanced learning. However, when longer periods intervene between learning and test, a more robust enhancement effect can be seen. Note that the persistence of the enhancement effect well past the time of drug action implies that state-dependent learning is not responsible. In general, long-term effects on learning are of greater practical value to people. Even students cramming for exams need to retain information for more than an hour or two. We therefore conclude that stimulant medication does enhance learning in ways that may be useful in the real world.
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).
We included studies of the effects of these drugs on cognitive processes including learning, memory, and a variety of executive functions, including working memory and cognitive control. These studies are listed in Table 2, along with each study’s sample size, gender, age and tasks administered. Given our focus on cognition enhancement, we excluded studies whose measures were confined to perceptual or motor abilities. Studies of attention are included when the term attention refers to an executive function but not when it refers to the kind of perceptual process taxed by, for example, visual search or dichotic listening or when it refers to a simple vigilance task. Vigilance may affect cognitive performance, especially under conditions of fatigue or boredom, but a more vigilant person is not generally thought of as a smarter person, and therefore, vigilance is outside of the focus of the present review. The search and selection process is summarized in Figure 2.