Nootropics (English pronunciation: noh-?-TROP-iks), also known as smart drugs and cognitive enhancers, are drugs, supplements, and other substances that improve cognitive function, particularly executive functions, memory, creativity, or motivation, in healthy individuals. The use of cognition-enhancing drugs by healthy individuals in the absence of a medical indication is one of the most debated topics among neuroscientists, psychiatrists, and physicians which spans a number of issues, including the ethics and fairness of their use, concerns over adverse effects, and the diversion of prescription drugs for nonmedical uses, among others. Nonetheless, the international sales of cognition-enhancing supplements exceeded US$1 billion in 2015 and the global demand for these compounds is still growing rapidly.
The word nootropic was coined in 1972 by a Romanian psychologist and chemist, Corneliu E. Giurgea, from the Greek words ? (nous), or "mind", and ? (trepein), meaning to bend or turn.
Availability and prevalence
There are only a few drugs that are known to improve some aspect of cognition. Many more are in different stages of development. The most commonly used class of drug is stimulants, such as caffeine.
These drugs are purportedly used primarily to treat cognitive or motor function difficulties attributable to disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and ADHD. Some researchers, however, report more widespread use despite concern for further research. Nevertheless, intense marketing may not correlate with efficacy. While scientific studies support the beneficial effects of some compounds, manufacturer's marketing claims for dietary supplements are usually not formally tested and verified by independent entities.
Use by students
Among students, nootropics have been used to increase productivity, despite their long-term effects lacking conclusive research in healthy individuals. The use of prescription stimulants is especially prevalent among students attending academically competitive colleges. Surveys suggest that 0.7-4.5% of German students have used cognitive enhancers in their lifetime. Stimulants such as dimethylamylamine and methylphenidate are used on college campuses and by younger groups. Based upon studies of self-reported illicit stimulant use, 5-35% of college students use diverted ADHD stimulants, which are primarily used for performance enhancement rather than as recreational drugs.
Several factors positively and negatively influence the use of drugs to increase cognitive performance. Among them are personal characteristics, drug characteristics, and characteristics of the social context.
The main concern with pharmaceutical drugs is adverse effects, and these concerns apply to cognitive-enhancing drugs as well. Long-term safety data is typically unavailable for some types of nootropics (e.g., many non-pharmaceutical cognitive enhancers, newly developed pharmaceuticals and pharmaceuticals with short-term therapeutic use). Racetams--piracetam and other compounds that are structurally related to piracetam--have few serious adverse effects and low toxicity, but there is little evidence that they enhance cognition in individuals without cognitive impairments. While addiction to stimulants is sometimes identified as a cause for concern, a very large body of research on the therapeutic use of the "more addictive" psychostimulants indicate that addiction is fairly rare in therapeutic doses. On their safety profile, a systematic review from June 2015 asserted, "evidence indicates that at low, clinically relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers."
In the United States dietary supplements may be marketed if the manufacturer can show that it can manufacture the supplement safely, that the supplement is indeed generally recognized as safe, and if the manufacturer does not make any claims about the supplement's use to treat or prevent any disease or condition; supplements that contain drugs or for which treatment or prevention claims are made are illegal under US law.
In 2015, systematic medical reviews and meta-analyses of clinical research in humans established consensus that certain stimulants, only when used at low (therapeutic) concentrations, unambiguously enhance cognition in the general population; in particular, the classes of stimulants that demonstrate cognition-enhancing effects in humans act as direct agonists or indirect agonists of dopamine receptor D1, adrenoceptor A2, or both receptors in the prefrontal cortex. Relatively high doses of stimulants cause cognitive deficits.
- Amphetamine pharmaceuticals (e.g., Adderall, dextroamphetamine, and lisdexamfetamine [an inactive prodrug]) - systematic reviews and meta-analyses report that amphetamine benefits a range of cognitive functions (e.g., inhibitory control, episodic memory, working memory, and aspects of attention) in the general population, and these effects are especially notable in individuals with ADHD. A systematic review from 2014 noted that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information in non-ADHD youth. It also improves task saliency (motivation to perform a task) and performance on tedious tasks that require a high degree of effort.
- Methylphenidate - a substituted phenethylamine that improves a range of cognitive functions (e.g., working memory, episodic memory, and inhibitory control, aspects of attention, and planning latency) in the general population. It also improves task saliency and performance on tedious tasks that require a high degree of effort. At above optimal doses, methylphenidate has off target effects that can decrease learning by activating neurons not involved in the task at hand.
- Eugeroics (armodafinil and modafinil) - wakefulness promoting agents; modafinil increases alertness, particularly in sleep deprived individuals, and was noted to facilitate reasoning and problem solving in a systematic review. They are clinically prescribed for narcolepsy, shift work sleep disorder, and daytime sleepiness remaining after sleep apnea treatments.
- Xanthines (most notably, caffeine) - shown to increase alertness, performance, and, in some studies, memory. Children and adults who consume low doses of caffeine showed increased alertness, yet a higher dose was needed to improve performance.
- Nicotine - A meta-analysis of 41 double-blind, placebo-controlled studies concluded that nicotine or smoking had significant positive effects on aspects of fine motor abilities, alerting and orienting attention, and episodic and working memory. A 2015 review noted that stimulation of the ?4?2 nicotinic receptor is responsible for certain improvements in attentional performance; among the nicotinic receptor subtypes, nicotine has the highest binding affinity at the ?4?2 receptor (ki=1 nM), which is also the biological target that mediates nicotine's addictive properties.
Racetams, such as piracetam, oxiracetam, and aniracetam, are structurally similar compounds, which are often marketed as cognitive enhancers and sold over-the-counter. Racetams are often referred to as nootropics, but this property of the drug class is not well established. The racetams have poorly understood mechanisms of action; however, piracetam and aniracetam are known to act as positive allosteric modulators of AMPA receptors and appear to modulate cholinergic systems.
According to the US Food and Drug Administration, "Piracetam is not a vitamin, mineral, amino acid, herb or other botanical, or dietary substance for use by man to supplement the diet by increasing the total dietary intake. Further, piracetam is not a concentrate, metabolite, constituent, extract or combination of any such dietary ingredient. [...] Accordingly, these products are drugs, under section 201(g)(1)(C) of the Act, 21 U.S.C. § 321(g)(1)(C), because they are not foods and they are intended to affect the structure or any function of the body. Moreover, these products are new drugs as defined by section 201(p) of the Act, 21 U.S.C. § 321(p), because they are not generally recognized as safe and effective for use under the conditions prescribed, recommended, or suggested in their labeling."
- L-Theanine - A 2014 systematic review and meta-analysis found that concurrent caffeine and L-theanine use has synergistic psychoactive effects that promote alertness, attention, and task switching; these effects are most pronounced during the first hour post-dose. However, the European Food Safety Authority reports that when L-theanine is used by itself (i.e. without caffeine) there is insufficient information to determine if positive health effects exist.
- Tolcapone - a systematic review noted that it improves verbal episodic memory and episodic memory encoding.
- Levodopa - a systematic review noted that it improves verbal episodic memory and episodic memory encoding.
- Atomoxetine - can improve working memory and aspects of attention when used at an optimal dose.
- Bacopa monnieri - A herb sold as a dietary supplement. There is some preliminary evidence for memory-enhancing effects.
- 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 "Although 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." According to a review published in the journal "Advances in Nutrition", multiple RCTs in healthy volunteers have indicated increases in accuracy of memory, speed in performing attention tasks and improvement in performing difficult mental arithmetic tasks, as well as reduction in fatigue and improvement in mood.
- Ginkgo biloba - An extract of Ginkgo biloba leaf (GBE) is marketed in dietary supplement form with claims it can enhance cognitive function in people without known cognitive problems. Studies have failed to find such effects on memory or attention in healthy people.
Null findings in systematic reviews
- Omega-3 fatty acids: DHA and EPA - two Cochrane Collaboration reviews on the use of supplemental omega-3 fatty acids for ADHD and learning disorders conclude that there is limited evidence of treatment benefits for either disorder. Two other systematic reviews noted no cognition-enhancing effects in the general population or middle-aged and older adults.
- Folate - no cognition-enhancing effects in middle-aged and older adults.
- Vitamin B6 - no cognition-enhancing effects in middle-aged and older adults.
- Vitamin B12 - no cognition-enhancing effects in middle-aged and older adults.
- Vitamin E - no cognition-enhancing effects in middle-aged and older adults.
- Pramipexole - no significant cognition-enhancing effects in healthy individuals.
- Guanfacine - no significant cognition-enhancing effects in healthy individuals.
- Clonidine - no significant cognition-enhancing effects in healthy individuals.
- Ampakines - no significant cognition-enhancing effects in healthy individuals.
- Fexofenadine - no significant cognition-enhancing effects in healthy individuals.
- Salvia officinalis - Although some evidence is suggestive of cognition benefits, the study quality is so poor that no conclusions can be drawn from it.
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International sales of non-prescription supplements for cognition also exceed $1bn (£650 000; EUR880 000) a year and are rapidly growing. Ginkgo biloba, vitamins, and even caffeine are common ingredients. Some add piracetam (related to the epilepsy drug levetiracetam), jellyfish proteins, or even "edible pure 23.5 carat gold flakes."
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Overall, 11.3% of responders admitted to misusing prescription stimulants. There was more misuse by respiratory therapy students, although this was not statistically significant (10.9% medicine, 9.7% pharmacy, 26.3% respiratory therapy; P = .087). Reasons for prescription stimulant misuse included to enhance alertness/energy (65.9%), to improve academic performance (56.7%), to experiment (18.2%), and to use recreationally/get high (4.5%).
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misuse of prescription stimulants has become a serious problem on college campuses across the US and has been recently documented in other countries as well. ... Indeed, large numbers of students claim to have engaged in the nonmedical use of prescription stimulants, which is reflected in lifetime prevalence rates of prescription stimulant misuse ranging from 5% to nearly 34% of students.
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The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine ?2 and dopamine D1 receptors. ... This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic ?2 versus ?1 receptors. Collectively, this evidence indicates that at low, clinically relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function). This information has potentially important clinical implications as well as relevance for public health policy regarding the widespread clinical use of psychostimulants and for the development of novel pharmacologic treatments for attention-deficit/hyperactivity disorder and other conditions associated with PFC dysregulation. ... In particular, in both animals and humans, lower doses maximally improve performance in tests of working memory and response inhibition, whereas maximal suppression of overt behavior and facilitation of attentional processes occurs at higher doses.
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The present meta-analysis was conducted to estimate the magnitude of the effects of methylphenidate and amphetamine on cognitive functions central to academic and occupational functioning, including inhibitory control, working memory, short-term episodic memory, and delayed episodic memory. In addition, we examined the evidence for publication bias. Forty-eight studies (total of 1,409 participants) were included in the analyses. We found evidence for small but significant stimulant enhancement effects on inhibitory control and short-term episodic memory. Small effects on working memory reached significance, based on one of our two analytical approaches. Effects on delayed episodic memory were medium in size. However, because the effects on long-term and working memory were qualified by evidence for publication bias, we conclude that the effect of amphetamine and methylphenidate on the examined facets of healthy cognition is probably modest overall. In some situations, a small advantage may be valuable, although it is also possible that healthy users resort to stimulants to enhance their energy and motivation more than their cognition. ... Earlier research has failed to distinguish whether stimulants' effects are small or whether they are nonexistent (Ilieva et al., 2013; Smith & Farah, 2011). The present findings supported generally small effects of amphetamine and methylphenidate on executive function and memory. Specifically, in a set of experiments limited to high-quality designs, we found significant enhancement of several cognitive abilities. ...
The results of this meta-analysis cannot address the important issues of individual differences in stimulant effects or the role of motivational enhancement in helping perform academic or occupational tasks. However, they do confirm the reality of cognitive enhancing effects for normal healthy adults in general, while also indicating that these effects are modest in size.
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Modafinil appears to improve reaction time (P = P
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Mild dopaminergic stimulation of the prefrontal cortex enhances working memory. ...
Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in normal subjects and those with ADHD. Positron emission tomography (PET) demonstrates that methylphenidate decreases regional cerebral blood flow in the doroslateral prefrontal cortex and posterior parietal cortex while improving performance of a spatial working memory task. This suggests that cortical networks that normally process spatial working memory become more efficient in response to the drug. ... [It] is now believed that dopamine and norepinephrine, but not serotonin, produce the beneficial effects of stimulants on working memory. At abused (relatively high) doses, stimulants can interfere with working memory and cognitive control ... stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks ... through indirect stimulation of dopamine and norepinephrine receptors.
Beyond these general permissive effects, dopamine (acting via D1 receptors) and norepinephrine (acting at several receptors) can, at optimal levels, enhance working memory and aspects of attention. Drugs used for this purpose include, as stated above, methylphenidate, amphetamines, atomoxetine, and desipramine.
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The studies reviewed here show that single doses of MPH improve cognitive performance in the healthy population in the domains of working memory (65% of included studies) and speed of processing (48%), and to a lesser extent may also improve verbal learning and memory (31%), attention and vigilance (29%) and reasoning and problem solving (18%), but does not have an effect on visual learning and memory. MPH effects are dose-dependent and the dose-response relationship differs between cognitive domains.
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Kis as follows; ?2?4=9900nM , ?3?2=14nM , ?3?4=187nM , ?4?2=1nM [4,6]. Due to the heterogeneity of nACh channels we have not tagged a primary drug target for nicotine, although the ?4?2 is reported to be the predominant high affinity subtype in the brain which mediates nicotine addiction [2-3].
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Omega-3 fatty acids, B vitamins, and vitamin E supplementation did not affect cognition in non-demented middle-aged and older adults.
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Unfortunately, promising beneficial effects showed in clinical studies are debased by methodological issues