Nootropics (// noh-ə-TROP-iks), also referred to as smart drugs, memory enhancers, neuro enhancers, cognitive enhancers, and intelligence enhancers, are drugs, supplements, nutraceuticals, and functional foods that improve one or more aspects of mental function, such as working memory, motivation, and attention. The word nootropic was coined in 1972 by the Romanian Dr. Corneliu E. Giurgea, derived from the Greek words νους nous, or "mind", and τρέπειν trepein meaning to bend or turn.
Availability and prevalence
At present, there are only a few drugs which have been shown to improve some aspect of cognition in medical reviews. 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 such disorders as Alzheimer's disease, Parkinson's disease, Huntington's disease and ADHD. However, more widespread use is being reported by some researchers, despite concern for further research. Nevertheless, intense marketing may not correlate with efficacy; while scientific studies support the beneficial effects of some compounds, the marketing claims by manufacturers of dietary supplements are usually not formally tested by independent entities.
In academia, nootropics have been used to increase productivity, despite their long-term effects lacking conclusive research in healthy individuals. Stimulants such as dimethylamylamine and methylphenidate are used on college campuses and by younger groups. One survey found that 7% of students had used stimulants for a cognitive edge, and on some campuses use in the past year is as high as 25%. The use of prescription stimulants is especially prevalent among students attending academically competitive colleges. Surveys suggest that 3–11% of American students and 0.7–4.5% of German students have used cognitive enhancers in their lifetime.
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). While certain racetam compounds are suspected to have nootropic qualities, few side-effects, and a wide therapeutic window (low overdose risk), other cognitive enhancers may be associated with a high incidence of adverse effects or a narrower therapeutic window (higher overdose risk).[clarification needed] While addiction to stimulants is sometimes asserted to be 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 that "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 2015, systematic medical reviews and meta-analyses of clinical research in humans had 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 which have demonstrated cognition-enhancing effects in humans are those which 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 will result in cognitive deficits.
- Amphetamine pharmaceuticals (Adderall, dextroamphetamine, and lisdexamfetamine [a prodrug]) – TAAR1 agonists that mimic the effect of endogenous phenethylamine and N-methylphenethylamine. Systematic reviews and meta-analyses report that amphetamine benefits a range of aspects of cognitive control (e.g., attentional control, inhibitory control, episodic memory, and working memory, among others) in the general population, and these effects are especially notable in individuals with ADHD. In particular, a 2015 meta-analysis of high quality evidence found that therapeutic doses of amphetamine and methylphenidate improve performance on working memory, episodic memory, and inhibitory control tests in normal healthy adults. 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 cognitive control (e.g., working memory, episodic memory, and inhibitory control) in the general population. It also improves performance on tedious tasks that require a high degree of effort. At above optimal doses, methylphenidate has offtarget 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. 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.
- 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.
- Phosphatidylserine (a phospholipid) with DHA and EPA (omega-3 fatty acids) – a review of literature and subsequent randomized controlled trial indicate concurrent supplemental use can protect and potentially improve brain function, with clinical benefits for those with ADHD and other disorders. Two Cochrane Collaboration reviews on the use of supplemental omega-3 fatty acids alone (without phosphatidylserine) for ADHD and learning disorders conclude that there is limited evidence of treatment benefits for either disorder.
- Tianeptine – enhances several metrics of cognition in animal models. It has also been shown to prevent stress-induced dendritic remodeling in various brain structures, and antagonizes alcohol's neurodegenerative effects.
- L-theanine – see the Xanthines entry above.
- Valproate – a study has suggested that valproate may be able to enhance the cognitive ability of absolute pitch.
- Bacopa monnieri – A nutraceutical herb with "neural tonic" and memory enhancing properties shown in humans in a double-blinded RCTs.
- Panax ginseng – 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.
- Salvia officinalis - Although some evidence is suggestive of cognition benefits, the study quality is so poor that no conclusions can be drawn from it.
- Ginkgo biloba – Different reviews come to different conclusions. A 2009 Cochrane review found not enough evidence to make conclusions in those with dementia. Another review stated "there is consistent evidence that chronic administration improves selective attention, some executive processes and long-term memory for verbal and non-verbal material."
- Isoflavones – A double-blind, placebo-controlled study showed improvement in spatial working memory after administration of isoflavones. One RCT showed soy isoflavone supplementation improved performance on 6 of 11 cognitive tests, including visual-spatial memory and construction, verbal fluency and speeded dexterity, but worse on two tests of executive function.
The racetams are structurally similar compounds, such as pramiracetam, oxiracetam, coluracetam, and aniracetam, 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.
- Cognitive science
- Human enhancement
- Neurobiological effects of physical exercise#Cognitive control and memory
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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 α2 and dopamine D1 receptors. ... This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic α2 versus α1 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.
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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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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 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 spacial 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.
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In addition to the main metabolic pathway, TAs can also be converted by nonspecific N-methyltransferase (NMT)  and phenylethanolamine N-methyltransferase (PNMT)  to the corresponding secondary amines (e.g. synephrine , N-methylphenylethylamine and N-methyltyramine ), which display similar activities on TAAR1 (TA1) as their primary amine precursors...Both dopamine and 3-methoxytyramine, which do not undergo further N-methylation, are partial agonists of TAAR1 (TA1). ...
The dysregulation of TA levels has been linked to several diseases, which highlights the corresponding members of the TAAR family as potential targets for drug development. In this article, we focus on the relevance of TAs and their receptors to nervous system-related disorders, namely schizophrenia and depression; however, TAs have also been linked to other diseases such as migraine, attention deficit hyperactivity disorder, substance abuse and eating disorders [7,8,36]. Clinical studies report increased β-PEA plasma levels in patients suffering from acute schizophrenia  and elevated urinary excretion of β-PEA in paranoid schizophrenics , which supports a role of TAs in schizophrenia. As a result of these studies, β-PEA has been referred to as the body’s ‘endogenous amphetamine’ 
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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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Cognitive deficits, such as an impairment of attention, memory and problem solving, have often been reported in patients with depressive disorders (69). Cognitive deficits and memory impairments in patients with depression may arise via disruption of the hypothalamic-pituitary adrenal (HPA) axis through hippocampal volume loss and changes in the amygdala. The magnitude of the hippocampal shrinkage reported in certain experimental conditions may partly underlie some of cognitive deficits that accompany major depression. Conversely, any prevention or restoration of these morphological changes in the hippocampus should be parallel to procognitive/promnesiant effects. Accordingly, tianeptine has particularly favorable effects on cognitive functions and the positive effect of tianeptine may be mediated through its upregulation of neurogenesis, but of course, the impact of neurogenesis on cognitive functions remains a matter of controversial debate.
Tianeptine prevents and reverses stress-induced glucocorticoid-mediated dendritic remodeling in CA3 pyramidal neurons in the hippocampus (40,41) and stress-induced increases in dendritic length and branching in the amygdala (50). Tianeptine blocks the dendritic remodeling caused by stress or glucocorticoids (41), blocks stress-induced impairments of spatial memory performance in radial and Y-maze (70,71) and antagonizes the deleterious effects of alcohol (72).
In a validated model of hippocampal-dependent memory impairment and synaptic plasticity changes by predator stress, acute tianeptine can prevent the deleterious effects of stress on spatial memory, an effect that does not depend on corticosterone levels (73). Tianeptine also facilitates focused attention behavior in the cat in response to its environment or towards a significant stimulus (74). It was shown to exert improving effects on learning as well as on working memory and on reference memory in rodents (72) and to exhibit vigilance-enhancing effects in rats (75) and monkeys (76)...
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Unfortunately, promising beneficial effects showed in clinical studies are debased by methodological issues
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Medical journal articles
- Whose well-being? Common conceptions and misconceptions in the enhancement debate – PMID 25191232 (Frontiers in Systems Neuroscience, August 2014)
- Towards responsible use of cognitive-enhancing drugs by the healthy – PMID 19060880 (Nature, December 2008)
- "A Pandora's box full of smart drugs" by Ann Robinson (The Guardian, February 23, 2010)
- "Brain Gain: The underground world of 'neuro-enhancing' drugs" by Margaret Talbot (The New Yorker, April 27, 2009)