Nootropic

Nootropics ( /noʊ.əˈtrɒpɪks/ noh-ə-TROP-iks)—also called smart drugs or cognitive enhancers—are drugs, supplements, or other substances that improve cognitive function, particularly executive functions, memory, creativity, or motivation, in healthy individuals.^[1][2] 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.^[1][3][4] 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.^[5]

The word nootropic was coined in 1972 by a Romanian psychologist and chemist, Corneliu E. Giurgea,^[6][7] from the Greek words νους (nous), or "mind", and τρέπειν (trepein), meaning to bend or turn.^[8]

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.^[9] The most commonly used class of drug is stimulants, such as caffeine.^[10]

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.^[11] 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.^[12]

Use by students

Among students, nootropics have been used to increase productivity, despite their long-term effects lacking conclusive research in healthy individuals.^[9] The use of prescription stimulants is especially prevalent among students attending academically competitive colleges.^[13] Surveys suggest that 0.7–4.5% of German students have used cognitive enhancers in their lifetime.^[14][15][16] Stimulants such as dimethylamylamine and methylphenidate are used on college campuses and by younger groups.^[9] 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.^[17][18][19]

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.^{[14][15][20][21]}

Side effects

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^[9] (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.^[22][23] While addiction to stimulants is sometimes identified as a cause for concern,^[24] a very large body of research on the therapeutic use of the "more addictive" psychostimulants indicate that addiction is fairly rare in therapeutic doses.^[25][26][27] 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."^[28]

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.^[29]

Drugs

Stimulants

Hebbian version of the Yerkes–Dodson 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;^{[28][30][31][32]} 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.^{[28][30][32][33]} Relatively high doses of stimulants cause cognitive deficits.^[32][33]

• 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.^{[28][30][31][33]} 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.^[31] It also improves task saliency (motivation to perform a task) and performance on tedious tasks that require a high degree of effort.^[30][32][33]
• 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.^{[28][30][31][34]} It also improves task saliency and performance on tedious tasks that require a high degree of effort.^[33] At above optimal doses, methylphenidate has off target effects that can decrease learning by activating neurons not involved in the task at hand.^[35]
• 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.^[31][36] They are clinically prescribed for narcolepsy, shift work sleep disorder, and daytime sleepiness remaining after sleep apnea treatments.^[37]
• Xanthines (most notably, caffeine) – shown to increase alertness, performance, and, in some studies, memory.^[32][38] Children and adults who consume low doses of caffeine showed increased alertness, yet a higher dose was needed to improve performance.^[39]
• 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.^[40] A 2015 review noted that stimulation of the α4β2 nicotinic receptor is responsible for certain improvements in attentional performance;^[41] among the nicotinic receptor subtypes, nicotine has the highest binding affinity at the α4β2 receptor (k_i=1 nM), which is also the biological target that mediates nicotine's addictive properties.^[42]

Racetams

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.^[43] 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.^[44]

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."^[45]

Miscellaneous

• 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;^[46] these effects are most pronounced during the first hour post-dose.^[46] 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.^[47]
• Tolcapone – a systematic review noted that it improves verbal episodic memory and episodic memory encoding.^[48]
• Levodopa – a systematic review noted that it improves verbal episodic memory and episodic memory encoding.^[48]
• Atomoxetine – can improve working memory and aspects of attention when used at an optimal dose.^[33]

Dietary supplements

• Bacopa monnieri – A herb sold as a dietary supplement. There is some preliminary evidence for memory-enhancing effects.^[49]
• 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."^[50] 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."^[51] 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.^[52]
• 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.^[53][54]

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.^[55][56] Two other systematic reviews noted no cognition-enhancing effects in the general population or middle-aged and older adults.^[57][58]
• Folate – no cognition-enhancing effects in middle-aged and older adults.^[58]
• Vitamin B6 – no cognition-enhancing effects in middle-aged and older adults.^[58]
• Vitamin B12 – no cognition-enhancing effects in middle-aged and older adults.^[58]
• Vitamin E – no cognition-enhancing effects in middle-aged and older adults.^[58]
• Pramipexole – no significant cognition-enhancing effects in healthy individuals.^[48]
• Guanfacine – no significant cognition-enhancing effects in healthy individuals.^[48]
• Clonidine – no significant cognition-enhancing effects in healthy individuals.^[48]
• Ampakines – no significant cognition-enhancing effects in healthy individuals.^[48]
• Fexofenadine – no significant cognition-enhancing effects in healthy individuals.^[48]
• Salvia officinalis – Although some evidence is suggestive of cognition benefits, the study quality is so poor that no conclusions can be drawn from it.^[59]

See also

• Cognitive science
• Human enhancement
• List of drugs used by militaries
• Neurobiological effects of physical exercise § Cognitive control and memory
• Neuroenhancement

References