Editing Nootropic (section)

==Types==
{{anchor|Drugs}}
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=== Central nervous system stimulants {{anchor|Xanthines|Stimulants}} ===
[[Systematic review]]s and [[meta-analyses]] of [[clinical research]] using low doses of certain [[central nervous system]] stimulants found that these drugs may enhance cognition in healthy people.<ref name="Unambiguous PFC D1 A2" /><ref name="Cognitive and motivational effects">{{cite journal | vauthors = Ilieva IP, Hook CJ, Farah MJ | title = Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis | journal = Journal of Cognitive Neuroscience | volume = 27 | issue = 6 | pages = 1069–1089 | date = June 2015 | pmid = 25591060 | doi = 10.1162/jocn_a_00776 | s2cid = 15788121 | url = https://repository.upenn.edu/neuroethics_pubs/130 | url-access = subscription }}</ref><ref name="Systematic 2014 – Amph, MPH, Modafinil">{{cite journal | vauthors = Bagot KS, Kaminer Y | title = Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: a systematic review | journal = Addiction | volume = 109 | issue = 4 | pages = 547–557 | date = April 2014 | pmid = 24749160 | pmc = 4471173 | doi = 10.1111/add.12460 }}</ref> In particular, the classes of stimulants that demonstrate possible cognition-enhancing effects in humans have evidence [[in vitro]] as [[receptor agonist|direct agonists]] or [[indirect agonist]]s of [[dopamine receptor D1|dopamine receptor D<sub>1</sub>]] or [[Alpha-2 adrenergic receptor|adrenoceptor A<sub>2</sub>]].<ref name="Unambiguous PFC D1 A2">{{cite journal | vauthors = Spencer RC, Devilbiss DM, Berridge CW | title = The cognition-enhancing effects of psychostimulants involve direct action in the prefrontal cortex | journal = Biological Psychiatry | volume = 77 | issue = 11 | pages = 940–950 | date = June 2015 | pmid = 25499957 | pmc = 4377121 | doi = 10.1016/j.biopsych.2014.09.013 }}</ref><ref name="Cognitive and motivational effects" /><ref name="Continuum">{{cite journal | vauthors = Wood S, Sage JR, Shuman T, Anagnostaras SG | title = Psychostimulants and cognition: a continuum of behavioral and cognitive activation | journal = Pharmacological Reviews | volume = 66 | issue = 1 | pages = 193–221 | date = January 2014 | pmid = 24344115 | pmc = 3880463 | doi = 10.1124/pr.112.007054 }}</ref><ref name="NHMH_3e-Higher Cognitive Function">{{cite book | vauthors = Malenka RC, Nestler EJ, Hyman SE, Holtzman DM | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2015 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071827706 | edition = 3| chapter = 14: Higher Cognitive Function and Behavioral Control}}</ref> Relatively high doses of stimulants cause cognitive deficits.<ref name="Continuum" /><ref name="NHMH_3e-Higher Cognitive Function" />
* [[Amphetamine]]{{snd}} systematic reviews and meta-analyses report that low-dose amphetamine may improve cognitive functions (e.g., [[inhibitory control]], [[episodic memory]], [[working memory]], and aspects of [[Attention#Clinical model|attention]]) in healthy people and in individuals with [[ADHD]].<ref name="Unambiguous PFC D1 A2" /><ref name="Cognitive and motivational effects" /><ref name="Systematic 2014 – Amph, MPH, Modafinil" /><ref name="NHMH_3e-Higher Cognitive Function" /> A 2014 systematic review noted that low doses of amphetamine also improve [[memory consolidation]], in turn leading to improved [[Recall (memory)|recall of information]] in non-ADHD youth.<ref name="Systematic 2014 – Amph, MPH, Modafinil" /> It also improves [[incentive salience|task saliency]] (motivation to perform a task) and performance on tedious tasks that required a high degree of effort.<ref name="Cognitive and motivational effects" /><ref name="Continuum" /><ref name="NHMH_3e-Higher Cognitive Function" />
* [[Caffeine]]{{snd}} a meta-analysis found an increase in alertness and attentional performance.<ref name="caffeine and theanine">{{cite journal | vauthors = Camfield DA, Stough C, Farrimond J, Scholey AB | title = Acute effects of tea constituents L-theanine, caffeine, and epigallocatechin gallate on cognitive function and mood: a systematic review and meta-analysis | journal = Nutrition Reviews | volume = 72 | issue = 8 | pages = 507–522 | date = August 2014 | pmid = 24946991 | doi = 10.1111/nure.12120 | doi-access = free }}</ref><ref name="Continuum" />
* [[Eugeroics]] ([[armodafinil]] and [[modafinil]]){{snd}} are classified as "wakefulness-promoting agents"; modafinil may increase alertness, particularly in [[sleep-deprived]] individuals, and may improve reasoning and problem solving in non-ADHD youth.<ref name="Systematic 2014 – Amph, MPH, Modafinil" /> In a systematic review of small, preliminary studies where the effects of modafinil were examined, when simple psychometric assessments were considered, modafinil intake enhanced executive function.<ref name="Modafinil SystRev">{{cite journal | vauthors = Battleday RM, Brem AK | title = Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review | journal = European Neuropsychopharmacology | volume = 25 | issue = 11 | pages = 1865–1881 | date = November 2015 | pmid = 26381811 | doi = 10.1016/j.euroneuro.2015.07.028 | s2cid = 23319688 }}</ref> Modafinil does not improve mood or motivation in sleep-deprived or non-sleep deprived individuals.<ref>{{cite book | vauthors = Mohamed AD | chapter = Does modafinil improve cognitive functioning in healthy individuals? | veditors = ter Meulen R, Hall W, Mohammed AD |title=Rethinking Cognitive Enhancement |date=2017 |publisher=Oxford University Press |isbn=9780198727392 |page=116 | chapter-url=https://books.google.com/books?id=aAIXDgAAQBAJ&pg=PA116 }}</ref>
* [[Methylphenidate]]{{snd}} a [[benzylpiperidine]] derivative that may improve [[working memory]], [[episodic memory]], and [[inhibitory control]], aspects of [[Attention#Clinical model|attention]], and planning latency in healthy people.<ref name="Unambiguous PFC D1 A2" /><ref name="Systematic 2014 – Amph, MPH, Modafinil" /> It also may improve task saliency and performance on tedious tasks.<ref name="NHMH_3e-Higher Cognitive Function" /> At above optimal doses, methylphenidate has off–target effects that decrease learning.<ref>{{cite journal | vauthors = Urban KR, Gao WJ | title = Performance enhancement at the cost of potential brain plasticity: neural ramifications of nootropic drugs in the healthy developing brain | journal = Frontiers in Systems Neuroscience | volume = 8 | pages = 38 | date = 2014 | pmid = 24860437 | pmc = 4026746 | doi = 10.3389/fnsys.2014.00038 | doi-access = free }}</ref>
* [[Nicotine]]{{snd}} has been associated with improved alertness, attention, memory, and motor performance, according to a [[meta-analysis]].<ref>{{cite journal | vauthors = Heishman SJ, Kleykamp BA, Singleton EG | title = Meta-analysis of the acute effects of nicotine and smoking on human performance | journal = Psychopharmacology | volume = 210 | issue = 4 | pages = 453–469 | date = July 2010 | pmid = 20414766 | pmc = 3151730 | doi = 10.1007/s00213-010-1848-1 }}</ref> However, a 2020 systematic review raised concerns about potential conflicts of interest, noting industry funding in many studies and inconsistent results regarding nicotine's cognitive effects. This review found that over half of the studies published after 2010 had tobacco industry affiliations, often undisclosed.<ref name="pmid32547048">{{cite journal |last1=Pasetes |first1=Sarah V. |last2=Ling |first2=Pamela M. |last3=Apollonio |first3=Dorie E. |title=Cognitive performance effects of nicotine and industry affiliation: a systematic review |journal=Substance Abuse: Research and Treatment |date=January 2020 |volume=14 |pages=117822182092654 |doi=10.1177/1178221820926545 |pmid=32547048 |language=en |issn=1178-2218 |pmc=7271274}}</ref>

===Cholinergics===
{{Main|Cholinergic}}
Some supposed nootropic substances are compounds and analogues of [[choline]], a [[precursor (chemistry)|precursor]] of acetylcholine (a [[neurotransmitter]]) and [[phosphatidylcholine]] (a structural component of [[cell membrane]]s).
* [[Alpha-GPC]] – L-alpha glycerylphosphorylcholine has been studied only in the context of cognitive performance alongside other substances such as caffeine.<ref>{{cite journal| vauthors = Parker AG, Byars A, Purpura M, Jäger R |date=September 21, 2015|title=The effects of alpha-glycerylphosphorylcholine, caffeine or placebo on markers of mood, cognitive function, power, speed, and agility|journal=Journal of the International Society of Sports Nutrition|volume=12|issue=Suppl 1|pages=P41|doi=10.1186/1550-2783-12-S1-P41|issn=1550-2783|pmc=4595381 |doi-access=free }}</ref>
* [[Choline bitartrate]] – Choline bitartrate is a [[tartaric acid]] salt containing choline (41% choline by molecular weight). One meta-analysis found choline bitartrate to be ineffective at improving any measure of cognitive performance.<ref>{{cite journal | vauthors = Lippelt DP, van der Kint S, van Herk K, Naber M | title = No Acute Effects of Choline Bitartrate Food Supplements on Memory in Healthy, Young, Human Adults | journal = PLOS ONE | volume = 11 | issue = 6 | pages = e0157714 | date = June 24, 2016 | pmid = 27341028 | pmc = 4920398 | doi = 10.1371/journal.pone.0157714 | doi-access = free | bibcode = 2016PLoSO..1157714L }}</ref>
* [[Citicoline]] – Compound consisting of choline and [[cytidine]]. A meta-analysis found that it may be effective for improving memory and learning in older people with mild cognitive decline, and in people recovering from a stroke.<ref>{{cite journal | vauthors = Fioravanti M, Buckley AE | title = Citicoline (Cognizin) in the treatment of cognitive impairment | journal = Clinical Interventions in Aging | volume = 1 | issue = 3 | pages = 247–251 | date = September 2006 | pmid = 18046877 | pmc = 2695184 | doi = 10.2147/ciia.2006.1.3.247 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Franco-Maside A, Caamaño J, Gómez MJ, Cacabelos R | title = Brain mapping activity and mental performance after chronic treatment with CDP-choline in Alzheimer's disease | journal = Methods and Findings in Experimental and Clinical Pharmacology | volume = 16 | issue = 8 | pages = 597–607 | date = October 1994 | pmid = 7760585 }}</ref>

===Racetams===
{{Main|Racetam}}
Racetams, such as piracetam, [[oxiracetam]], [[phenylpiracetam]], and [[aniracetam]], are often marketed as cognitive enhancers and sold [[over the counter]].<ref name="NeuroClin">{{cite journal | vauthors = Cohen PA, Avula B, Wang YH, Zakharevich I, Khan I | title = Five Unapproved Drugs Found in Cognitive Enhancement Supplements | journal = Neurology. Clinical Practice | volume = 11 | issue = 3 | pages = e303–e307 | date = June 2021 | pmid = 34484905 | pmc = 8382366 | doi = 10.1212/CPJ.0000000000000960 }}</ref><ref name="JAMAIM">{{cite journal | vauthors = Cohen PA, Zakharevich I, Gerona R | title = Presence of Piracetam in Cognitive Enhancement Dietary Supplements | journal = JAMA Internal Medicine | volume = 180 | issue = 3 | pages = 458–459 | date = March 2020 | pmid = 31764936 | pmc = 6902196 | doi = 10.1001/jamainternmed.2019.5507 }}</ref> A 2019 study found that piracetam supplements sold in the United States were inaccurately labeled.<ref name="JAMAIM"/> Racetams are often referred to as nootropics, but this property is not well established in humans, and nootropics are not consistently found in all racetams.<ref name="NHM">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | page = 454 | edition = 2 }}</ref> The racetams have poorly understood [[mechanism of action|mechanisms]], although piracetam and aniracetam are known to act as [[positive allosteric modulator]]s of [[AMPA receptor]]s and appear to modulate [[acetylcholine|cholinergic]] systems.<ref>{{cite journal | vauthors = Gualtieri F, Manetti D, Romanelli MN, Ghelardini C | title = Design and study of piracetam-like nootropics, controversial members of the problematic class of cognition-enhancing drugs | journal = Current Pharmaceutical Design | volume = 8 | issue = 2 | pages = 125–138 | year = 2002 | pmid = 11812254 | doi = 10.2174/1381612023396582 }}</ref> Similar compounds, such as [[N-Phenylacetyl-L-prolylglycine ethyl ester|noopept]] and [[aloracetam]], do not meet the chemical definition for being a racetam, though they are considered "racetam-like" due to their high similarity.<ref name="WHO-INN-Stembook2018">[https://cdn.who.int/media/docs/default-source/international-nonproprietary-names-(inn)/stembook-2018.pdf The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances.] Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1).</ref>

According to the FDA,

<blockquote>Piracetam is not a [[vitamin]], mineral, [[amino acid]], herb or other [[botanical]], or dietary substance for use by humans 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.<ref name="unlimited">{{cite web|url=https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2010/ucm225605.htm|archive-url=https://wayback.archive-it.org/7993/20170112004501/https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2010/ucm225605.htm|url-status=dead|archive-date=12 January 2017|title=FDA Warning Letter: Unlimited Nutrition|author=John Gridley|date=30 August 2010|publisher=Office of Compliance, Center for Food Safety and Applied Nutrition, Inspections, Compliance, Enforcement, and Criminal Investigations, US Food and Drug Administration |access-date=5 April 2016}}</ref></blockquote>