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{{Short description|Compound intended to improve cognitive function}}
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| image1 = Coffea arabica - Köhler–s Medizinal-Pflanzen-189.jpg
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'''Nootropics''' ({{IPAc-en|n|oʊ|.|ə|ˈ|t|r|oʊ|p|ᵻ|k|s}} {{respell|noh|ə|TROHP|iks}} or {{IPAc-en|n|oʊ|.|ə|ˈ|t|r|ɒ|p|ᵻ|k|s}} {{respell|noh|ə|TROP|iks}}),<ref name="Lexico">{{cite encyclopedia |title=Shubham |url=https://www.oed.com/search/advanced/Meanings?scope=HistoricalThesaurus&q=nootropic|encyclopedia=Oxford English Dictionary|date=2024|accessdate=14 January 2024 |language=en}}</ref> colloquially '''brain supplements''', '''smart drugs''' and '''cognitive enhancers''', are natural, semisynthetic or synthetic ] which purportedly improve ]s, such as ], ] or ].
'''Nootropics''' ({{IPAc-en|n|oʊ|.|ə|ˈ|t|r|ɒ|p|ɨ|k|s}} {{respell|noh-ə|TROP|iks}}), also referred to as ''smart drugs'', ''memory enhancers'', ''neuro enhancers'', ''cognitive enhancers'', and ''intelligence enhancers'', are ]s, ]s, ]s, and ]s that purportedly improve mental functions such as ], ], ], ], ], and concentration.<ref>{{Cite web|url=http://www.mercksource.com/pp/us/cns/cns_hl_dorlands.jspzQzpgzEzzSzppdocszSzuszSzcommonzSzdorlandszSzdorlandzSzdmd_n_10zPzhtm |title=Dorlands Medical Dictionary |work= |accessdate= |archiveurl = http://web.archive.org/web/20080130031824/http://www.mercksource.com/pp/us/cns/cns_hl_dorlands.jspzQzpgzEzzSzppdocszSzuszSzcommonzSzdorlandszSzdorlandzSzdmd_n_10zPzhtm |archivedate = January 30, 2008}}</ref><ref>{{Cite journal|author=Lanni C, Lenzken SC, Pascale A, ''et al.'' |title=Cognition enhancers between treating and doping the mind |journal=Pharmacol. Res. |volume=57 |issue=3 |pages=196–213 |date=March 2008 |pmid=18353672 |doi=10.1016/j.phrs.2008.02.004 |url=}}</ref> The word ''nootropic'' was coined in 1972 by the ] Dr. ],<ref name="isbn0-06-088473-8">{{Cite book|author=Gazzaniga, Michael S. |title=The Ethical Brain: The Science of Our Moral Dilemmas (P.S.) |publisher=Harper Perennial |location=New York, N.Y |year=2006 |pages=184 |isbn=0-06-088473-8 |oclc= |doi= |accessdate=}}</ref><ref name="pmid4541214">{{Cite journal|author=Giurgea C |title= ("Vers une pharmacologie de l'active integrative du cerveau: Tentative du concept nootrope en psychopharmacologie") |language=French |journal=Actual Pharmacol (Paris) |volume=25 |issue= |pages=115–56 |year=1972 |pmid=4541214 |doi= |url=}}</ref> derived from the ] words νους ''nous'', or "mind," and τρέπειν ''trepein'' meaning "to bend/turn". Nootropics are thought to work by altering the availability of the ] supply of neurochemicals (], ], and ]), by improving the brain's ] supply, or by stimulating nerve growth.


While commonly in the form of ]s, ]s or ]s,<ref name="NeuroClin"/> some nootropic compounds are ] and non-prescription drugs in various countries.
==Availability and prevalence==
At present, there are several drugs on the market that improve memory, concentration, and planning, and reduce impulsive behavior. Many more are in different stages of development.<ref name=NatureProfessor>{{Cite journal|author1=Sahakian B|author1-link=Barbara Sahakian|author2=Morein-Zamir S |title=Professor's little helper |journal=Nature |volume=450 |issue=7173 |pages=1157–9 |date=December 2007 |pmid=18097378 |doi=10.1038/4501157a |url=|bibcode = 2007Natur.450.1157S }}</ref> The most commonly used class of drug is ].<ref name="Nature2008">{{cite journal |url=http://www.nature.com/nature/journal/v456/n7223/full/456702a.html |title=Towards responsible use of cognitive-enhancing drugs by the healthy |work=] |date=December 10, 2008 |publisher=] |issn=1476-4687 |oclc=01586310 |bibcode = 2008Natur.456..702G |accessdate=March 25, 2014 |doi=10.1038/456702a |pages=702–705 |volume=456 |issue=7223 |subscription=yes |first1=Henry |last1=Greely |first2=Barbara |last2=Sahakian |first3=John |last3=Harris |first4=Ronald C. |last4=Kessler |first5=Michael |last5=Gazzaniga |first6=Philip |last6=Campbell |first7=Martha J. |last7=Farah}}</ref>


In the United States, nootropics are commonly advertised with unproven claims of effectiveness for improving cognition. The ] and ] have warned manufacturers and consumers about possible ] and ] concerning nootropic supplements.<ref name="ftc" /><ref name="fda-fraud" />
These drugs are used primarily to treat people with cognitive or motor function difficulties attributable to such disorders as ], ], ] and ]. However, more widespread use is being recommended by some researchers.<ref>{{Cite web|url=http://blogs.dnalc.org/2009/09/21/smart-drugs-and-should-we-take-them/|title=Smart Drugs and Should We Take Them?|publisher=]|accessdate=November 4, 2012}}</ref> These drugs have a variety of ] applications as well, and are marketed heavily on the ]. Nevertheless, intense marketing may not correlate with ]; while scientific studies support the beneficial effects of some compounds, the marketing claims by manufacturers of ] products are not formally tested.


===Academic doping=== ==History of term==
The term ''nootropic'' is derived {{ety|grc|''{{wikt-lang|grc|νόος}}'' (nóos)|mind||''{{wikt-lang|grc|τροπή}}'' (tropḗ)|turning}}.<ref name="Lexico"/><ref name="Giurgea1972">{{cite journal | vauthors = Giurgea C | title = | language = fr | journal = Actualites Pharmacologiques | volume = 25 | pages = 115–156 | date = 1972 | pmid = 4541214 }}</ref><ref name="Giurgea1977">{{cite journal| vauthors = Giurgea C, Salama M |date=January 1, 1977|title=Nootropic drugs|journal=Progress in Neuro-Psychopharmacology |volume=1 |issue=3 |pages=235–247 |doi=10.1016/0364-7722(77)90046-7 |quote=The term "nootropic" (noos = mind; tropein = towards) was proposed by us (Giurgea, 1972,1973) to designate psychotropic drugs}}</ref>
{{main|Academic doping}}


The first documented use of "nootropic" in reference to substances purported to increase cognitive functions was by ] in 1972.<ref name="Giurgea1972"/><ref name="Giurgea1977"/><ref name="malik">{{cite journal | vauthors = Malík M, Tlustoš P | title = Nootropics as Cognitive Enhancers: Types, Dosage and Side Effects of Smart Drugs | journal = Nutrients | volume = 14 | issue = 16 | page = 3367 | date = August 2022 | pmid = 36014874 | pmc = 9415189 | doi = 10.3390/nu14163367 | doi-access = free }}</ref> When researching a new compound, Giurgea found a spectrum of effects that did not align with any psychotropic drug category, leading to his proposal of a new category and the concept of the term nootropic.<ref name="Giurgea1977"/>
In academia, ] has been used to increase productivity, although its long-term effects have not been assessed in healthy individuals.<ref name=NatureProfessor/> Stimulants such as ] and ] are used on college campuses and by younger groups.<ref name=NatureProfessor/> 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%.<ref name=Nature2008/><ref name=StudentSurvey>{{cite journal|last=McCabe|first=Sean Esteban|coauthors=Knight, John R.; Teter, Christian J.; Wechsler, Henry|title=Non-medical use of prescription stimulants among US college students: prevalence and correlates from a national survey|journal=Addiction|date=January 1, 2005|volume=100|issue=1|pages=96–106|doi=10.1111/j.1360-0443.2005.00944.x|pmid=15598197|url=http://www.ncbi.nlm.nih.gov/pubmed/15598197|accessdate=August 15, 2013}}</ref> The use of prescription stimulants is especially prevalent among students attending academically competitive colleges and students who are members of a fraternity or sorority.<ref name=StudentSurvey/>


Giurgea stated that nootropic drugs should have the following characteristics:
Surveys suggest that 3–11% of American students and 0.7–4.5% of German students have used cognitive enhancers in their lifetime.<ref name="doi10.1371/journal.pone.0068821">{{cite doi|10.1371/journal.pone.0068821}}</ref><ref name="C4WDefault-10.3109/10826084.2012.751426">{{cite journal |url=http://informahealthcare.com/doi/abs/10.3109/10826084.2012.751426 |title=Cognitive Test Anxiety and Cognitive Enhancement: The Influence of Students’ Worries on Their Use of Performance-Enhancing Drugs |work=Substance Use & Misuse |volume = 48 |number = 3 |pages=220–232 |date=February 25, 2013 |publisher=Informa Healthcare New York |accessdate=April 5, 2014 |doi=10.3109/10826084.2012.751426 |first1=Sebastian |last1=Sattler |first2=Constantin |last2=Wiegel}}</ref>


# They should enhance ] and ].
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.<ref name="doi10.1371/journal.pone.0068821"/><ref name="C4WDefault-10.3109/10826084.2012.751426"/><ref name="C4WDefault-10.1186/1747-597X-9-8">{{cite web |url=http://www.substanceabusepolicy.com/content/9/1/8 |title=Evaluating the drivers of and obstacles to the willingness to use cognitive enhancement drugs: the influence of drug characteristics, social environment, and personal characteristics |date=February 1, 2014 |publisher=BioMed Central Ltd |issn=1747-597X |accessdate=April 5, 2014 |doi=10.1186/1747-597X-9-8 |issue=1 |volume=9 |page=8 |journal=Substance Abuse Treatment, Prevention, and Policy |first1=Sebastian |last1=Sattler |first2=Guido |last2=Mehlkop |first3=Peter |last3=Graeff |first4=Carsten |last4=Sauer}}</ref><ref name="PLOS ONE-10.1371/journal.pone.0071452">{{cite journal |url=http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0071452 |title=Impact of Contextual Factors and Substance Characteristics on Perspectives toward Cognitive Enhancement |date=August 5, 2013 |publisher=] |issn=1932-6203 |oclc=228234657 |accessdate=April 5, 2014 |journal=] |lccn=2006214532 |doi=10.1371/journal.pone.0071452 |issue=8 |volume=8 |page=e71452 |first1=Sebastian |last1=Sattler |first2=Cynthia |last2=Forlini |first3=Éric |last3=Racine |first4=Carsten |last4=Sauer}}</ref>
# They should enhance the resistance of learned behaviors or memories to conditions which tend to disrupt them (e.g. ], ]).
# They should protect the brain against various physical or chemical injuries.
# They should increase the efficacy of the tonic ] control mechanisms.
# They should lack the usual pharmacology of other ] drugs (e.g. ], motor stimulation) and possess few ]s and low ].


However, there is no globally accepted or clinical definition of a nootropic. Most compounds described as nootropic do not correspond to Giurgea's characteristics.<ref name="malik" />
==Hazards==
The main concern with ]s is ]s, and these concerns apply to cognitive-enhancing drugs as well. Cognitive enhancers are often taken for the long-term when little data is available.<ref name=NatureProfessor/> While certain ] compounds are suspected to have nootropic qualities, few side-effects, and a wide ] (low overdose risk),<ref name=BetterBrain>{{Cite journal|author=Malik R, Sangwan A, Saihgal R, Jindal DP, Piplani P |title=Towards better brain management: nootropics |journal=Curr. Med. Chem. |volume=14 |issue=2 |pages=123–31 |year=2007 |pmid=17266573 |doi= 10.2174/092986707779313408|url=http://www.bentham-direct.org/pages/content.php?CMC/2007/00000014/00000002/0001C.SGM}}</ref> other cognitive enhancers may be associated with a high incidence of adverse effects or a narrower therapeutic window (higher overdose risk). While addiction to stimulants is sometimes asserted to be a cause for concern,<ref name="pmid23164208">{{cite journal | author = Noble KA | title = Brain gain: adolescent use of stimulants for achievement | journal = J. Perianesth. Nurs. | volume = 27 | issue = 6 | pages = 415–9 |date=December 2012 | pmid = 23164208 | doi = 10.1016/j.jopan.2012.09.001 | url = }}</ref> a very large body of research on the therapeutic use of the "more addictive" psychostimulants indicate that addiction is fairly rare in therapeutic doses.<ref name="EncycOfPsychopharm">{{Cite book | author = Stolerman IP | editor = Stolerman IP | title = Encyclopedia of Psychopharmacology | year = 2010 | publisher = Springer | location = Berlin; London | isbn = 9783540686989 | page = 78}}</ref><ref name="Westfall">{{cite book | editor = Brunton LL, Chabner BA, Knollmann BC | title = Goodman & Gilman's Pharmacological Basis of Therapeutics | year = 2010 | publisher = McGraw-Hill | location = New York | isbn = 9780071624428 | author = Westfall DP, Westfall TC | section = Miscellaneous Sympathomimetic Agonists | sectionurl = http://www.accessmedicine.com/content.aspx?aID=16661601 | edition = 12th }}</ref><ref name="FDA Abuse & OD">{{cite web | title = Adderall XR Prescribing Information | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf | page = 11 | work = United States Food and Drug Administration |date=December 2013 | accessdate = December 30, 2013 }}</ref>


==Unproven marketing claims==
In the United States, ] or dietary supplements do not require safety or efficacy approval before being sold.<ref>{{Cite journal|author=Goldman P |title=Herbal medicines today and the roots of modern pharmacology |journal=Annals of Internal Medicine |volume=135 |issue=8 Pt 1 |pages=594–600 |year=2001 |pmid=11601931 |doi=10.7326/0003-4819-135-8_Part_1-200110160-00010}}</ref>
In the United States, nootropics are commonly advertised with unproven claims of effectiveness for improving cognition. Manufacturers' marketing claims for dietary supplements are usually not formally tested and verified by independent entities.<ref>{{cite web|title=Dietary Supplements: What You Need to Know|url=https://www.fda.gov/Food/DietarySupplements/UsingDietarySupplements/ucm109760.htm|publisher=US Food and Drug Administration|access-date=February 14, 2015}}</ref> In 2019, the US FDA and ] ] manufacturers and consumers about possible advertising fraud and marketing scams concerning nootropic supplement products.<ref name="ftc">{{cite web |date=February 11, 2019 |title=FTC and FDA Send Warning Letters to Companies Selling Dietary Supplements Claiming to Treat Alzheimer's Disease and Remediate or Cure Other Serious Illnesses Such as Parkinson's, Heart Disease, and Cancer |url=https://www.ftc.gov/news-events/press-releases/2019/02/ftc-fda-send-warning-letters-companies-selling-dietary |access-date=May 11, 2019 |publisher=US Food and Drug Administration, US Federal Trade Commission}}</ref><ref name="fda-fraud">{{cite web |date=December 22, 2018 |title=Health fraud scams: Unproven Alzheimer's disease products |url=https://www.fda.gov/consumers/health-fraud-scams/unproven-alzheimers-disease-products |access-date=May 11, 2019 |publisher=US Food and Drug Administration}}</ref><ref name="fda">{{cite web |url=https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/peak-nootropics-llc-aka-advanced-nootropics-565256-02052019 |title=FDA Warning Letter: Peak Nootropics LLC aka Advanced Nootropics | vauthors = Correll Jr WA |date=February 5, 2019 |publisher=Office of Compliance, Center for Food Safety and Applied Nutrition, Inspections, Compliance, Enforcement, and Criminal Investigations, US Food and Drug Administration |access-date=May 11, 2019}}</ref><ref name="fda2">{{cite web |url=https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/tek-naturals-565026-02042019 |title=FDA Warning Letter: TEK Naturals | vauthors = Correll Jr WA |date=February 5, 2019 |publisher=Office of Compliance, Center for Food Safety and Applied Nutrition, Inspections, Compliance, Enforcement, and Criminal Investigations, US Food and Drug Administration |access-date=May 11, 2019}}</ref> The FDA and FTC stated that some nootropic products had not been ] as a prescription drug effective for any medical purpose, were not proven to be safe, and were illegally marketed in the United States under violation of the ].<ref name=ftc/><ref name=fda-fraud/>


In 2018 in the United States, some nootropic supplements were identified as having misleading ingredients and illegal marketing.<ref name="schultz">{{cite web | vauthors = Schultz H |date=May 17, 2018 |title=Some shady ingredients find home in nootropics category |url=https://www.nutraingredients-usa.com/Article/2018/05/17/Some-shady-ingredients-find-home-in-nootropics-category# |access-date=May 11, 2019 |publisher=NutraIngredients-USA.com, William Reed Business Media Ltd}}</ref><ref name="heid">{{cite web | vauthors = Heid M |date=January 23, 2019 |title=Nootropics, or 'Smart Drugs,' Are Gaining Popularity. But Should You Take Them? |url=https://time.com/5509993/nootropics-smart-drugs-brain/ |access-date=May 12, 2019 |publisher=Time}}</ref> In 2019, the FDA and FTC warned manufacturers and consumers about possible advertising fraud and marketing scams concerning nootropic supplements.<ref name="ftc" /><ref name="fda-fraud" />
==Drugs==


Over the years 2010 to 2019, the FDA warned numerous supplement manufacturers about the illegal status of their products as unapproved drugs with no proven safety or efficacy at the doses listed on the products, together with misleading marketing.<ref name="ftc" /><ref name="fda-fraud" /><ref name="fda" /><ref name="fda2" /><ref name="cerebral">{{cite web |url=https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2010/ucm198452.htm |archive-url=https://wayback.archive-it.org/7993/20170112195041/https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2010/ucm198452.htm |url-status=dead |archive-date=January 12, 2017 |title=FDA Warning Letter: Cerebral Health LLC | vauthors = Singleton ER |date=January 7, 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=May 12, 2019}}</ref><ref name="unlimited" />
===Vitamins and supplements===


== Availability and prevalence ==
* ]&nbsp;–&nbsp;may influence cognitive function through an effect on ] and ] levels, as excess homocysteine has been associated with cognitive impairment and the B vitamins work to reduce homocysteine.<ref name=Selhub2000>{{cite journal |author= Selhub J, Bagley L, Miller J, Rosenberg I |title=B vitamins, homocysteine, and neurocognitive function in the elderly |journal=American Journal of Clinical Nutrition |volume=71 |issue=2 |pages=614S–620s |year=2000 |pmid=10681269}}</ref> A 2008 systematic review of trials found "little evidence of a beneficial impact" from supplements on cognitive function later in life.<ref>{{cite journal |author=Jia X, McNeill G, Avenell A |title=Does taking vitamin, mineral and fatty acid supplements prevent cognitive decline? A systematic review of randomized controlled trials |journal=J Hum Nutr Diet |volume=21 |issue=4 |pages=317–36 |date=August 2008 |pmid=18721399 |doi=10.1111/j.1365-277X.2008.00887.x |url=}}</ref>
In 2008, stimulants, such as caffeine, were the most commonly used nootropic agent.<ref name="Nature2008">{{cite journal | vauthors = Greely H, Sahakian B, Harris J, Kessler RC, Gazzaniga M, Campbell P, Farah MJ | title = Towards responsible use of cognitive-enhancing drugs by the healthy | journal = Nature | volume = 456 | issue = 7223 | pages = 702–705 | date = December 2008 | pmid = 19060880 | doi = 10.1038/456702a | s2cid = 3598099 | bibcode = 2008Natur.456..702G | oclc = 01586310 | url = https://pure.manchester.ac.uk/ws/files/28322116/POST-PEER-REVIEW-PUBLISHERS.PDF }}</ref> In 2016, the ] adopted a policy to discourage prescriptions of nootropics for healthy people, on the basis that the cognitive effects appear to be highly variable among individuals, are dose-dependent, and limited or modest at best.<ref name="ama">{{cite web |title=AMA confronts the rise of nootropics |url=https://www.ama-assn.org/press-center/press-releases/ama-confronts-rise-nootropics |publisher=American Medical Association |access-date=May 12, 2019 |date=June 14, 2016}}</ref> ], ] and ] have been sold as dietary supplements.<ref name="NeuroClin"/><ref name="JAMAIM"/><ref>{{cite journal | vauthors = Cohen PA, Avula B, Khan I | title = The unapproved drug centrophenoxine (meclofenoxate) in cognitive enhancement dietary supplements | journal = Clinical Toxicology | volume = 60 | issue = 10 | pages = 1156–1158 | date = October 2022 | pmid = 35959800 | doi = 10.1080/15563650.2022.2109485 | s2cid = 251516603 }}</ref>


==Adverse effects==
* ] (a ]) with ] and ] (]s)&nbsp;–&nbsp;concurrent supplemental use can protect and potentially improve brain function.<ref name="Review1">{{cite journal | author = Kidd PM | title = Omega-3 DHA and EPA for cognition, behavior, and mood: clinical findings and structural-functional synergies with cell membrane phospholipids | journal = Altern Med Rev | volume = 12 | issue = 3 | pages = 207–27 |date=September 2007 | pmid = 18072818 | doi = | url = }}</ref><ref name="RCT1">{{cite journal | author = Manor I, Magen A, Keidar D, Rosen S, Tasker H, Cohen T, Richter Y, Zaaroor-Regev D, Manor Y, Weizman A | title = The effect of phosphatidylserine containing Omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children: a double-blind placebo-controlled trial, followed by an open-label extension | journal = Eur. Psychiatry | volume = 27 | issue = 5 | pages = 335–42 |date=July 2012 | pmid = 21807480 | doi = 10.1016/j.eurpsy.2011.05.004 | url = }}</ref> DHA and EPA are compounds that support brain function and ], especially during brain development.<ref>{{cite journal | author= Sheila M. Innis | title= Dietary (n-3) fatty acids and brain development | journal= The journal of nutrition | volume=137 | issue=4 |date=April 2007}}</ref> A ] and a more recent ] on supplemental phosphatidylserine with DHA and EPA indicate that there are clinical benefits for those with ADHD,<ref name="Review1" /><ref name="RCT1" /> in addition to a range of other clinical applications.<ref name="Review1" /> However, ] reviews on the use of supplemental omega-3 fatty acids alone (''without'' phosphatidylserine) indicate that there is limited evidence of treatment benefits for individuals with ADHD<ref name="Cochrane ADHD">{{cite journal | author = Gillies D, Sinn JKh, Lad SS, Leach MJ, Ross MJ | title = Polyunsaturated fatty acids (PUFA) for attention deficit hyperactivity disorder (ADHD) in children and adolescents | journal = Cochrane Database Syst Rev | volume = 7 | issue = | pages = CD007986 | year = 2012 | pmid = 22786509 | doi = 10.1002/14651858.CD007986.pub2 | url = }}</ref> or other learning disorders.<ref name="Cochrane LD">{{cite journal | author = Tan ML, Ho JJ, Teh KH | title = Polyunsaturated fatty acids (PUFAs) for children with specific learning disorders | journal = Cochrane Database Syst Rev | volume = 12 | issue = | pages = CD009398 | year = 2012 | pmid = 23235675 | doi = 10.1002/14651858.CD009398.pub2 | url = }}</ref> A Norwegian study demonstrated a ''potential'' link between Omega-3 consumption during pregnancy and child intelligence test scores.<ref>''Pediatrics''. 2003 Jan;111(1) e39–44</ref><ref name="Chillot">Prevention Chillot yr.2004 vol.56 iss.1 pg. 122–129</ref>
The main concern with ]s and dietary supplements are ]s. Long-term safety evidence is typically unavailable for many nootropic compounds. ], piracetam and other compounds that are structurally related to piracetam, have few serious adverse effects and low ], but there is little evidence that they enhance cognition in people having no cognitive impairments.<ref name="Racetam efficacy review 2010">{{cite journal | vauthors = Malykh AG, Sadaie MR | title = Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders | journal = Drugs | volume = 70 | issue = 3 | pages = 287–312 | date = February 2010 | pmid = 20166767 | doi = 10.2165/11319230-000000000-00000 | s2cid = 12176745 }}</ref>


In the United States, dietary supplements may be marketed if the manufacturer can show that the supplement is ], and if the manufacturer does not make any claims about using the supplement to treat or prevent any disease or condition; supplements that contain drugs or advertise ]s are illegal under US law.<ref>{{cite journal | vauthors = Goldman P | title = Herbal medicines today and the roots of modern pharmacology | journal = Annals of Internal Medicine | volume = 135 | issue = 8 Pt 1 | pages = 594–600 | date = October 2001 | pmid = 11601931 | doi = 10.7326/0003-4819-135-8_Part_1-200110160-00010 | s2cid = 35766876 }}</ref>
* ]&nbsp;–&nbsp;has positive effects on cardiovascular health and may have positive effects on cognitive function separately; the active form of Vitamin D seems to be involved in brain development and in adult brain function. In particular, metabolic pathways for Vitamin D in the hippocampus and cerebellum have been found. Epidemiological data show that higher Vitamin D levels (>20&nbsp;ng/mL or 50&nbsp;nmol/L) are associated with better cognitive function, but do not seem to be associated with better memory performance.<ref>{{cite journal |author=Buell JS, Scott TM, Dawson-Hughes B, Dallal GE, Rosenberg IH, Folstein MF, Tucker KL |title=Vitamin D is associated with cognitive function in elders receiving home health services |journal=J Gerontol a Biol Sci Med Sci. |volume=64 |issue=8 |pages=888–95 |date=Aug 2009 |pmid=19377013 |url= |doi=10.1093/gerona/glp032 |pmc=2981461}}</ref> Vitamin D has also been shown to be necessary in the production of ].<ref>{{cite web | author=Thomas H. J. Burne, PhD | title= vitamin d and the brain |date=May 2013 | website= http://chemistry.beloit.edu/Ordman/nutrition/aln13/1305lpi.htm}}</ref>


===Stimulants=== ==Types==
{{anchor|Drugs}}
] are often seen as ''smart drugs,'' but may be more accurately termed ''productivity enhancers.'' These typically improve concentration and a few areas of cognitive performance, but only while the drug is still in the blood at therapeutic concentrations.
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* Anti-ADHD agents
** ] pharmaceuticals (], ], and ] ]])&nbsp;–&nbsp;] agonists that mimic the effect of endogenous ].<ref name="Miller">{{cite journal | author = Miller GM | title = The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity | journal = J. Neurochem. | volume = 116 | issue = 2 | pages = 164–176 |date=January 2011 | pmid = 21073468 | pmc = 3005101 | doi = 10.1111/j.1471-4159.2010.07109.x }}</ref> Benefits in ] and ] are evident in the general population, and especially in individuals with ADHD.<ref name="Malenka_2009">{{cite book| author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | page = 318 | edition = 2nd | chapter = Chapter 13: Higher Cognitive Function and Behavioral Control | quote=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.&nbsp;...&nbsp; 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&nbsp;...&nbsp;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&nbsp;...&nbsp;through indirect stimulation of dopamine and norepinephrine receptors.}}</ref><ref name="cognition enhancers">{{cite journal | author = Bidwell LC, McClernon FJ, Kollins SH | title = Cognitive enhancers for the treatment of ADHD | journal = Pharmacol. Biochem. Behav. | volume = 99 | issue = 2 | pages = 262–274 |date=August 2011 | pmid = 21596055 | pmc = 3353150 | doi = 10.1016/j.pbb.2011.05.002 }}</ref>
** ]&nbsp;–&nbsp;a ] that improves working memory and cognitive control.<ref name="Malenka_2009" /><ref name="cognition enhancers" />
* ]&nbsp;–&nbsp;wakefulness promoting agents; increase alertness, particularly in ] individuals<ref name="Mod" />
** ]<ref name="Mod">{{cite journal | author = Mereu M, Bonci A, Newman AH, Tanda G | title = The neurobiology of modafinil as an enhancer of cognitive performance and a potential treatment for substance use disorders | journal = Psychopharmacology (Berl.) | volume = 229 | issue = 3 | pages = 415–34 |date=October 2013 | pmid = 23934211 | doi = 10.1007/s00213-013-3232-4 | url = }}</ref>
** ]<ref name="Mod" />
* ] A meta-analysis of 41&nbsp;], ]-controlled studies concluded that ] or smoking had significant positive effects on fine motor, alerting attention-accuracy and response time (RT), orienting attention-RT, short-term episodic memory-accuracy, and working memory-RT.<ref>{{cite journal |title=Meta-analysis of the acute effects of nicotine and smoking on human performance |author=Heishman SJ, Kleykamp BA, Singleton EG |journal=] |volume=210 |issue=4 |pages=453–69 |date=June 2010 |accessdate=March 23, 2012 |pmid=20414766 |pmc=3151730 |doi=10.1007/s00213-010-1848-1}}</ref>
*]&nbsp;–&nbsp;most notably, ]&nbsp;–&nbsp;shown to increase alertness, performance, and in some studies, memory.<ref>{{Cite journal| author = Rogers, P. |title = Caffeine, mood and mental performance in everyday life|journal = Psychology Today| volume = 32|issue = 1| pages = 84–89|year = 2007| accessdate = November 1, 2009| doi = 10.1111/j.1467-3010.2007.00607.x}}</ref> Children and adults who consume low doses of caffeine showed increase alertness, yet a higher dose was needed to improve performance.<ref name=Kiefer2007>{{Cite journal| author = Kiefer, I.|title = Brain Food|journal = Scientific American Mind| volume = 18|issue = 5| pages = 58–63|year = 2007| url = http://www.nature.com/scientificamericanmind/journal/v18/n5/full/scientificamericanmind1007-58.html| accessdate = November 1, 2009 | doi = 10.1038/scientificamericanmind1007-58
}}</ref>


=== Central nervous system stimulants {{anchor|Xanthines|Stimulants}} ===
===Miscellaneous===
]s and ] of ] using low doses of certain ] 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 }}</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 ] as ] or ]s of ] or ].<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" />
* ] and ]&nbsp;–&nbsp;]s with neuroprotective properties, especially for those with ].<ref name="Neuroprotection review">{{cite journal | author = Naoi M, Maruyama W, Inaba-Hasegawa K | title = Revelation in the neuroprotective functions of rasagiline and selegiline: the induction of distinct genes by different mechanisms | journal = Expert Rev Neurother | volume = 13 | issue = 6 | pages = 671–84 |date=June 2013 | pmid = 23739004 | doi = 10.1586/ern.13.60 | url = }}</ref>
* ]{{snd}} systematic reviews and meta-analyses report that low-dose amphetamine may improve cognitive functions (e.g., ], ], ], and aspects of ]) in healthy people and in individuals with ].<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 ], in turn leading to improved ] in non-ADHD youth.<ref name="Systematic 2014 – Amph, MPH, Modafinil" /> It also improves ] (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" />
* ]&nbsp;–&nbsp;Tianeptine prevents stress-induced dendritic remodeling in various brain structures, enhances several metrics of cognition in animal models, and antagonizes alcohol's neurodegenerative effects.<ref name="pmid19704408">{{cite journal | author = McEwen BS, Chattarji S, Diamond DM, Jay TM, Reagan LP, Svenningsson P, Fuchs E | title = The neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation | journal = Mol. Psychiatry | volume = 15 | issue = 3 | pages = 237–49 |date=March 2010 | pmid = 19704408 | pmc = 2902200 | doi = 10.1038/mp.2009.80 | quote = 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.<br /><br />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).<br /><br />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)...}}</ref>
* ]{{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" />
* ]&nbsp;–&nbsp;]
* ] (] and ]){{snd}} are classified as "wakefulness-promoting agents"; modafinil may increase alertness, particularly in ] 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>

* ]{{snd}} a ] derivative that may improve ], ], and ], aspects of ], 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>
===Nutraceuticals===
* ]{{snd}} has been associated with improved alertness, attention, memory, and motor performance, according to a ].<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>
* ]&nbsp;–&nbsp;A neutraceutical herb with "neural tonic" and memory enhancing properties shown in humans in a double-blinded ]s.<ref name="Bacopa Review">{{cite journal |url=http://www.ncbi.nlm.nih.gov/pubmed/23772955 |title=Neuropharmacological review of the nootropic herb Bacopa monnieri. |date=Aug 2013 |accessdate=March 27, 2014 |doi=10.1089/rej.2013.1431 |issue=4 |volume=16 |pmid=23772955 |pmc=3746283 |pages=313–26 |journal=Rejuvenation Research |first1=Sebastian |last1=Aguiar |first2=Thomas |last2=Borowski}}</ref><ref name="PubMed-22747190">{{cite journal |url=http://www.ncbi.nlm.nih.gov/pubmed/22747190 |title=The cognitive-enhancing effects of Bacopa monnieri: a systematic review of randomized, controlled human clinical trials |date=July 2012 |accessdate=March 27, 2014 |doi=10.1089/acm.2011.0367 |issue=7 |volume=18 |pmid=22747190 |pmc= |pages=647–52 |journal=The Journal of Alternative and Complementary Medicine |first1=Matthew P. |last1=Pase |first2=James |last2=Kean |first3=Jerome |last3=Sarris |first4=Chris |last4=Neale |first5=Andrew B. |last5=Scholey |first6=Con |last6=Stough}}</ref><ref>{{Cite journal | last1 = Morgan | first1 = A. | last2 = Stevens | first2 = J. | doi = 10.1089/acm.2009.0342 | title = DoesBacopa monnieriImprove Memory Performance in Older Persons? Results of a Randomized, Placebo-Controlled, Double-Blind Trial | journal = The Journal of Alternative and Complementary Medicine | volume = 16 | issue = 7 | pages = 753–759 |date=July 2010 | pmid = 20590480 }}</ref>
* ]&nbsp;–&nbsp;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.<ref name="Neutraceuticals Review">{{Cite journal|author=Kennedy DO, Wightman EL |title=Herbal extracts and phytochemicals: plant secondary metabolites and the enhancement of human brain function |journal=Adv Nutr. |volume=2 |issue=1 |pages=32–50 |date=Jan 2011 |pmid=22211188 |doi=10.3945/an.110.000117}}</ref>
* ]&nbsp;–&nbsp;A ] of 29 RCTs stated "there is consistent evidence that chronic administration improves selective attention, some executive processes and long-term memory for verbal and non-verbal material."<ref>{{Cite journal|author=Kaschel R |title=Ginkgo biloba: specificity of neuropsychological improvement—a selective review in search of differential effects |journal=Hum Psychopharmacol |volume=24 |issue=5 |pages=345–70 |year=2009 |pmid=19551805 |doi=10.1002/hup.1037}}</ref>
* ]<ref name="Neutraceuticals Review" />
* ]<ref name="Neutraceuticals Review" />
* ]<ref name="Neutraceuticals Review" />
* ]<ref name="Neutraceuticals Review" />
* ]<ref name="Neutraceuticals Review" />
* ]&nbsp;–&nbsp;Anti-inflammatory, antibiotic, and neuroprotective antidepressant compound which has extremely low toxicity.<ref name="Neutraceuticals Review" />
* ]s&nbsp;–&nbsp;A double-blind, placebo-controlled study showed improvement in spatial working memory after administration of isoflavones.<ref name="PubMed-9071926">{{cite journal |url=http://www.ncbi.nlm.nih.gov/pubmed/19480732 |title=Soya isoflavone supplementation enhances spatial working memory in men. |date=Nov 2009 |publisher=] |accessdate=March 24, 2014 |doi=10.1017/S0007114509990201 |pmid=19480732 |issue=9 |volume=102 |pages=1348–54 |journal=Br J Nutr |first1=Aa |last1=Thorp |first2=N |last2=Sinn |first3=Jd |last3=Buckley |first4=Am |last4=Coates |first5=Pr |last5=Howe}}</ref> 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.<ref>{{cite journal |author=Gleason CE, Carlsson CM, Barnet JH, Meade SA, Setchell KD, Atwood CS, Johnson SC, Ries ML, Asthana S |title=A preliminary study of the safety, feasibility and cognitive efficacy of soy isoflavone supplements in older men and women |journal=Age Ageing |volume=38 |issue=1 |pages=86–93 |date=January 2009 |pmid=19054783 |pmc=2720778 |doi=10.1093/ageing/afn227}}</ref>
* ]&nbsp;–&nbsp;Stimulated ] in an ''in vitro'' experiment<ref name="pmid12675022">{{Cite journal|author=Kolotushkina EV, Moldavan MG, Voronin KY, Skibo GG |title=The influence of Hericium erinaceus extract on myelination process in vitro |journal=Fiziol Zh |volume=49 |issue=1 |pages=38–45 |year=2003 |pmid=12675022 |doi= |url=}}</ref> and stimulated ] in an ''in vitro'' experiment with human ] cells.<ref name="pmid18758067">{{Cite journal|author=Mori K, Obara Y, Hirota M, ''et al.'' |title=Nerve growth factor-inducing activity of Hericium erinaceus in 1321N1 human astrocytoma cells |journal=Biol. Pharm. Bull. |volume=31 |issue=9 |pages=1727–32 |date=September 2008 |pmid=18758067 |doi= 10.1248/bpb.31.1727|url=}}</ref>{{npsn|date=May 2014}} Also improved cognitive ability, in a double-blind, parallel-group, placebo-controlled trial.<ref name="pmid18844328">{{Cite journal|author=Mori K, Inatomi S, Ouchi K, Azumi Y, Tuchida T |title=Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: a double-blind placebo-controlled clinical trial |journal=Phytotherapy Research |volume=23 |issue=3 |pages=367–72 |date=March 2009 |pmid=18844328 |doi=10.1002/ptr.2634}}</ref>{{npsn|date=May 2014}}


===Racetams=== ===Racetams===
{{Main|Racetam}}
Racetams, such as piracetam, ], ], and ], are often marketed as cognitive enhancers and sold ].<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 ], although piracetam and aniracetam are known to act as ]s of ]s and appear to modulate ] 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>

According to the FDA,

<blockquote>Piracetam is not a ], mineral, ], herb or other ], 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>

===Cholinergics===
{{Main|Cholinergic}}
Some supposed nootropic substances are compounds and analogues of ], a ] of acetylcholine (a ]) and ] (a structural component of ]s).
* ] – 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 is a ] 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>
* ] – Compound consisting of choline and ]. 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>

==Herbs==
* '']''{{snd}} A 2017 meta-analysis showed no significant improvement in cognitive function.<ref name="pmid28878245">{{cite journal | vauthors = Puttarak P, Dilokthornsakul P, Saokaew S, Dhippayom T, Kongkaew C, Sruamsiri R, Chuthaputti A, Chaiyakunapruk N | title = Effects of Centella asiatica (L.) Urb. on cognitive function and mood related outcomes: A Systematic Review and Meta-analysis | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 10646 | date = September 2017 | pmid = 28878245 | pmc = 5587720 | doi = 10.1038/s41598-017-09823-9 | bibcode = 2017NatSR...710646P }}</ref> Clinical efficacy and safety have not been scientifically confirmed for this herb.<ref name="drugs">{{cite web|title=Gotu kola|url=https://www.drugs.com/npp/gotu-kola.html|publisher=Drugs.com|access-date=21 September 2023|date=23 January 2023}}</ref>
* '']''{{snd}} An extract of ''Ginkgo biloba'' leaf is marketed in ] form with claims it can enhance ] in people without known cognitive problems, although there is no high-quality evidence to support such effects on memory or attention in healthy people.<ref>{{cite journal | vauthors = Laws KR, Sweetnam H, Kondel TK | title = Is Ginkgo biloba a cognitive enhancer in healthy individuals? A meta-analysis | journal = Human Psychopharmacology | volume = 27 | issue = 6 | pages = 527–533 | date = November 2012 | pmid = 23001963 | doi = 10.1002/hup.2259 | s2cid = 6307491 }}</ref><ref name="nccih">{{cite web|url=http://nccih.nih.gov/health/ginkgo/ataglance.htm|date=September 2016|title=Ginkgo|publisher=National Center for Complementary and Integrative Health, US National Institutes of Health|access-date=July 9, 2018}}</ref>
* '']''{{snd}} A ] found possible "improvement of some aspects of cognitive function, behavior and quality of life", but 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."<ref>{{cite journal | vauthors = Geng J, Dong J, Ni H, Lee MS, Wu T, Jiang K, Wang G, Zhou AL, Malouf R | title = Ginseng for cognition | journal = The Cochrane Database of Systematic Reviews | issue = 12 | pages = CD007769 | date = December 2010 | pmid = 21154383 | doi = 10.1002/14651858.CD007769.pub2 }}</ref>

==Nutrients and dietary supplements==


* ]{{snd}} no cognition-enhancing effects in ] and older adults without ].<ref name="Systematic rev – B vitamins">{{cite journal | vauthors = Forbes SC, Holroyd-Leduc JM, Poulin MJ, Hogan DB | title = Effect of Nutrients, Dietary Supplements and Vitamins on Cognition: a Systematic Review and Meta-Analysis of Randomized Controlled Trials | journal = Canadian Geriatrics Journal | volume = 18 | issue = 4 | pages = 231–245 | date = December 2015 | pmid = 26740832 | pmc = 4696451 | doi = 10.5770/cgj.18.189 }}</ref>
The ] are structurally similar compounds, such as ], ], ], and ], which are often marketed as cognitive enhancers and sold ]. Racetams are often referred to as nootropics, but this property of the drug class is not well established.<ref name="NHM">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = 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 = 2nd }}</ref> The racetams have a poorly understood ]; however, piracetam and aniracetam are known to act as ]s of ]s and appear to modulate ] systems.<ref>{{Cite journal|author=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=Curr. Pharm. Des. |volume=8 |issue=2 |pages=125–38 |year=2002 |pmid=11812254 |doi=10.2174/1381612023396582 |url=}}</ref>
* ]: ] and ]{{snd}} two ] 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.<ref>{{cite journal | vauthors = Gillies D, Leach MJ, Perez Algorta G | title = Polyunsaturated fatty acids (PUFA) for attention deficit hyperactivity disorder (ADHD) in children and adolescents | journal = The Cochrane Database of Systematic Reviews | volume = 2023 | issue = 4 | pages = CD007986 | date = April 2023 | pmid = 37058600 | pmc = 10103546 | doi = 10.1002/14651858.CD007986.pub3 }}</ref><ref name="Cochrane LD">{{cite journal | vauthors = Tan ML, Ho JJ, Teh KH | title = Polyunsaturated fatty acids (PUFAs) for children with specific learning disorders | journal = The Cochrane Database of Systematic Reviews | volume = 12 | pages = CD009398 | date = December 2012 | pmid = 23235675 | doi = 10.1002/14651858.CD009398.pub2 | veditors = Tan ML }}</ref> Two other systematic reviews found no cognition-enhancing effects in the general population.<ref name="Systematic rev – B vitamins" /><ref name="Systematic review: Omega-3s">{{cite journal | vauthors = Cooper RE, Tye C, Kuntsi J, Vassos E, Asherson P | title = Omega-3 polyunsaturated fatty acid supplementation and cognition: A systematic review and meta-analysis | journal = Journal of Psychopharmacology | volume = 29 | issue = 7 | pages = 753–763 | date = July 2015 | pmid = 26040902 | doi = 10.1177/0269881115587958 | s2cid = 358375 | url = https://kclpure.kcl.ac.uk/portal/en/publications/dcd51fd9-ba02-4e7c-b84e-6b2086ae91af }}</ref>
* ]{{snd}} no cognition-enhancing effects in middle-aged and older adults without ].<ref name="Systematic rev – B vitamins" />
* ]{{snd}} no cognition-enhancing effects in middle-aged and older adults without ].<ref name="Systematic rev – B vitamins" />
* ]{{snd}} no cognition-enhancing effects in middle-aged and older adults without ].<ref name="Systematic rev – B vitamins" />


==See also== == See also ==
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==References== == References ==
{{Reflist|2}} {{Reflist}}
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==External links== == External links ==
{{wiktionary|nootropic}}
* {{cite journal |url=http://www.nature.com/nature/journal/v456/n7223/full/456702a.html |title=Towards responsible use of cognitive-enhancing drugs by the healthy |work=] |date=December 10, 2008 |publisher=] |issn=1476-4687 |oclc=01586310 |bibcode = 2008Natur.456..702G |accessdate=March 25, 2014 |doi=10.1038/456702a |pages=702–5 |volume=456 |issue=7223 |subscription=yes |first1=Henry |last1=Greely |first2=Barbara |last2=Sahakian |first3=John |last3=Harris |first4=Ronald C. |last4=Kessler |first5=Michael |last5=Gazzaniga |first6=Philip |last6=Campbell |first7=Martha J. |last7=Farah}}
* {{Commons category-inline|Nootropics}}


{{Major Drug Groups}}
{{Psychostimulants, agents used for ADHD and nootropics}}
{{Authority control}}


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Latest revision as of 18:47, 1 January 2025

Compound intended to improve cognitive function

Illustration of Coffea arabica plant and seedsCaffeine from the Coffea arabica plant is the world's most consumed nootropic.

Nootropics (/noʊ.əˈtroʊpɪks/ noh-ə-TROHP-iks or /noʊ.əˈtrɒpɪks/ noh-ə-TROP-iks), colloquially brain supplements, smart drugs and cognitive enhancers, are natural, semisynthetic or synthetic compounds which purportedly improve cognitive functions, such as executive functions, attention or memory.

While commonly in the form of dietary supplements, nutraceuticals or energy drinks, some nootropic compounds are prescription and non-prescription drugs in various countries.

In the United States, nootropics are commonly advertised with unproven claims of effectiveness for improving cognition. The Federal Trade Commission and FDA have warned manufacturers and consumers about possible advertising fraud and marketing scams concerning nootropic supplements.

History of term

The term nootropic is derived from Ancient Greek νόος (nóos) 'mind' and τροπή (tropḗ) 'turning'.

The first documented use of "nootropic" in reference to substances purported to increase cognitive functions was by Corneliu E. Giurgea in 1972. When researching a new compound, Giurgea found a spectrum of effects that did not align with any psychotropic drug category, leading to his proposal of a new category and the concept of the term nootropic.

Giurgea stated that nootropic drugs should have the following characteristics:

  1. They should enhance learning and memory.
  2. They should enhance the resistance of learned behaviors or memories to conditions which tend to disrupt them (e.g. electroconvulsive shock, hypoxia).
  3. They should protect the brain against various physical or chemical injuries.
  4. They should increase the efficacy of the tonic cortical control mechanisms.
  5. They should lack the usual pharmacology of other psychotropic drugs (e.g. sedation, motor stimulation) and possess few adverse effects and low toxicity.

However, there is no globally accepted or clinical definition of a nootropic. Most compounds described as nootropic do not correspond to Giurgea's characteristics.

Unproven marketing claims

In the United States, nootropics are commonly advertised with unproven claims of effectiveness for improving cognition. Manufacturers' marketing claims for dietary supplements are usually not formally tested and verified by independent entities. In 2019, the US FDA and FTC warned manufacturers and consumers about possible advertising fraud and marketing scams concerning nootropic supplement products. The FDA and FTC stated that some nootropic products had not been approved as a prescription drug effective for any medical purpose, were not proven to be safe, and were illegally marketed in the United States under violation of the Federal Food, Drug, and Cosmetic Act.

In 2018 in the United States, some nootropic supplements were identified as having misleading ingredients and illegal marketing. In 2019, the FDA and FTC warned manufacturers and consumers about possible advertising fraud and marketing scams concerning nootropic supplements.

Over the years 2010 to 2019, the FDA warned numerous supplement manufacturers about the illegal status of their products as unapproved drugs with no proven safety or efficacy at the doses listed on the products, together with misleading marketing.

Availability and prevalence

In 2008, stimulants, such as caffeine, were the most commonly used nootropic agent. In 2016, the American Medical Association adopted a policy to discourage prescriptions of nootropics for healthy people, on the basis that the cognitive effects appear to be highly variable among individuals, are dose-dependent, and limited or modest at best. Piracetam, noopept and meclofenoxate have been sold as dietary supplements.

Adverse effects

The main concern with pharmaceutical drugs and dietary supplements are adverse effects. Long-term safety evidence is typically unavailable for many nootropic compounds. 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 people having no cognitive impairments.

In the United States, dietary supplements may be marketed if the manufacturer can show that the supplement is generally recognized as safe, and if the manufacturer does not make any claims about using the supplement to treat or prevent any disease or condition; supplements that contain drugs or advertise health claims are illegal under US law.

Types

Central nervous system stimulants

Systematic reviews 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. In particular, the classes of stimulants that demonstrate possible cognition-enhancing effects in humans have evidence in vitro as direct agonists or indirect agonists of dopamine receptor D1 or adrenoceptor A2. Relatively high doses of stimulants cause cognitive deficits.

  • Amphetamine – 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) in healthy people and in individuals with ADHD. A 2014 systematic review 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 required a high degree of effort.
  • Caffeine – a meta-analysis found an increase in alertness and attentional performance.
  • Eugeroics (armodafinil and modafinil) – 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. 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. Modafinil does not improve mood or motivation in sleep-deprived or non-sleep deprived individuals.
  • Methylphenidate – a benzylpiperidine derivative that may improve working memory, episodic memory, and inhibitory control, aspects of attention, and planning latency in healthy people. It also may improve task saliency and performance on tedious tasks. At above optimal doses, methylphenidate has off–target effects that decrease learning.
  • Nicotine – has been associated with improved alertness, attention, memory, and motor performance, according to a meta-analysis. 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.

Racetams

Main article: Racetam

Racetams, such as piracetam, oxiracetam, phenylpiracetam, and aniracetam, are often marketed as cognitive enhancers and sold over the counter. A 2019 study found that piracetam supplements sold in the United States were inaccurately labeled. 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. The racetams have poorly understood mechanisms, although piracetam and aniracetam are known to act as positive allosteric modulators of AMPA receptors and appear to modulate cholinergic systems.

According to the FDA,

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.

Cholinergics

Main article: Cholinergic

Some supposed nootropic substances are compounds and analogues of choline, a precursor of acetylcholine (a neurotransmitter) and phosphatidylcholine (a structural component of cell membranes).

  • Alpha-GPC – L-alpha glycerylphosphorylcholine has been studied only in the context of cognitive performance alongside other substances such as caffeine.
  • 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.
  • 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.

Herbs

  • Centella asiatica – A 2017 meta-analysis showed no significant improvement in cognitive function. Clinical efficacy and safety have not been scientifically confirmed for this herb.
  • Ginkgo biloba – An extract of Ginkgo biloba leaf is marketed in dietary supplement form with claims it can enhance cognitive function in people without known cognitive problems, although there is no high-quality evidence to support such effects on memory or attention in healthy people.
  • Panax ginseng – A Cochrane review found possible "improvement of some aspects of cognitive function, behavior and quality of life", but 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."

Nutrients and dietary supplements

See also

References

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  43. ^ Forbes SC, Holroyd-Leduc JM, Poulin MJ, Hogan DB (December 2015). "Effect of Nutrients, Dietary Supplements and Vitamins on Cognition: a Systematic Review and Meta-Analysis of Randomized Controlled Trials". Canadian Geriatrics Journal. 18 (4): 231–245. doi:10.5770/cgj.18.189. PMC 4696451. PMID 26740832.
  44. Gillies D, Leach MJ, Perez Algorta G (April 2023). "Polyunsaturated fatty acids (PUFA) for attention deficit hyperactivity disorder (ADHD) in children and adolescents". The Cochrane Database of Systematic Reviews. 2023 (4): CD007986. doi:10.1002/14651858.CD007986.pub3. PMC 10103546. PMID 37058600.
  45. Tan ML, Ho JJ, Teh KH (December 2012). Tan ML (ed.). "Polyunsaturated fatty acids (PUFAs) for children with specific learning disorders". The Cochrane Database of Systematic Reviews. 12: CD009398. doi:10.1002/14651858.CD009398.pub2. PMID 23235675.
  46. Cooper RE, Tye C, Kuntsi J, Vassos E, Asherson P (July 2015). "Omega-3 polyunsaturated fatty acid supplementation and cognition: A systematic review and meta-analysis". Journal of Psychopharmacology. 29 (7): 753–763. doi:10.1177/0269881115587958. PMID 26040902. S2CID 358375.

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