In the United States, nootropics can beover-the-counter drugs and commonly advertised with unproven claims of effectiveness for improving cognition. TheFederal Trade Commission andFDA have warned manufacturers and consumers about possibleadvertising fraud andmarketing scams concerning nootropic supplements.[2][3] Nootropics include bothprescription drugs anddietary supplements marketed to enhance brain function, but whileFDA-approved drugs have proven benefits and oversight, many dietary supplements lack evidence, may contain unapproved or hiddendrugs, and pose safety and regulatory risks.[4]
The first documented use of "nootropic" in reference to substances purported to increase cognitive functions was byCorneliu E. Giurgea in 1972.[5][6][7] 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.[6]
Giurgea stated that nootropic drugs should have the following characteristics:
However, there is no globally accepted or clinical definition of a nootropic. Most compounds described as nootropic do not correspond to Giurgea's characteristics.[7]
Nootropics include bothprescription drugs anddietary supplements marketed to enhance brain function, but whileFDA-approved drugs have proven benefits and oversight, many dietary supplements lack evidence, may contain unapproved or hiddendrugs, and pose safety and regulatory risks.[4]
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.[8] In 2019, the US FDA andFTCwarned manufacturers and consumers about possible advertising fraud and marketing scams concerning nootropic supplement products.[2][3][9][10] The FDA and FTC stated that some nootropic products had not beenapproved 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 theFederal Food, Drug, and Cosmetic Act.[2][3]
In 2018 in the United States, some nootropic supplements were identified as having misleading ingredients and illegal marketing.[11][12] In 2019, the FDA and FTC warned manufacturers and consumers about possible advertising fraud and marketing scams concerning nootropic supplements.[2][3]
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.[2][3][9][10][13][14]
In 2008, stimulants, such as caffeine, were the most commonly used nootropic agent.[15] In 2016, theAmerican 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.[16]Piracetam,noopept andmeclofenoxate have been sold as dietary supplements.[17][18][19]
The main concern withpharmaceutical drugs and dietary supplements areadverse effects, including the potential forpsychological dependence. 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 lowtoxicity, but there is little evidence that they enhance cognition in people having no cognitive impairments.[20]
In the United States, dietary supplements may be marketed if the manufacturer can show that the supplement isgenerally 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 advertisehealth claims are illegal under US law.[21]
Caffeine – a meta-analysis found an increase in alertness and attentional performance.[27][25]
Eugeroics (armodafinil andmodafinil) – are classified as "wakefulness-promoting agents"; modafinil may increase alertness, particularly insleep-deprived individuals, and may improve reasoning and problem solving in non-ADHD youth.[24] 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.[28] Modafinil does not improve mood or motivation in sleep-deprived or non-sleep deprived individuals.[29]
Nicotine – has been associated with improved alertness, attention, memory, and motor performance, according to ameta-analysis.[31] 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.[32]
Choline bitartrate – Choline bitartrate is atartaric 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.[33]
Citicoline – Compound consisting of choline andcytidine. 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.[34][35]
Racetams, such as piracetam,oxiracetam,phenylpiracetam, andaniracetam, are often marketed as cognitive enhancers and soldover the counter.[17][18] A 2019 study found that piracetam supplements sold in the United States were inaccurately labeled.[18] 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.[36] The racetams have poorly understoodmechanisms, although piracetam and aniracetam are known to act aspositive allosteric modulators ofAMPA receptors and appear to modulatecholinergic systems.[37] Similar compounds, such asnoopept andaloracetam, do not meet the chemical definition for being a racetam, though they are considered "racetam-like" due to their high similarity.[38]
According to the FDA,
Piracetam is not avitamin, mineral,amino acid, herb or otherbotanical, 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.[14]
Centella asiatica – A 2017 meta-analysis showed no significant improvement in cognitive function.[39] Clinical efficacy and safety have not been scientifically confirmed for this herb.[40]
Ginkgo biloba – An extract ofGinkgo biloba leaf is marketed indietary supplement form with claims it can enhancecognitive 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.[41][42]
Panax ginseng – ACochrane 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 ofPanax ginseng in healthy participants and no high quality evidence about its efficacy in patients with dementia."[43]
Omega-3 fatty acids:DHA andEPA – twoCochrane 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.[45][46] Two other systematic reviews found no cognition-enhancing effects in the general population.[44][47]
^abGiurgea C (1972). "[Pharmacology of integrative activity of the brain. Attempt at nootropic concept in psychopharmacology]".Actualites Pharmacologiques (in French).25:115–156.PMID4541214.
^abcGiurgea C, Salama M (January 1, 1977). "Nootropic drugs".Progress in Neuro-Psychopharmacology.1 (3):235–247.doi:10.1016/0364-7722(77)90046-7.The term "nootropic" (noos = mind; tropein = towards) was proposed by us (Giurgea, 1972,1973) to designate psychotropic drugs
^abCorrell Jr WA (February 5, 2019)."FDA Warning Letter: Peak Nootropics LLC aka Advanced Nootropics". Office of Compliance, Center for Food Safety and Applied Nutrition, Inspections, Compliance, Enforcement, and Criminal Investigations, US Food and Drug Administration. RetrievedMay 11, 2019.[dead link]
^abCorrell Jr WA (February 5, 2019)."FDA Warning Letter: TEK Naturals". Office of Compliance, Center for Food Safety and Applied Nutrition, Inspections, Compliance, Enforcement, and Criminal Investigations, US Food and Drug Administration. RetrievedMay 11, 2019.[dead link]
^Singleton ER (January 7, 2010)."FDA Warning Letter: Cerebral Health LLC". Office of Compliance, Center for Food Safety and Applied Nutrition, Inspections, Compliance, Enforcement, and Criminal Investigations, US Food and Drug Administration. Archived fromthe original on January 12, 2017. RetrievedMay 12, 2019.
^abJohn Gridley (August 30, 2010)."FDA Warning Letter: Unlimited Nutrition". Office of Compliance, Center for Food Safety and Applied Nutrition, Inspections, Compliance, Enforcement, and Criminal Investigations, US Food and Drug Administration. Archived fromthe original on January 12, 2017. RetrievedApril 5, 2016.
^Cohen PA, Avula B, Khan I (October 2022). "The unapproved drug centrophenoxine (meclofenoxate) in cognitive enhancement dietary supplements".Clinical Toxicology.60 (10):1156–1158.doi:10.1080/15563650.2022.2109485.PMID35959800.S2CID251516603.
^abcdeMalenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "14: Higher Cognitive Function and Behavioral Control".Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3 ed.). New York: McGraw-Hill Medical.ISBN978-0-07-182770-6.
^Battleday RM, Brem AK (November 2015). "Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review".European Neuropsychopharmacology.25 (11):1865–1881.doi:10.1016/j.euroneuro.2015.07.028.PMID26381811.S2CID23319688.
^Franco-Maside A, Caamaño J, Gómez MJ, Cacabelos R (October 1994). "Brain mapping activity and mental performance after chronic treatment with CDP-choline in Alzheimer's disease".Methods and Findings in Experimental and Clinical Pharmacology.16 (8):597–607.PMID7760585.
^Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY (eds.).Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2 ed.). New York: McGraw-Hill Medical. p. 454.ISBN978-0-07-148127-4.
^Gualtieri F, Manetti D, Romanelli MN, Ghelardini C (2002). "Design and study of piracetam-like nootropics, controversial members of the problematic class of cognition-enhancing drugs".Current Pharmaceutical Design.8 (2):125–138.doi:10.2174/1381612023396582.PMID11812254.
^"Gotu kola". Drugs.com. January 23, 2023. RetrievedSeptember 21, 2023.
^Laws KR, Sweetnam H, Kondel TK (November 2012). "Is Ginkgo biloba a cognitive enhancer in healthy individuals? A meta-analysis".Human Psychopharmacology.27 (6):527–533.doi:10.1002/hup.2259.PMID23001963.S2CID6307491.
^"Ginkgo". National Center for Complementary and Integrative Health, US National Institutes of Health. September 2016. RetrievedJuly 9, 2018.
^Geng J, Dong J, Ni H, Lee MS, Wu T, Jiang K, Wang G, Zhou AL, Malouf R (December 2010). "Ginseng for cognition".The Cochrane Database of Systematic Reviews (12) CD007769.doi:10.1002/14651858.CD007769.pub2.PMID21154383.
^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.PMID23235675.
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