Chemistry:Nootropic

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Short description: Compound intended to improve cognitive function
Illustration of Coffea arabica plant and seeds
Caffeine 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[1]) (colloquial: 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,[2] some nootropic compounds are prescription and non-prescription drugs in various countries.

In the United States, the Federal Trade Commission and FDA have warned manufacturers and consumers about possible advertising fraud and marketing scams concerning nootropic supplements.[3][4]

Definition and history

The term nootropic is derived from grc νόος (nóos) 'mind', and τροπή (tropḗ) 'turning'.[1][5][6]

The first documented use of "nootropic" in reference to substances purported to increase cognitive functions was by Corneliu 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:

  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.

There is no globally accepted or clinical definition of a nootropic. The colloquialism of the term nootropic refers to compounds outside the bounds of Giurgea's characteristics.[7]

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.[8] In 2019, the US FDA and FTC warned manufacturers and consumers about possible advertising fraud and marketing scams concerning nootropic supplement products.[3][4][9][10] 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.[3][4]

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.[3][4]

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.[3][4][9][10][13][14]

Availability and prevalence

In 2008, stimulants, such as caffeine, were the most commonly used nootropic agent.[15] 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.[16] Piracetam, noopept and meclofenoxate have been sold as dietary supplements.[2][17][18]

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.[19]

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.[20]

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.[21][22][23] 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.[21][22][24][25] Relatively high doses of stimulants cause cognitive deficits.[24][25]

  • 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.[21][22][23][25] 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.[23] It also improves task saliency (motivation to perform a task) and performance on tedious tasks that required a high degree of effort.[22][24][25]
  • Caffeine – a meta-analysis found an increase in alertness and attentional performance.[26][24]
  • 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.[23] 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.[27] Modafinil does not improve mood or motivation in sleep-deprived or non-sleep deprived individuals.[28]
  • Methylphenidate – a benzylpiperidine derivative that may improve working memory, episodic memory, and inhibitory control, aspects of attention, and planning latency in healthy people.[21][23] It also may improve task saliency and performance on tedious tasks.[25] At above optimal doses, methylphenidate has off–target effects that decrease learning.[29]
  • Nicotine – has been associated with improved alertness, attention, memory, and motor performance, according to a meta-analysis.[30] 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.[31]

Racetams

Racetams, such as piracetam, oxiracetam, phenylpiracetam, and aniracetam, are often marketed as cognitive enhancers and sold over the counter.[2][17] A 2019 study found that piracetam supplements sold in the United States were inaccurately labeled.[17] 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.[32] 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.[33]

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.[14]

Cholinergics

Main page: Biology: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.[34]
  • 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.[35]
  • 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.[36][37]

Herbs

  • Centella asiatica – A 2017 meta-analysis showed no significant improvement in cognitive function.[38] Clinical efficacy and safety have not been scientifically confirmed for this herb.[39]
  • 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.[40][41]
  • 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."[42]

Nutrients and dietary supplements

  • Folate – no cognition-enhancing effects in middle-aged and older adults without folate deficiency.[43]
  • Omega-3 fatty acids: DHA and EPA – two Cochrane Collaboration reviews on the use of supplemental omega-3 fatty acids for ADHD and learning disorders conclude that there is limited evidence of treatment benefits for either disorder.[44][45] Two other systematic reviews found no cognition-enhancing effects in the general population.[43][46]
  • Vitamin B12 – no cognition-enhancing effects in middle-aged and older adults without B12 deficiency.[43]
  • Vitamin B6 – no cognition-enhancing effects in middle-aged and older adults without B6 deficiency.[43]
  • Vitamin E – no cognition-enhancing effects in middle-aged and older adults without vitamin E deficiency.[43]

See also

References

  1. ↑ 1.0 1.1 "Nootropic" (in en). Oxford English Dictionary. 2024. https://www.oed.com/search/advanced/Meanings?scope=HistoricalThesaurus&q=nootropic. Retrieved 14 January 2024. 
  2. ↑ 2.0 2.1 2.2 "Five Unapproved Drugs Found in Cognitive Enhancement Supplements". Neurology. Clinical Practice 11 (3): e303–e307. June 2021. doi:10.1212/CPJ.0000000000000960. PMID 34484905. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "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". US Food and Drug Administration, US Federal Trade Commission. February 11, 2019. https://www.ftc.gov/news-events/press-releases/2019/02/ftc-fda-send-warning-letters-companies-selling-dietary. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 "Health fraud scams: Unproven Alzheimer's disease products". US Food and Drug Administration. December 22, 2018. https://www.fda.gov/consumers/health-fraud-scams/unproven-alzheimers-disease-products. 
  5. ↑ 5.0 5.1 "[Pharmacology of integrative activity of the brain. Attempt at nootropic concept in psychopharmacology]" (in fr). Actualites Pharmacologiques 25: 115–156. 1972. PMID 4541214. 
  6. ↑ 6.0 6.1 6.2 "Nootropic drugs". Progress in Neuro-Psychopharmacology 1 (3): 235–247. January 1, 1977. 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". 
  7. ↑ 7.0 7.1 "Nootropics as Cognitive Enhancers: Types, Dosage and Side Effects of Smart Drugs". Nutrients 14 (16): 3367. August 2022. doi:10.3390/nu14163367. PMID 36014874. 
  8. ↑ "Dietary Supplements: What You Need to Know". US Food and Drug Administration. https://www.fda.gov/Food/DietarySupplements/UsingDietarySupplements/ucm109760.htm. 
  9. ↑ 9.0 9.1 "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. February 5, 2019. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/peak-nootropics-llc-aka-advanced-nootropics-565256-02052019. 
  10. ↑ 10.0 10.1 "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. February 5, 2019. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/tek-naturals-565026-02042019. 
  11. ↑ "Some shady ingredients find home in nootropics category". NutraIngredients-USA.com, William Reed Business Media Ltd. May 17, 2018. https://www.nutraingredients-usa.com/Article/2018/05/17/Some-shady-ingredients-find-home-in-nootropics-category#. 
  12. ↑ "Nootropics, or 'Smart Drugs,' Are Gaining Popularity. But Should You Take Them?". Time. January 23, 2019. http://time.com/5509993/nootropics-smart-drugs-brain/. 
  13. ↑ "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. January 7, 2010. https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2010/ucm198452.htm. 
  14. ↑ 14.0 14.1 John Gridley (30 August 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. https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2010/ucm225605.htm. 
  15. ↑ "Towards responsible use of cognitive-enhancing drugs by the healthy". Nature 456 (7223): 702–705. December 2008. doi:10.1038/456702a. OCLC 01586310. PMID 19060880. Bibcode: 2008Natur.456..702G. https://pure.manchester.ac.uk/ws/files/28322116/POST-PEER-REVIEW-PUBLISHERS.PDF. 
  16. ↑ "AMA confronts the rise of nootropics". American Medical Association. June 14, 2016. https://www.ama-assn.org/press-center/press-releases/ama-confronts-rise-nootropics. 
  17. ↑ 17.0 17.1 17.2 "Presence of Piracetam in Cognitive Enhancement Dietary Supplements". JAMA Internal Medicine 180 (3): 458–459. March 2020. doi:10.1001/jamainternmed.2019.5507. PMID 31764936. 
  18. ↑ "The unapproved drug centrophenoxine (meclofenoxate) in cognitive enhancement dietary supplements". Clinical Toxicology 60 (10): 1156–1158. October 2022. doi:10.1080/15563650.2022.2109485. PMID 35959800. 
  19. ↑ "Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders". Drugs 70 (3): 287–312. February 2010. doi:10.2165/11319230-000000000-00000. PMID 20166767. 
  20. ↑ "Herbal medicines today and the roots of modern pharmacology". Annals of Internal Medicine 135 (8 Pt 1): 594–600. October 2001. doi:10.7326/0003-4819-135-8_Part_1-200110160-00010. PMID 11601931. 
  21. ↑ 21.0 21.1 21.2 21.3 "The cognition-enhancing effects of psychostimulants involve direct action in the prefrontal cortex". Biological Psychiatry 77 (11): 940–950. June 2015. doi:10.1016/j.biopsych.2014.09.013. PMID 25499957. 
  22. ↑ 22.0 22.1 22.2 22.3 "Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis". Journal of Cognitive Neuroscience 27 (6): 1069–1089. June 2015. doi:10.1162/jocn_a_00776. PMID 25591060. https://repository.upenn.edu/neuroethics_pubs/130. 
  23. ↑ 23.0 23.1 23.2 23.3 23.4 "Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: a systematic review". Addiction 109 (4): 547–557. April 2014. doi:10.1111/add.12460. PMID 24749160. 
  24. ↑ 24.0 24.1 24.2 24.3 "Psychostimulants and cognition: a continuum of behavioral and cognitive activation". Pharmacological Reviews 66 (1): 193–221. January 2014. doi:10.1124/pr.112.007054. PMID 24344115. 
  25. ↑ 25.0 25.1 25.2 25.3 25.4 "14: Higher Cognitive Function and Behavioral Control". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3 ed.). New York: McGraw-Hill Medical. 2015. ISBN 9780071827706. 
  26. ↑ "Acute effects of tea constituents L-theanine, caffeine, and epigallocatechin gallate on cognitive function and mood: a systematic review and meta-analysis". Nutrition Reviews 72 (8): 507–522. August 2014. doi:10.1111/nure.12120. PMID 24946991. 
  27. ↑ "Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review". European Neuropsychopharmacology 25 (11): 1865–1881. November 2015. doi:10.1016/j.euroneuro.2015.07.028. PMID 26381811. 
  28. ↑ "Does modafinil improve cognitive functioning in healthy individuals?". Rethinking Cognitive Enhancement. Oxford University Press. 2017. p. 116. ISBN 9780198727392. https://books.google.com/books?id=aAIXDgAAQBAJ&pg=PA116. 
  29. ↑ "Performance enhancement at the cost of potential brain plasticity: neural ramifications of nootropic drugs in the healthy developing brain". Frontiers in Systems Neuroscience 8: 38. 2014. doi:10.3389/fnsys.2014.00038. PMID 24860437. 
  30. ↑ "Meta-analysis of the acute effects of nicotine and smoking on human performance". Psychopharmacology 210 (4): 453–469. July 2010. doi:10.1007/s00213-010-1848-1. PMID 20414766. 
  31. ↑ Pasetes, Sarah V.; Ling, Pamela M.; Apollonio, Dorie E. (January 2020). "Cognitive performance effects of nicotine and industry affiliation: a systematic review" (in en). Substance Abuse: Research and Treatment 14: 117822182092654. doi:10.1177/1178221820926545. ISSN 1178-2218. PMID 32547048. 
  32. ↑ Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2 ed.). New York: McGraw-Hill Medical. 2009. p. 454. ISBN 9780071481274. 
  33. ↑ "Design and study of piracetam-like nootropics, controversial members of the problematic class of cognition-enhancing drugs". Current Pharmaceutical Design 8 (2): 125–138. 2002. doi:10.2174/1381612023396582. PMID 11812254. 
  34. ↑ "The effects of alpha-glycerylphosphorylcholine, caffeine or placebo on markers of mood, cognitive function, power, speed, and agility". Journal of the International Society of Sports Nutrition 12 (Suppl 1): P41. September 21, 2015. doi:10.1186/1550-2783-12-S1-P41. ISSN 1550-2783. 
  35. ↑ "No Acute Effects of Choline Bitartrate Food Supplements on Memory in Healthy, Young, Human Adults". PLOS ONE 11 (6): e0157714. June 24, 2016. doi:10.1371/journal.pone.0157714. PMID 27341028. Bibcode: 2016PLoSO..1157714L. 
  36. ↑ "Citicoline (Cognizin) in the treatment of cognitive impairment". Clinical Interventions in Aging 1 (3): 247–251. September 2006. doi:10.2147/ciia.2006.1.3.247. PMID 18046877. 
  37. ↑ "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. October 1994. PMID 7760585. 
  38. ↑ "Effects of Centella asiatica (L.) Urb. on cognitive function and mood related outcomes: A Systematic Review and Meta-analysis". Scientific Reports 7 (1): 10646. September 2017. doi:10.1038/s41598-017-09823-9. PMID 28878245. Bibcode: 2017NatSR...710646P. 
  39. ↑ "Gotu kola". Drugs.com. 23 January 2023. https://www.drugs.com/npp/gotu-kola.html. 
  40. ↑ "Is Ginkgo biloba a cognitive enhancer in healthy individuals? A meta-analysis". Human Psychopharmacology 27 (6): 527–533. November 2012. doi:10.1002/hup.2259. PMID 23001963. 
  41. ↑ "Ginkgo". National Center for Complementary and Integrative Health, US National Institutes of Health. September 2016. http://nccih.nih.gov/health/ginkgo/ataglance.htm. 
  42. ↑ "Ginseng for cognition". The Cochrane Database of Systematic Reviews (12): CD007769. December 2010. doi:10.1002/14651858.CD007769.pub2. PMID 21154383. 
  43. ↑ 43.0 43.1 43.2 43.3 43.4 "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. December 2015. doi:10.5770/cgj.18.189. PMID 26740832. 
  44. ↑ "Polyunsaturated fatty acids (PUFA) for attention deficit hyperactivity disorder (ADHD) in children and adolescents". The Cochrane Database of Systematic Reviews 2023 (4): CD007986. April 2023. doi:10.1002/14651858.CD007986.pub3. PMID 37058600. 
  45. ↑ "Polyunsaturated fatty acids (PUFAs) for children with specific learning disorders". The Cochrane Database of Systematic Reviews 12: CD009398. December 2012. doi:10.1002/14651858.CD009398.pub2. PMID 23235675. 
  46. ↑ "Omega-3 polyunsaturated fatty acid supplementation and cognition: A systematic review and meta-analysis". Journal of Psychopharmacology 29 (7): 753–763. July 2015. doi:10.1177/0269881115587958. PMID 26040902. https://kclpure.kcl.ac.uk/portal/en/publications/dcd51fd9-ba02-4e7c-b84e-6b2086ae91af. 

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