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Theanine

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Not to be confused with threonine, a distinct amino acid, or theine, an archaic synonym of caffeine.
Theanine
skeletal formula of L-theanine
L-Theanine
Clinical data
Other namesγ-L-Glutamylethylamide
Dependence
liability		None
Routes of
administration		Oral
Drug classdietary supplement
ATC code
  • none
Legal status
Legal status
  • US: OTC
  • UN: Unscheduled
Pharmacokinetic data
Onset of actionabout 1 hour[1]
Elimination half-lifeCapsule ~1.2 hours
Green Tea ~0.8 hours[1]
Identifiers
  • (2S)-2-Ammonio-5-(ethylamino)-5-oxopentanoate[2] or N-Ethyl-L-glutamine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.019.436 Edit this at Wikidata
Chemical and physical data
FormulaC7H14N2O3
Molar mass174.200 g·mol−1
3D model (JSmol)
Melting point174.20 °C (345.56 °F) [3]
Boiling point215 °C (419 °F) [3]
  • CCNC(=O)CC[C@H](N)C(=O)O

  • CCNC(=O)CCC(N)C(O)=O
  • InChI=1S/C7H14N2O3/c1-2-9-6(10)4-3-5(8)7(11)12/h5H,2-4,8H2,1H3,(H,9,10)(H,11,12) checkY
  • Key:DATAGRPVKZEWHA-UHFFFAOYSA-N checkY

Theanine /ˈθiːəniːn/, commonly known as L-theanine and sometimes L-gamma-glutamylethylamide or N5-ethyl-L-glutamine, is an amino acid analogue of the proteinogenic amino acids L-glutamate and L-glutamine and is found primarily in particular plant and fungal species.[3][4] It was discovered as a constituent of green tea in 1949 and isolated from gyokuro leaves in 1950, thus rendering it a natural product.[5] It constitutes about 1–2% of the dry weight of green tea leaves.[4]

The name theanine without a prefix generally implies the enantiomer L-theanine, which is the form found in tea leaves from which it is extracted as a powder.[4][6] The right-handed enantiomer, D-theanine, has been comparatively studied less.

Theanine is sold as a dietary supplement and is considered to be safe at doses up to 250 milligrams (mg) by the US Food and Drug Administration.[4][7] It is packaged in gelatin capsules, tablets, and as a powder, and may be an ingredient in branded supplements with caffeine.

The European Food Safety Authority found there was insufficient evidence for a causal relationship between theanine consumption and improved cognitive function, alleviation of psychological stress, maintenance of normal sleep, or reduction of menstrual discomfort.[8]

Structure and properties

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The chemical name N5-ethyl-L-glutamine[2] and other synonyms (see box) for theanine reflect its chemical structure. The name theanine, without prefix, is generally understood to imply the L- (S-) enantiomer, derived from the related proteinogenic L-amino acid glutamic acid. Theanine is an analog of this amino acid, and its primary amide, L-glutamine (also a proteinogenic amino acid). Theanine is a derivative of glutamine that is ethylated on the amide nitrogen (as the name N5-ethyl-L-glutamine describes), or alternatively, to the amide formed from ethylamine and L-glutamic acid at its γ- (5-) side chain carboxylic acid group (as the name γ-L-glutamylethylamide describes).[citation needed]

Relative to theanine, the opposite (D-, R-) enantiomer is largely absent from the literature,[2] except implicitly. While natural extracts that are not harshly treated are presumed to contain only the biosynthetic L- enantiomeric form, mishandled isolates and racemic chemical preparations of theanines necessarily contain both theanine and its D-enantiomer (and from racemic syntheses, in equal proportion), and studies have suggested that the D-isomer may actually predominate in some commercial supplement preparations.[9][10] Amino acid racemization in aqueous media is a well-established chemical process promoted by elevated temperature and non-neutral pH values; prolonged heating of Camellia extracts—possible for oversteeped teas and in undisclosed commercial preparative processes—has been reported to result in increasing racemization of theanine to give increasing proportions of the nonnatural D-theanine, up to equal proportions of each enantiomer.[10]

Discovery and distribution

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Theanine is found primarily in plant and fungal species. It was discovered as a constituent of tea (Camellia sinensis) in 1949, and in 1950 a laboratory in Kyoto[11] successfully isolated it from gyokuro leaf, which has high theanine content.[12] Theanine is substantially present in black, green, and white teas from Camellia sinensis in quantities of about 1% of the dry weight.[13][14] Deliberately shading tea plants from direct sunlight, as is done for matcha and gyokuro green tea, increases L-theanine content.[15] The L-enantiomer[2] is the form found in freshly prepared teas and some human dietary supplements.[10]

Digestion and metabolism

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As a structural analog of glutamate and glutamine, the theanine in teas or supplements is absorbed in the small intestine after oral ingestion; its hydrolysis to L-glutamate and ethylamine occur both in the intestine and liver, possibly functioning as a donor for glutamate synthesis.[16]

Pharmacology

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In vitro

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Theanine is structurally similar to the excitatory neurotransmitter glutamate, and in accordance, binds to glutamate receptors in vitro, though with much lower affinity in comparison. Specifically, it binds to ionotropic glutamate receptors in the micromolar range, including the AMPA and kainate receptors and, to a lesser extent, the NMDA receptor.[17][18] It acts as an antagonist of the former two sites, and a partial co-agonist of the NMDA receptors.[19] In vitro, theanine also binds to group I mGluRs.[17][20] In addition, it inhibits glutamine transporters and glutamate transporters, and thus blocks the reuptake of glutamine and glutamate.[18][21]

Theanine may elicit umami taste, a consequence potentially associated with binding to and activation of the T1R1 + T1R3 heterodimer or umami (savory) taste receptor.[22]

Regulatory status

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The regulatory status of theanine varies by country. In Japan, L-theanine has been approved for use in all foods, with some restrictions in the case of infant foods.[11][23] In the United States, the FDA considers it to be GRAS and allows its use as an ingredient in dietary supplements or foods up to a maximum of 250 mg per serving.[4]

The German Federal Institute for Risk Assessment, an agency of their Federal Ministry of Food and Agriculture, objects to the addition of L-theanine to beverages. In 2003, the German Federal Institute for Risk Assessment (Bundesinstitut für Risikobewertung, BfR) objected to the addition of isolated theanine to beverages.[24][25] The institute stated the amount of theanine consumed by regular drinkers of tea or coffee is virtually impossible to determine.

While it was estimated the quantity of green tea consumed by the average Japanese tea drinker per day contains about 20 mg of the substance, there are no studies measuring the amount of theanine being extracted by typical preparation methods, or the percentage lost by discarding the first infusion. Therefore, with the Japanese being exposed to possibly much less than 20 mg per day, and Europeans presumably even less, it was the opinion of the BfR that pharmacological reactions to drinks typically containing 50 mg of theanine per 500 milliliters could not be excluded—reactions such as impairment of psychomotor skills and amplification of the sedating effects of alcohol and hypnotics.[26]

On 13 November 2023, the Inspection by the Administration of Food Safety, Veterinary Medicine and Plant Protection of the Republic of Slovenia banned the sale of Prime energy drinks in Slovenia as they contain L-theanine, which is not allowed in non-alcoholic beverages. Prime Hydration may be freely sold.[27]

Research on supplement use

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A 2020 review concluded that L-theanine supplementation of 200–400 milligrams per day may reduce stress and anxiety in people with acute stress, but there was insufficient evidence for the use of L-theanine as a prescription drug to treat stress and anxiety.[28]

Theanine supplements have been marketed with a variety of claims that they improve cognitive performance, reduce stress, improve sleep quality, and alleviate menstrual cramps. Evaluating these claims in 2011, the European Food Safety Authority assessed they were not supported by evidence.[8]

See also

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References

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  1. ^ a b Scheid L, Ellinger S, Alteheld B, Herholz H, Ellinger J, Henn T, et al. (December 2012). "Kinetics of L-theanine uptake and metabolism in healthy participants are comparable after ingestion of L-theanine via capsules and green tea". The Journal of Nutrition. 142 (12): 2091–2096. doi:10.3945/jn.112.166371. PMID 23096008.
  2. ^ a b c d "D-theanine | C7H14N2O3". ChemSpider.com. Retrieved 2015-05-21.
  3. ^ a b c "L-Theanine". PubChem, US National Library of Medicine. 13 May 2023. Retrieved 16 May 2023.
  4. ^ a b c d e "L-Theanine". Drugs.com. 20 February 2023. Retrieved 16 May 2023.
  5. ^ "Components of Gyokuro｜ IPPODO". Ippodo-tea.co.jp. Archived from the original on 2015-12-23. Retrieved 2015-05-07.
  6. ^ Schuster J, Mitchell ES (March 2019). "More than just caffeine: psychopharmacology of methylxanthine interactions with plant-derived phytochemicals". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 89: 263–274. doi:10.1016/j.pnpbp.2018.09.005. PMID 30213684. S2CID 52274913.
  7. ^ "GRAS notice for L-theanine". US Food and Drug Administration. 5 February 2007. Retrieved 1 May 2023.
  8. ^ a b EFSA Panel on Dietetic Products, Nutrition and Allergies, European Food Safety Authority (2011). "Scientific Opinion on the substantiation of health claims related to L-theanine from Camellia sinensis (L.) Kuntze (Tea) and improvement of cognitive function (ID 1104, 1222, 1600, 1601, 1707, 1935, 2004, 2005), alleviation of psychological stress (ID 1598, 1601), maintenance of normal sleep (ID 1222, 1737, 2004) and reduction of menstrual discomfort (ID 1599) pursuant to Article 13(1) of Regulation (EC) No 1924/2006". EFSA Journal. 9 (6): 2238. doi:10.2903/j.efsa.2011.2238.
  9. ^ Vuong QV, Bowyer MC, Roach PD (August 2011). "L-Theanine: properties, synthesis and isolation from tea". Journal of the Science of Food and Agriculture. 91 (11): 1931–1939. Bibcode:2011JSFA...91.1931V. doi:10.1002/jsfa.4373. PMID 21735448.
  10. ^ a b c Desai MJ, Armstrong DW (2004). "Analysis of derivatized and underivatized theanine enantiomers by high-performance liquid chromatography/atmospheric pressure ionization-mass spectrometry". Rapid Communications in Mass Spectrometry. 18 (3): 251–256. Bibcode:2004RCMS...18..251D. doi:10.1002/rcm.1319. PMID 14755608.
  11. ^ a b Sakato Y (1949). "The chemical constituents of tea: III. A new amide theanine". Nippon Nogeikagaku Kaishi. 23: 262–267. doi:10.1271/nogeikagaku1924.23.262.
  12. ^ "How Gyokuro is Processed ｜ IPPODO". Ippodo-tea.co.jp. Archived from the original on 2018-04-25. Retrieved 2015-05-07.
  13. ^ Finger A, Kuhr S, Engelhardt UH (October 1992). "Chromatography of tea constituents". Journal of Chromatography. 624 (1–2): 293–315. doi:10.1016/0021-9673(92)85685-M. PMID 1494009.
  14. ^ Casimir J, Jadot J, Renard M (April 1960). "[Separation and characterization of N-ethyl-gamma-glutamine from Xerocomus badius]" [Separation and characterization of N-ethyl-γ-glutamine from Xerocomus badius]. Biochimica et Biophysica Acta (in French). 39 (3): 462–468. doi:10.1016/0006-3002(60)90199-2. PMID 13808157.
  15. ^ Chen X, Ye K, Xu Y, Zhao Y, Zhao D (November 2022). "Effect of Shading on the Morphological, Physiological, and Biochemical Characteristics as Well as the Transcriptome of Matcha Green Tea". International Journal of Molecular Sciences. 23 (22): 14169. doi:10.3390/ijms232214169. PMC 9696345. PMID 36430647.
  16. ^ Kurihara S, Shibakusa T, Tanaka KA (November 2013). "Cystine and theanine: amino acids as oral immunomodulative nutrients". SpringerPlus. 2: 635. doi:10.1186/2193-1801-2-635. PMC 3851524. PMID 24312747.
  17. ^ a b Nathan PJ, Lu K, Gray M, Oliver C (2006). "The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent". Journal of Herbal Pharmacotherapy. 6 (2): 21–30. doi:10.1300/J157v06n02_02. PMID 17182482.
  18. ^ a b Kakuda T (August 2011). "Neuroprotective effects of theanine and its preventive effects on cognitive dysfunction". Pharmacological Research. 64 (2): 162–168. doi:10.1016/j.phrs.2011.03.010. PMID 21477654.
  19. ^ Sebih F, Rousset M, Bellahouel S, Rolland M, de Jesus Ferreira MC, Guiramand J, et al. (August 2017). "Characterization of l-Theanine Excitatory Actions on Hippocampal Neurons: Toward the Generation of Novel N-Methyl-d-aspartate Receptor Modulators Based on Its Backbone" (PDF). ACS Chemical Neuroscience. 8 (8): 1724–1734. doi:10.1021/acschemneuro.7b00036. PMID 28511005. S2CID 3533449.
  20. ^ Nagasawa K, Aoki H, Yasuda E, Nagai K, Shimohama S, Fujimoto S (July 2004). "Possible involvement of group I mGluRs in neuroprotective effect of theanine". Biochemical and Biophysical Research Communications. 320 (1): 116–122. doi:10.1016/j.bbrc.2004.05.143. PMID 15207710.
  21. ^ Sugiyama T, Sadzuka Y, Tanaka K, Sonobe T (April 2001). "Inhibition of glutamate transporter by theanine enhances the therapeutic efficacy of doxorubicin". Toxicology Letters. 121 (2): 89–96. doi:10.1016/s0378-4274(01)00317-4. PMID 11325559.
  22. ^ Narukawa M, Toda Y, Nakagita T, Hayashi Y, Misaka T (June 2014). "L-Theanine elicits umami taste via the T1R1 + T1R3 umami taste receptor". Amino Acids. 46 (6): 1583–1587. doi:10.1007/s00726-014-1713-3. PMID 24633359. S2CID 17380461.
  23. ^ Mason R (April 2001). "200 mg of Zen: L-theanine boosts alpha waves, promotes alert relaxation". Alternative & Complementary Therapies. 7 (2): 91–95. doi:10.1089/10762800151125092.
  24. ^ "Getränke mit isoliertem L-Theanin" [Drinks with isolated L-Theanine] (PDF). Bundesinstitut für Riskobewertung (BfR) [Federal Institute for Risk Assessment (BfR)] (in German). June 2001.
  25. ^ Kanarek RB, Lieberman HR (2011). Diet, Brain, Behavior: Practical Implications. CRC Press. pp. 239–. ISBN 978-1-4398-2156-5.
  26. ^ "Getränke mit isoliertem L-Theanin" [Beverages with isolated L-theanine] (PDF) (in German). Bundesinstitut für Risikobewertung. August 2003.
  27. ^ "Inšpekcija prepovedala prodajo pijače Prime zaradi nedovoljene sestavine" [Inspection Bans Sale of Prime Because of an Unauthorised Ingredient]. Delo.si (in Slovenian). 13 November 2023.
  28. ^ Williams JL, Everett JM, D'Cunha NM, et al. (March 2020). "The Effects of Green Tea Amino Acid L-Theanine Consumption on the Ability to Manage Stress and Anxiety Levels: a Systematic Review" (PDF). Plant Foods for Human Nutrition. 75 (1): 12–23. doi:10.1007/s11130-019-00771-5. PMID 31758301. S2CID 208213702.

Further reading

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  • Keenan EK, Finnie MD, Jones PS, Rogers PJ, Priestley CM (2011). "How much theanine in a cup of tea? Effects of tea type and method of preparation". Food Chemistry. 125 (2): 588–594. doi:10.1016/j.foodchem.2010.08.071.
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