Theanine

Theanine /ˈθiːəniːn/, also known as L-γ-glutamylethylamide and 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. It was discovered as a constituent of green tea in 1949; in 1950, it was isolated from gyokuro leaves.[4] Theanine provides a unique brothy or savory (umami) flavor to green tea infusions.

Not to be confused with threonine, a distinct amino acid, or theine, an archaic synonym of caffeine.
Theanine
L-Theanine
Clinical data
Other namesγ-L-Glutamylethylamide
Pregnancy
category
  • US: A (No risk in human studies)
    Dependence
    liability    		None
    Routes of
    administration    		Oral
    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
    CAS Number
    PubChem CID
    ChemSpider
    UNII
    KEGG
    ChEBI
    CompTox Dashboard (EPA)
    ECHA InfoCard100.019.436
    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]

    The name "theanine" without a prefix generally implies the enantiomer L-theanine, which is the form found in tea leaves and as a dietary supplement ingredient. Most studies have used L-theanine. The opposite enantiomer, D-theanine, has been studied less.

    The regulatory status of theanine varies by country. In Japan, L-theanine has been approved for use in all foods, including herb teas, soft drinks, desserts, etc. Restrictions apply to infant foods.[5][6] In the United States, the Food and Drug Administration (FDA) considers it to be generally recognized as safe (GRAS) and allows its sale as a dietary supplement. 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. The European Food Safety Authority EFSA advised negatively on the use of L-theanine for improving cognitive function, alleviation of psychological stress, maintenance of normal sleep, and reduction of menstrual discomfort.[7] Therefore, health claims for L-theanine are not recognized in the European Union.

    Structure and properties

    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).

    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.[8][9] 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.[9]

    Discovery and distribution

    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[5] successfully isolated it from gyokuro leaf, which has high theanine content.[10] Theanine is substantially present in black, green, and white teas from Camellia sinensis in quantities of about 1% of the dry weight.[11][12] Deliberately shading tea plants from direct sunlight, as is done for matcha and gyokuro green tea, increases L-theanine content. The L-enantiomer[2] is the form found in freshly prepared teas and some, but not all, human dietary supplements.[9]

    Digestion and metabolism

    As a structural analog of glutamate and glutamine, the theanine in preparations (teas, pure supplements, etc.) is absorbed in the small intestine after oral ingestion; its hydrolysis to L-glutamate and ethylamine occur both in the intestine and liver.[13] It can also cross the blood–brain barrier intact, and register pharmacological effects directly.[14]

    Pharmacology

    Pharmacodynamics

    Theanine is structurally similar to the excitatory neurotransmitter glutamate, and in accordance, binds to glutamate receptors, 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.[15][16][17][18] It acts as an antagonist of the former two sites[18] and as an agonist of the latter site.[19] Theanine also binds to group I mGluRs.[15][20] In addition, it inhibits glutamine transporters and glutamate transporters, and thus blocks the reuptake of glutamine and glutamate.[17][21][22] Lastly, theanine elicits umami taste, and this effect has been found to be a consequence of the fact that it directly binds to and activates the T1R1 + T1R3 heterodimer or umami (savory) taste receptor.[23]

    Theanine increases serotonin, dopamine, GABA, and glycine levels in various areas of the brain, as well as BDNF and NGF levels in certain brain areas.[15][19][24][25] However, its effect on serotonin is still a matter of debate in the scientific community, with studies showing increases and decreases in brain serotonin levels using similar experimental protocols.[14][26] It has also been found that injecting spontaneously hypertensive mice with theanine significantly lowered levels of 5-hydroxyindoles in the brain.[27] Researchers also speculate that it may inhibit glutamate excitotoxicity.[15]

    Effects

    Able to cross the blood–brain barrier, theanine has reported psychoactive properties.[28] Theanine has been studied for its potential ability to reduce mental and physical stress,[29] improve cognition,[30] and boost mood and cognitive performance in a synergistic manner with caffeine.[31][32][33][34][35][36]

    A Natural Standard monograph that reviews current research on theanine reports that it is likely safe in doses of 200–250 mg up to a maximum daily dose of 1,200 mg. Though some people use theanine for these purposes, Natural Standard rates the evidence to support the usage for anxiety reduction, blood pressure control, and mood improvement as "unclear or conflicting scientific evidence" and the evidence for improved cognition as "fair negative scientific evidence". Many of the studies of theanine were done in combination with caffeine as found in tea. While the studies found that the combination had some effect on mood, the studies found that theanine alone had little effect.[37] A review by other researchers of a small set of trials concluded that there are benefits of L-theanine in reducing acute stress and anxiety in people with stressful conditions.[38]

    Supplement use

    In 2001, the German Federal Institute for Risk Assessment (Bundesinstitut für Risikobewertung, BfR) objected to the addition of isolated theanine to beverages.[39][40] 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.[41]

    In 2006, a study found no consistent, statistically significant treatment-related adverse effects on behavior, morbidity, mortality, body weight, food consumption and efficiency, clinical chemistry, hematology, or urinalysis in rats fed high doses of theanine for 13 weeks.[42] Large studies in humans have not been undertaken; however, several smaller-scale studies (fewer than 100 participants) have shown increased alpha wave generation and lowered anxiety, along with benefits to sleep quality in people with ADHD.[29][43][44]

    The combination of theanine and caffeine has been shown to promote faster simple reaction time, faster numeric working memory reaction time and improved sentence verification accuracy.[31][33][45][46] Due to this, the combination has become popular over recent years as a nootropic supplement typically found in the form of a pill, drink, or gum.

    Theanine has been reported to raise levels of brain serotonin, dopamine, and GABA, with possible improvement in specific memory and learning tasks.[47]

    In brewed teabags

    A study of teabags sold in British supermarkets in 2011 found that the teabags containing the most L-theanine per cup (24 mg versus 8 mg per cup) were the lower-quality brands containing black tea, with a supermarket brand of black tea having the highest theanine content. The study demonstrates that brewing time is a major determinant of the amount of l-theanine extracted. Addition of sugar and small quantities of milk make no significant difference, while larger quantities of milk reduced the measured theanine content.[48]

    See also

    Notes and references
    1. Scheid, L.; Ellinger, S.; Alteheld, B.; Herholz, H.; Ellinger, J.; Henn, T.; Helfrich, H.-P.; Stehle, P. (2012). "Kinetics of L-Theanine Uptake and Metabolism in Healthy Participants Are Comparable after Ingestion of L-Theanine via Capsules and Green Tea". Journal of Nutrition. 142 (12): 2091–2096. doi:10.3945/jn.112.166371. ISSN 0022-3166. PMID 23096008.
    2. "D-theanine | C7H14N2O3". ChemSpider.com. Retrieved 2015-05-21.
    3. "Theanine". Pubchem Compound. NCBI. Retrieved 21 February 2015.
    4. "Components of Gyokuro｜ IPPODO". Ippodo-tea.co.jp. Retrieved 2015-05-07.
    5. SAKATO Y. J. Agri. Chem. Soc. 1949, 23, 262-7
    6. MASON R. Altern. & Complementary Ther. 2001, 7, 91-5
    7. http://www.efsa.europa.eu/en/efsajournal/pub/2238%5B%5D
    8. Vuong, Quan V; Bowyer, Michael C; Roach, Paul D (2011). "L-Theanine: Properties, synthesis and isolation from tea". Journal of the Science of Food and Agriculture. 91 (11): 1931–9. doi:10.1002/jsfa.4373. PMID 21735448.
    9. Desai, M. J.; Armstrong, D. W. (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): 251–6. doi:10.1002/rcm.1319. PMID 14755608.
    10. "How Gyokuro is Processed ｜ IPPODO". Ippodo-tea.co.jp. Retrieved 2015-05-07.
    11. Finger, Andreas; Kuhr, Susanne; Engelhardt, Ulrich (1992). "Chromatography of tea constituents". Journal of Chromatography. 624 (1–2): 309–310. doi:10.1016/0021-9673(92)85685-M.
    12. Casimir, J.; Jadot, J.; Renard, M. (1960). "Séparation et caractérisation de la N-éthyl-γ-glutamine à partir de Xerocomus badius" [Separation and characterization of N-ethyl-γ-glutamine from Xerocomus badius]. Biochimica et Biophysica Acta (in French). 39 (3): 462–8. doi:10.1016/0006-3002(60)90199-2. PMID 13808157.
    13. Kurihara, Shigekazu; Shibakusa, Tetsuro; Tanaka, Kenji AK (2013). "Cystine and theanine: Amino acids as oral immunomodulative nutrients". SpringerPlus. 2: 635. doi:10.1186/2193-1801-2-635. PMC 3851524. PMID 24312747.
    14. Yokogoshi, Hidehiko; Kobayashi, Miki; Mochizuki, Mikiko; Terashima, Takehiko (1998). "Effect of theanine, γ-glutamylethylamide, on brain monoamines and striatal dopamine release in conscious rats". Neurochemical Research. 23 (5): 667–73. doi:10.1023/A:1022490806093. PMID 9566605.
    15. Nathan, Pradeep; Lu, Kristy; Gray, M.; Oliver, C. (2006). "The Neuropharmacology of L-Theanine(N-Ethyl-L-Glutamine)". Journal of Herbal Pharmacotherapy. 6 (2): 21–30. doi:10.1300/J157v06n02_02. PMID 17182482.
    16. Kakuda T, Nozawa A, Sugimoto A, Niino H (2002). "Inhibition by theanine of binding of [3H]AMPA, [3H]kainate, and [3H]MDL 105,519 to glutamate receptors". Biosci. Biotechnol. Biochem. 66 (12): 2683–6. doi:10.1271/bbb.66.2683. PMID 12596867.
    17. Kakuda T (2011). "Neuroprotective effects of theanine and its preventive effects on cognitive dysfunction". Pharmacol. Res. 64 (2): 162–8. doi:10.1016/j.phrs.2011.03.010. PMID 21477654.
    18. Kakuda T (2002). "Neuroprotective effects of the green tea components theanine and catechins". Biol. Pharm. Bull. 25 (12): 1513–8. doi:10.1248/bpb.25.1513. PMID 12499631.
    19. Wakabayashi C, Numakawa T, Ninomiya M, Chiba S, Kunugi H (2012). "Behavioral and molecular evidence for psychotropic effects in L-theanine". Psychopharmacology. 219 (4): 1099–109. doi:10.1007/s00213-011-2440-z. PMID 21861094.
    20. Nagasawa K, Aoki H, Yasuda E, Nagai K, Shimohama S, Fujimoto S (2004). "Possible involvement of group I mGluRs in neuroprotective effect of theanine". Biochem. Biophys. Res. Commun. 320 (1): 116–22. doi:10.1016/j.bbrc.2004.05.143. PMID 15207710.
    21. Sugiyama T, Sadzuka Y, Tanaka K, Sonobe T (2001). "Inhibition of glutamate transporter by theanine enhances the therapeutic efficacy of doxorubicin". Toxicol. Lett. 121 (2): 89–96. doi:10.1016/s0378-4274(01)00317-4. PMID 11325559.
    22. Sugiyama T, Sadzuka Y (2003). "Theanine and glutamate transporter inhibitors enhance the antitumor efficacy of chemotherapeutic agents". Biochim. Biophys. Acta. 1653 (2): 47–59. doi:10.1016/s0304-419x(03)00031-3. PMID 14643924.
    23. Narukawa M, Toda Y, Nakagita T, Hayashi Y, Misaka T (2014). "L-Theanine elicits umami taste via the T1R1 + T1R3 umami taste receptor". Amino Acids. 46 (6): 1583–7. doi:10.1007/s00726-014-1713-3. PMID 24633359.
    24. Yamada T, Terashima T, Wada K, Ueda S, Ito M, Okubo T, Juneja LR, Yokogoshi H (2007). "Theanine, r-glutamylethylamide, increases neurotransmission concentrations and neurotrophin mRNA levels in the brain during lactation". Life Sci. 81 (16): 1247–55. doi:10.1016/j.lfs.2007.08.023. PMID 17904164.
    25. Yokogoshi H, Kobayashi M, Mochizuki M, Terashima T (1998). "Effect of theanine, r-glutamylethylamide, on brain monoamines and striatal dopamine release in conscious rats". Neurochem. Res. 23 (5): 667–73. doi:10.1023/A:1022490806093. PMID 9566605.
    26. Yokogoshi, Hidehiko; Mochizuki, Mikiko; Saitoh, Kotomi (1998). "Theanine-induced Reduction of Brain Serotonin Concentration in Rats". Bioscience, Biotechnology, and Biochemistry. 62 (4): 816–7. doi:10.1271/bbb.62.816. PMID 9614715.
    27. Yokogoshi, Hidehiko; Kato, Yukiko; Sagesaka, Yuko M.; Takihara-Matsuura, Takanobu; Kakuda, Takami; Takeuchi, Naokazu (1995). "Reduction Effect of Theanine on Blood Pressure and Brain 5-Hydroxyindoles in Spontaneously Hypertensive Rats". Bioscience, Biotechnology, and Biochemistry. 59 (4): 615–8. doi:10.1271/bbb.59.615. PMID 7539642.
    28. Gomez-Ramirez, Manuel; Higgins, Beth A.; Rycroft, Jane A.; Owen, Gail N.; Mahoney, Jeannette; Shpaner, Marina; Foxe, John J. (2007). "The Deployment of Intersensory Selective Attention". Clinical Neuropharmacology. 30 (1): 25–38. doi:10.1097/01.WNF.0000240940.13876.17. PMID 17272967.
    29. Kimura, Kenta; Ozeki, Makoto; Juneja, Lekh Raj; Ohira, Hideki (2007). "L-Theanine reduces psychological and physiological stress responses". Biological Psychology. 74 (1): 39–45. doi:10.1016/j.biopsycho.2006.06.006. PMID 16930802.
    30. Park, Sang-Ki; Jung, In-Chul; Lee, Won Kyung; Lee, Young Sun; Park, Hyoung Kook; Go, Hyo Jin; Kim, Kiseong; Lim, Nam Kyoo; et al. (2011). "A Combination of Green Tea Extract andl-Theanine Improves Memory and Attention in Subjects with Mild Cognitive Impairment: A Double-Blind Placebo-Controlled Study". Journal of Medicinal Food. 14 (4): 334–43. doi:10.1089/jmf.2009.1374. PMID 21303262.
    31. Haskell, Crystal F.; Kennedy, David O.; Milne, Anthea L.; Wesnes, Keith A.; Scholey, Andrew B. (2008). "The effects of l-theanine, caffeine and their combination on cognition and mood". Biological Psychology. 77 (2): 113–22. doi:10.1016/j.biopsycho.2007.09.008. PMID 18006208.
    32. Raloff, Janet (September 29, 2007). "Distracted? Tea might help your focus". Science News. 172 (13): 206. doi:10.1002/scin.2007.5591721319.
    33. Owen, Gail N.; Parnell, Holly; De Bruin, Eveline A.; Rycroft, Jane A. (2008). "The combined effects of L-theanine and caffeine on cognitive performance and mood". Nutritional Neuroscience. 11 (4): 193–8. doi:10.1179/147683008X301513. PMID 18681988.
    34. Einöther, Suzanne J.L.; Martens, Vanessa E.G.; Rycroft, Jane A.; De Bruin, Eveline A. (2010). "L-Theanine and caffeine improve task switching but not intersensory attention or subjective alertness". Appetite. 54 (2): 406–9. doi:10.1016/j.appet.2010.01.003. PMID 20079786.
    35. Giesbrecht, T.; Rycroft, J.A.; Rowson, M.J.; De Bruin, E.A. (2010). "The combination of L-theanine and caffeine improves cognitive performance and increases subjective alertness". Nutritional Neuroscience. 13 (6): 283–90. doi:10.1179/147683010X12611460764840. PMID 21040626.
    36. Kelly, Simon P.; Gomez-Ramirez, Manuel; Montesi, Jennifer L.; Foxe, John J. (2008). "L-theanine and caffeine in combination affect human cognition as evidenced by oscillatory alpha-band activity and attention task performance". The Journal of Nutrition. 138 (8): 1572S–1577S. doi:10.1093/jn/138.8.1572S. PMID 18641209.
    37. "Theanine Monograph". Natural Standard. Archived from the original on December 24, 2014. Retrieved 30 October 2014.
    38. Everett, J.M.; Gunathilake, D.; Dufficy, L.; Roach, P.; Thomas, J.; Upton, D.; Naumovski, N. (2016). "Theanine consumption, stress and anxiety in human clinical trials: A systematic review". Journal of Nutrition & Intermediary Metabolism. 4: 41–42. doi:10.1016/j.jnim.2015.12.308.
    39. https://www.bfr.bund.de/cm/343/getraenke_mit_isoliertem_l_theanin.pdf
    40. Robin B. Kanarek; Harris R. Lieberman (6 October 2011). Diet, Brain, Behavior: Practical Implications. CRC Press. pp. 239–. ISBN 978-1-4398-2156-5.
    41. "Getränke mit isoliertem L-Theanin" [Beverages with isolated L-theanine] (PDF) (in German). Bundesinstitut für Risikobewertung. August 2003.
    42. Borzelleca, J.F.; Peters, D.; Hall, W. (2006). "A 13-week dietary toxicity and toxicokinetic study with l-theanine in rats". Food and Chemical Toxicology. 44 (7): 1158–66. doi:10.1016/j.fct.2006.03.014. PMID 16759779.
    43. Lyon, Michael R.; Kapoor, Mahendra P.; Juneja, Lekh R. (2011). "The effects of L-theanine (Suntheanine®) on objective sleep quality in boys with attention deficit hyperactivity disorder (ADHD): a randomized, double-blind, placebo-controlled clinical trial" (PDF). Alternative Medicine Review. 16 (4): 348–54. PMID 22214254.
    44. Kobayashi, Kanari; Nagato, Yukiko; Aoi, Nobuyuki; Juneja, Lekh Raj; Kim, Mujo; Yamamoto, Takehiko; Sugimoto, Sukeo (1998). "L-テアニンのヒトの脳波に及ぼす影響" [Effects of L-Theanine on the Release of α-Brain Waves in Human Volunteers]. Journal of the Agricultural Chemical Society of Japan (in Japanese). 72 (2): 153–7. doi:10.1271/nogeikagaku1924.72.153.
    45. Bryan, Janet (2008). "Psychological effects of dietary components of tea: Caffeine and L-theanine". Nutrition Reviews. 66 (2): 82–90. doi:10.1111/j.1753-4887.2007.00011.x. PMID 18254874.
    46. Kelly, Simon P.; Gomez-Ramirez, Manuel; Montesi, Jennifer L.; Foxe, John J. (2008). "L-Theanine and Caffeine in Combination Affect Human Cognition as Evidenced by Oscillatory alpha-Band Activity and Attention Task Performance". The Journal of Nutrition. 138 (8): 1572S–1577S. doi:10.1093/jn/138.8.1572S. PMID 18641209.
    47. Nathan, PJ; Lu, K; Gray, M; Oliver, C (2015-04-20). "The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent". J Herb Pharmacother. 6 (2): 21–30. doi:10.1300/J157v06n02_02. PMID 17182482.
    48. Keenan, Emma K.; Finnie, Mike D.A.; Jones, Paul S.; Rogers, Peter J.; Priestley, Caroline M. (2011). "How much theanine in a cup of tea? Effects of tea type and method of preparation". Food Chemistry. 125 (2): 588. doi:10.1016/j.foodchem.2010.08.071.

    Further reading
    • Y. Orihara; T. Furuya (1990). "Production of theanine and other γ-glutamyl derivatives by Camellia sinensis cultured cells". Plant Cell Reports. 9 (2): 65–68. doi:10.1007/BF00231550. PMID 24226431.
    • E.K. Keenan; M.D.A. Finnie; P.S. Jones; P.J. Rogers; C.M. Priestley (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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