Theanine

{{Distinguish|text=threonine, a distinct amino acid, or theine, an archaic synonym of caffeine}}

{{Infobox drug

| image = Theanine-3D-balls.png

| image2 = L-Theanine.svg

| caption = L-Theanine

| alt = skeletal formula of L-theanine

| IUPAC_name = (2S)-2-Ammonio-5-(ethylamino)-5-oxopentanoate or N-Ethyl-L-glutamine

| tradename =

| Drugs.com =

| pregnancy_US = A

| legal_AU =

| legal_CA =

| legal_UK =

| legal_US = OTC

| legal_UN = Unscheduled

| licence_US =

| dependency_liability = None

| addiction_liability =

| routes_of_administration = Oral

| bioavailability =

| protein_bound =

| metabolism =

| onset = about 1 hour{{cite journal | vauthors = Scheid L, Ellinger S, Alteheld B, Herholz H, Ellinger J, Henn T, Helfrich HP, Stehle P | title = Kinetics of L-theanine uptake and metabolism in healthy participants are comparable after ingestion of L-theanine via capsules and green tea | journal = The Journal of Nutrition | volume = 142 | issue = 12 | pages = 2091–2096 | date = December 2012 | pmid = 23096008 | doi = 10.3945/jn.112.166371 | doi-access = free }}

| elimination_half-life = Capsule ~1.2 hours

Green Tea ~0.8 hours

| excretion =

| class = dietary supplement

| index_label =

| index2_label =

| CAS_number = 3081-61-6

| CAS_number_Ref = {{cascite|correct|??}}

| ATC_prefix = none

| PubChem = 439378

| DrugBank = DB12444

| ChemSpiderID = 388498

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| UNII = 8021PR16QO

| UNII_Ref = {{fdacite|correct|FDA}}

| ChEBI = 17394

| ChEBI_Ref = {{ebicite|correct|EBI}}

| KEGG = C01047

| ChEMBL = 3039113

| smiles = CCNC(=O)CC[C@H](N)C(=O)O

| smiles2 = CCNC(=O)CCC(N)C(O)=O

| StdInChI = 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)

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = DATAGRPVKZEWHA-UHFFFAOYSA-N

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| synonyms = γ-L-Glutamylethylamide

| C = 7

| H = 14

| N = 2

| O = 3

| density =

| boiling_point = 215

| boiling_notes = {{cite web|title=L-Theanine|url=https://pubchem.ncbi.nlm.nih.gov/compound/439378|publisher=PubChem, US National Library of Medicine|date=13 May 2023|access-date=16 May 2023}}

| melting_point = 174.20

| melting_notes =

}}

Theanine {{IPAc-en|ˈ|θ|iː|ən|iː|n}}, also known as L-theanine, L-gamma-glutamylethylamide, or N⁵-ethyl-L-glutamine, is a non-proteinogenic amino acid similar to the proteinogenic amino acids L-glutamate and L-glutamine. It is produced by certain plants such as the tea plant (Camellia sinensis), and by some fungi.{{cite web |title=L-Theanine |url=https://www.drugs.com/npp/l-theanine.html |publisher=Drugs.com |access-date=16 May 2023 |date=20 February 2023}} Theanine was discovered in 1949 as a constituent of green tea and was isolated in 1950 from gyokuro tea leaves.{{cite web |url=http://www.ippodo-tea.co.jp/en/tea/gyokuro_02.html |title=Components of Gyokuro｜ IPPODO |publisher=Ippodo-tea.co.jp |access-date=2015-05-07 |archive-date=2015-12-23 |archive-url=https://web.archive.org/web/20151223084441/http://www.ippodo-tea.co.jp/en/tea/gyokuro_02.html |url-status=dead }} It constitutes about 1–2% of the dry weight of green tea leaves.

The name theanine usually refers to the enantiomer L-theanine, which is the form found in tea leaves from which it is extracted as a powder.{{cite journal | vauthors = Schuster J, Mitchell ES | title = More than just caffeine: psychopharmacology of methylxanthine interactions with plant-derived phytochemicals | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 89 | pages = 263–274 | date = March 2019 | pmid = 30213684 | doi = 10.1016/j.pnpbp.2018.09.005 | s2cid = 52274913 | doi-access = free }} The right-handed enantiomer, D-theanine, is less-studied.

Theanine is sold as a dietary supplement. It is packaged in gelatin capsules, tablets, and as a powder, and may be an ingredient in branded supplements with caffeine. It is also used as an ingredient in food and beverages. In 1964 Japan approved its unlimited use in all foods (including chocolates, soft drinks, and herb teas) except infant food,{{Cite web |title=The Japan Food Chemical Research Foundation |url=https://www.ffcr.or.jp/en/tenka/list-of-designated-additives/list-of-designated-additives.html |access-date=2025-03-29 |website=www.ffcr.or.jp}} while since 2007 it is considered to be safe at doses up to 250 milligrams (mg) per serving by the US Food and Drug Administration.{{cite web |title=GRAS notice for L-theanine |url=https://www.hfpappexternal.fda.gov/scripts/fdcc/index.cfm?set=GRASNotices&id=209 |publisher=US Food and Drug Administration |access-date=1 May 2023 |date=5 February 2007}}

In 2011 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.{{Cite journal|title=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|author1=EFSA Panel on Dietetic Products, Nutrition and Allergies|author2= European Food Safety Authority|journal=EFSA Journal|year=2011|volume=9|issue=6|page=2238|doi=10.2903/j.efsa.2011.2238|doi-access=free}}

Structure and properties

The chemical name N⁵-ethyl-L-glutamine 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|date=April 2023}}

Relative to theanine, the opposite (D-, R-) enantiomer is largely absent from the literature,{{cite web|url=http://www.chemspider.com/Chemical-Structure.8139819.html?rid=c1b3b94c-9d23-4b66-9b0b-57208603c57a |title=D-theanine | C7H14N2O3 |publisher=ChemSpider.com |access-date=2015-05-21}} 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.{{cite journal | vauthors = Vuong QV, Bowyer MC, Roach PD | title = L-Theanine: properties, synthesis and isolation from tea | journal = Journal of the Science of Food and Agriculture | volume = 91 | issue = 11 | pages = 1931–1939 | date = August 2011 | pmid = 21735448 | doi = 10.1002/jsfa.4373 | bibcode = 2011JSFA...91.1931V }}{{cite journal | vauthors = Desai MJ, Armstrong DW | title = Analysis of derivatized and underivatized theanine enantiomers by high-performance liquid chromatography/atmospheric pressure ionization-mass spectrometry | journal = Rapid Communications in Mass Spectrometry | volume = 18 | issue = 3 | pages = 251–256 | year = 2004 | pmid = 14755608 | doi = 10.1002/rcm.1319 | bibcode = 2004RCMS...18..251D }} 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.

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 successfully isolated it from gyokuro leaf, which has high theanine content.{{cite web |url=http://www.ippodo-tea.co.jp/en/tea/gyokuro_03.html |title=How Gyokuro is Processed ｜ IPPODO |publisher=Ippodo-tea.co.jp |access-date=2015-05-07 |archive-date=2018-04-25 |archive-url=https://web.archive.org/web/20180425233636/http://www.ippodo-tea.co.jp/en/tea/gyokuro_03.html |url-status=dead }} Theanine is substantially present in black, green, and white teas from Camellia sinensis in quantities of about 1% of the dry weight.{{cite journal | vauthors = Finger A, Kuhr S, Engelhardt UH | title = Chromatography of tea constituents | journal = Journal of Chromatography | volume = 624 | issue = 1–2 | pages = 293–315 | date = October 1992 | pmid = 1494009 | doi = 10.1016/0021-9673(92)85685-M }}{{cite journal | vauthors = Casimir J, Jadot J, Renard M | title = [Separation and characterization of N-ethyl-gamma-glutamine from Xerocomus badius] | language = fr | journal = Biochimica et Biophysica Acta | volume = 39 | issue = 3 | pages = 462–468 | date = April 1960 | pmid = 13808157 | doi = 10.1016/0006-3002(60)90199-2 | trans-title = Separation and characterization of N-ethyl-γ-glutamine from Xerocomus badius }} Deliberately shading tea plants from direct sunlight, as is done for matcha and gyokuro green tea, increases L-theanine content.{{cite journal | vauthors = Chen X, Ye K, Xu Y, Zhao Y, Zhao D | title = Effect of Shading on the Morphological, Physiological, and Biochemical Characteristics as Well as the Transcriptome of Matcha Green Tea | journal = International Journal of Molecular Sciences | volume = 23 | issue = 22 | pages = 14169 | date = November 2022 | pmid = 36430647 | pmc = 9696345 | doi = 10.3390/ijms232214169 | doi-access = free }} The L-enantiomer is the form found in freshly prepared teas and some human dietary supplements.

Digestion and metabolism

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.{{cite journal | vauthors = Kurihara S, Shibakusa T, Tanaka KA | title = Cystine and theanine: amino acids as oral immunomodulative nutrients | journal = SpringerPlus | volume = 2 | pages = 635 | date = November 2013 | pmid = 24312747 | pmc = 3851524 | doi = 10.1186/2193-1801-2-635 | doi-access = free }}

Pharmacology

=In vitro=

Theanine is structurally similar to the excitatory neurotransmitter glutamate, and 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.{{cite journal | vauthors = Nathan PJ, Lu K, Gray M, Oliver C | title = The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent | journal = Journal of Herbal Pharmacotherapy | volume = 6 | issue = 2 | pages = 21–30 | year = 2006 | pmid = 17182482 | doi = 10.1300/J157v06n02_02 }}{{cite journal | vauthors = Kakuda T | title = Neuroprotective effects of theanine and its preventive effects on cognitive dysfunction | journal = Pharmacological Research | volume = 64 | issue = 2 | pages = 162–168 | date = August 2011 | pmid = 21477654 | doi = 10.1016/j.phrs.2011.03.010 }} It acts as an antagonist of the former two sites, and a partial co-agonist of the NMDA receptors.{{cite journal | vauthors = Sebih F, Rousset M, Bellahouel S, Rolland M, de Jesus Ferreira MC, Guiramand J, Cohen-Solal C, Barbanel G, Cens T, Abouazza M, Tassou A, Gratuze M, Meusnier C, Charnet P, Vignes M, Rolland V | title = Characterization of l-Theanine Excitatory Actions on Hippocampal Neurons: Toward the Generation of Novel N-Methyl-d-aspartate Receptor Modulators Based on Its Backbone | journal = ACS Chemical Neuroscience | volume = 8 | issue = 8 | pages = 1724–1734 | date = August 2017 | pmid = 28511005 | doi = 10.1021/acschemneuro.7b00036 | s2cid = 3533449 | url = https://hal.umontpellier.fr/hal-01687653/file/2017-ACSN%20%281%29.pdf }} In vitro, theanine also binds to group I mGluRs.{{cite journal | vauthors = Nagasawa K, Aoki H, Yasuda E, Nagai K, Shimohama S, Fujimoto S | title = Possible involvement of group I mGluRs in neuroprotective effect of theanine | journal = Biochemical and Biophysical Research Communications | volume = 320 | issue = 1 | pages = 116–122 | date = July 2004 | pmid = 15207710 | doi = 10.1016/j.bbrc.2004.05.143 }} In addition, it inhibits glutamine transporters and glutamate transporters, and thus blocks the reuptake of glutamine and glutamate.{{cite journal | vauthors = Sugiyama T, Sadzuka Y, Tanaka K, Sonobe T | title = Inhibition of glutamate transporter by theanine enhances the therapeutic efficacy of doxorubicin | journal = Toxicology Letters | volume = 121 | issue = 2 | pages = 89–96 | date = April 2001 | pmid = 11325559 | doi = 10.1016/s0378-4274(01)00317-4 }}

Theanine may elicit umami taste, a consequence potentially associated with binding to and activation of the T1R1 + T1R3 heterodimer or umami (savory) taste receptor.{{cite journal | vauthors = Narukawa M, Toda Y, Nakagita T, Hayashi Y, Misaka T | title = L-Theanine elicits umami taste via the T1R1 + T1R3 umami taste receptor | journal = Amino Acids | volume = 46 | issue = 6 | pages = 1583–1587 | date = June 2014 | pmid = 24633359 | doi = 10.1007/s00726-014-1713-3 | s2cid = 17380461 }}

Regulatory status

The regulatory status of theanine varies by country. It is sold as a dietary supplement across the United States and European Union. {{Cite web |title=Food and Feed Information Portal Database {{!}} FIP |url=https://ec.europa.eu/food/food-feed-portal/screen/novel-food-catalogue/search?utm_medium=email&_hsmi=2&_hsenc=p2ANqtz-8DmHXDF7nCNB1S2bcaAR_gEZn-lK6edi0HkDcfo3s6lEf0gcBubCz7Beju4Wh1h2AbTpBKDMd0NHRcW_U2T0h_c8sKckpJXXP3acemu2h_vJpDYlg&utm_content=2&utm_source=hs_email |access-date=2025-03-29 |website=ec.europa.eu}} In Japan, L-theanine has been approved for use in all foods, with some restrictions in the case of infant foods.{{cite journal | vauthors = Sakato Y | title = The chemical constituents of tea: III. A new amide theanine. | journal = Nippon Nogeikagaku Kaishi | date = 1949 | volume = 23 | pages = 262–267 | doi = 10.1271/nogeikagaku1924.23.262| url = https://cir.nii.ac.jp/crid/1571135649467738752 | doi-access = free }}{{cite journal | vauthors = Mason R | title = 200 mg of Zen: L-theanine boosts alpha waves, promotes alert relaxation. | journal = Alternative & Complementary Therapies | date = April 2001 | volume = 7 | issue = 2 | pages = 91–95 | doi = 10.1089/10762800151125092 }} In the United States, the FDA considers it to be GRAS and allows its use as an ingredient in foods and beverages up to a maximum of 250 mg per serving.

In 2003, the German Federal Institute for Risk Assessment (Bundesinstitut für Risikobewertung, BfR), an agency of their Federal Ministry of Food and Agriculture, objected to the addition of isolated theanine to beverages.{{cite web | title = Getränke mit isoliertem L-Theanin | trans-title = Drinks with isolated L-Theanine | date = June 2001 | work = Bundesinstitut für Riskobewertung (BfR) | trans-work = Federal Institute for Risk Assessment (BfR) | language = de | url = https://www.bfr.bund.de/cm/343/getraenke_mit_isoliertem_l_theanin.pdf}}{{cite book| vauthors = Kanarek RB, Lieberman HR |title=Diet, Brain, Behavior: Practical Implications|url=https://books.google.com/books?id=uTmyN1g5JgwC&pg=PA239|year= 2011|publisher=CRC Press|isbn=978-1-4398-2156-5|pages=239–}} 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 were 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, 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.{{cite web |url=http://www.bfr.bund.de/cm/208/getraenke_mit_isoliertem_l_theanin.pdf |title=Getränke mit isoliertem L-Theanin |trans-title=Beverages with isolated L-theanine |publisher=Bundesinstitut für Risikobewertung |language=de |date=August 2003}}

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.{{cite news |url=https://www.delo.si/novice/slovenija/inspekcija-prepovedala-prodajo-pijace-prime-zaradi-nedovoljene-sestavine/ |title=Inšpekcija prepovedala prodajo pijače Prime zaradi nedovoljene sestavine |language=sl |trans-title=Inspection Bans Sale of Prime Because of an Unauthorised Ingredient |newspaper=Delo.si |date=13 November 2023}}

Research on supplement use

A 2020 review suggested 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 medication to treat stress and anxiety.{{cite journal | vauthors = Williams JL, Everett JM, D'Cunha NM, Sergi D, Georgousopoulou EN, Keegan RJ, McKune AJ, Mellor DD, Anstice N, Naumovski N | title = The Effects of Green Tea Amino Acid L-Theanine Consumption on the Ability to Manage Stress and Anxiety Levels: a Systematic Review | journal = Plant Foods for Human Nutrition | volume = 75 | issue = 1 | pages = 12–23 | date = March 2020 | pmid = 31758301 | pmc = | doi = 10.1007/s11130-019-00771-5 | bibcode = 2020PFHN...75...12W | hdl-access = free | s2cid = 208213702 | hdl = 11392/2459663 }} Evidence from a systematic review of randomised controlled trials suggests that L-theanine supplementation may be more effective than placebo in alleviating psychopathological symptoms associated with anxiety disorders, ADHD, and schizophrenia.{{cite journal | vauthors = Moshfeghinia R, Sanaei E, Mostafavi S, Assadian K, Sanaei A, Ayano G | title = The effects of L-theanine supplementation on the outcomes of patients with mental disorders: a systematic review | journal = BMC Psychiatry | volume = 24 | issue = 1 | pages = 886 | date = December 2024 | pmid = 39633316 | pmc = 11616108 | doi = 10.1186/s12888-024-06285-y | doi-access = free }}

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 in studies provided at that time.