Theanine

L-Theanine
Clinical data
Other names	γ-L-Glutamylethylamide
Dependence liability	None
Routes of administration	Oral
ATC code	none
Legal status
Legal status	US: OTC UN: Unscheduled
Pharmacokinetic data
Onset of action	about 1 hour[1]
Elimination half-life	Capsule ~1.2 hours Green Tea ~0.8 hours[1]
Identifiers
IUPAC name (2S)-2-Ammonio-5-(ethylamino)-5-oxopentanoate[2] or N-Ethyl-L-glutamine
CAS Number	3081-61-6 Y
PubChem CID	439378
DrugBank	DB12444
ChemSpider	388498 Y
UNII	8021PR16QO
KEGG	C01047
ChEBI	CHEBI:17394 Y
ChEMBL	ChEMBL3039113
CompTox Dashboard (EPA)	DTXSID80184817
ECHA InfoCard	100.019.436
Chemical and physical data
Formula	C7H14N2O3
Molar mass	174.200 g·mol−1
3D model (JSmol)	Interactive image Interactive image
Melting point	174.20 °C (345.56 °F) [3]
Boiling point	215 °C (419 °F) [3]
SMILES CCNC(=O)CC[C@H](N)C(=O)O CCNC(=O)CCC(N)C(O)=O
InChI 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) Y Key:DATAGRPVKZEWHA-UHFFFAOYSA-N Y

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.^[3][4] It was discovered as a constituent of green tea in 1949; in 1950, it was isolated from gyokuro leaves.^[5] It constitutes about 1–2% of the dry weight of green tea leaves.^[4] Theanine provides a unique brothy or savory (umami) flavor to green tea infusions.

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.^[6] Most studies have used L-theanine. The opposite enantiomer, D-theanine, has been 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] The European Food Safety Authority found there was insufficient evidence for a cause-and-effect 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

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

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

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, so theanine can be considered to function as a donor that supplies glutamate to the body.^[16] Glutamate can be metabolized to glutamine in astrocytes, a process catalysed by Glutamine synthetase and can also be decarboxylated to GABA by Glutamate decarboxylase, thus theanine can supply the neurotransmitter pools of amino acids.^[17] It can also cross the blood–brain barrier intact, and register pharmacological effects directly.^[18]

Pharmacology

In vitro

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.^[19][20] It acts as an antagonist of the former two sites, and a partial co-agonist of the NMDA receptors.^[21] In vitro, theanine also binds to group I mGluRs.^[19][22] In addition, it inhibits glutamine transporters and glutamate transporters, and thus blocks the reuptake of glutamine and glutamate.^[20][23]

Theanine may elicit umami taste, a consequence potentially associated with binding to and activation of the T1R1 + T1R3 heterodimer or umami (savory) taste receptor.^[24]

In vivo

In laboratory studies, theanine increases serotonin, dopamine and glycine levels in various areas of the brain, as well as BDNF and NGF levels in certain brain areas.^[25]

Regulatory status

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][26] 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.^[27][28] 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.^[29]

Research on supplement use

A 2020 systematic review concluded that L-theanine supplementation between 200 and 400 mg per day may help reduce stress and anxiety in people with acute stress, but there was insufficient evidence for treatment of chronic stress.^[30]

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