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Theanine , also known as L-γ-glutamylethylamide and ''N''5-ethyl-L-glutamine, is an
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
analogue of the
proteinogenic amino acid Proteinogenic amino acids are amino acids that are incorporated biosynthetically into proteins during translation. The word "proteinogenic" means "protein creating". Throughout known life, there are 22 genetically encoded (proteinogenic) amino aci ...
s L-glutamate and L-glutamine and is found primarily in particular
plant Plants are predominantly photosynthetic eukaryotes of the kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all current definitions of Plantae exclud ...
and fungal species. It was discovered as a constituent of
green tea Green tea is a type of tea that is made from '' Camellia sinensis'' leaves and buds that have not undergone the same withering and oxidation process which is used to make oolong teas and black teas. Green tea originated in China, and since the ...
in 1949; in 1950, it was isolated from
gyokuro is a type of shaded green tea from Japan. It differs from the standard ''sencha'' (a classic unshaded green tea) in being grown under the shade rather than the full sun. The name "gyokuro" translates as "jewel dew" (or "jade dew"). While most s ...
leaves. Theanine provides a unique brothy or savory (
umami Umami ( from ja, 旨味 ), or savoriness, is one of the five basic tastes. It has been described as savory and is characteristic of broths and cooked meats. People taste umami through taste receptors that typically respond to glutamates and ...
) flavor to green tea infusions. The name "theanine" without a prefix generally implies the
enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...
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, with some restrictions in the case of infant foods.Sakato,Y. J. Agri. Chem. Soc. 1949, 23, 262–267 In the United States, the
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(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 The Federal Ministry of Food and Agriculture (german: Bundesministerium für Ernährung und Landwirtschaft, ), abbreviated BMEL, is a cabinet-level ministry of the Federal Republic of Germany. Its primary headquarters are located in Bonn with ...
, objects to the addition of L-theanine to beverages. In 2011 the
European Food Safety Authority The European Food Safety Authority (EFSA) is the agency of the European Union (EU) that provides independent scientific advice and communicates on existing and emerging risks associated with the food chain. EFSA was established in February 2002, ...
, when asked to provide a scientific opinion, concluded that a cause and effect relationship had not been established between consumption of L-theanine and improved cognitive function, alleviation of psychological stress, maintenance of normal sleep, or reduction of menstrual discomfort. Therefore, health claims for L-theanine are not recognized in the European Union.


Structure and properties

The chemical name ''N''5-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 In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...
, derived from the related proteinogenic L-amino acid
glutamic acid Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...
. Theanine is an analog of this amino acid, and its primary
amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...
, L-
glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral, ...
(also a proteinogenic amino acid). Theanine is a derivative of glutamine that is ethylated on the
amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...
nitrogen (as the name ''N''5-ethyl-L-glutamine describes), or alternatively, to the amide formed from ethylamine and L-glutamic acid at its γ- (5-) side chain
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...
group (as the name γ-L-glutamylethylamide describes). Relative to theanine, the opposite (D-, ''R-'') enantiomer is largely absent from the literature, except implicitly. While natural extracts that are not harshly treated are presumed to contain only the
biosynthetic Biosynthesis is a multi-step, enzyme-Catalysis, catalyzed process where substrate (chemistry), substrates are converted into more complex Product (chemistry), products in living organisms. In biosynthesis, simple Chemical compound, compounds are mo ...
L- enantiomeric form, mishandled isolates and racemic chemical preparations of theanines necessarily contain both theanine and its D-enantiomer (and from
racemic In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...
syntheses, in equal proportion), and studies have suggested that the D-isomer may actually ''predominate'' in some commercial supplement preparations. Amino acid
racemization In chemistry, racemization is a conversion, by heat or by chemical reaction, of an optically active compound into a racemic (optically inactive) form. This creates a 1:1 molar ratio of enantiomers and is referred too as a racemic mixture (i.e. con ...
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 ''Camellia sinensis'' is a species of evergreen shrub or small tree in the flowering plant family Theaceae. Its leaves and leaf buds are used to produce the popular beverage, tea. Common names include tea plant, tea shrub, and tea tree (not to ...
)'' in 1949, and in 1950 a laboratory in Kyoto successfully isolated it from
gyokuro is a type of shaded green tea from Japan. It differs from the standard ''sencha'' (a classic unshaded green tea) in being grown under the shade rather than the full sun. The name "gyokuro" translates as "jewel dew" (or "jade dew"). While most s ...
leaf, which has high theanine content. Theanine is substantially present in black, green, and white
tea Tea is an aromatic beverage prepared by pouring hot or boiling water over cured or fresh leaves of '' Camellia sinensis'', an evergreen shrub native to East Asia which probably originated in the borderlands of southwestern China and northe ...
s from ''Camellia sinensis'' in quantities of about 1% of the dry weight. Deliberately shading tea plants from direct sunlight, as is done for
matcha is finely ground powder of specially grown and processed green tea leaves, traditionally consumed in East Asia. The green tea plants used for matcha are shade-grown for three to four weeks before harvest; the stems and veins are removed during ...
and
gyokuro is a type of shaded green tea from Japan. It differs from the standard ''sencha'' (a classic unshaded green tea) in being grown under the shade rather than the full sun. The name "gyokuro" translates as "jewel dew" (or "jade dew"). While most s ...
green tea, increases L-theanine content. The L-
enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...
is the form found in freshly prepared teas and some human dietary supplements.


Digestion and metabolism

As a
structural analog A structural analog (analogue in modern traditional English; Commonwealth English), also known as a chemical analog or simply an analog, is a compound having a structure similar to that of another compound, but differing from it in respect to a ce ...
of
glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
and
glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral, ...
, 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. Glutamate can be metabolized to
glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral, ...
in astrocytes, a process catalysed by
Glutamine synthetase Glutamine synthetase (GS) () is an enzyme that plays an essential role in the metabolism of nitrogen by catalyzing the condensation of glutamate and ammonia to form glutamine: Glutamate + Adenosine triphosphate, ATP + NH3 → Glutamine + Ad ...
and can also be decarboxylated to GABA by
Glutamate decarboxylase Glutamate decarboxylase or glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the decarboxylation of glutamate to gamma-aminobutyric acid (GABA) and carbon dioxide (). GAD uses pyridoxal-phosphate (PLP) as a cofactor. The reaction p ...
, thus theanine can supply the neurotransmitter pools of amino acids. It can also cross the
blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
intact, and register pharmacological effects directly.


Pharmacology


Pharmacodynamics

Theanine is structurally similar to the excitatory neurotransmitter
glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
, and in accordance, binds to
glutamate receptor Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate (the conjugate base of glutamic acid) is abundant in the human body, but particularly in the nervous system a ...
s, though with much lower affinity in comparison. Specifically, it binds to
ionotropic glutamate receptor Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that are activated by the neurotransmitter glutamate. They mediate the majority of excitatory synaptic transmission throughout the central nervous system and are key players in ...
s in the
micromolar Molar concentration (also called molarity, amount concentration or substance concentration) is a measure of the concentration of a chemical species, in particular of a solute in a solution, in terms of amount of substance per unit volume of sol ...
range, including the
AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, better known as AMPA, is a compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter glutamate. There are several types of glutamatergic ...
and
kainate receptor Kainate receptors, or kainic acid receptors (KARs), are ionotropic receptors that respond to the neurotransmitter glutamate. They were first identified as a distinct receptor type through their selective activation by the agonist kainate, a drug ...
s and, to a lesser extent, the
NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA rece ...
. It acts as an
antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
of the former two sites, and a partial co-agonist of the
NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA rece ...
s. Theanine also binds to
group I Group 1 may refer to: * Alkali metal, a chemical element classification for Alkali metal * Group 1 (racing), a historic (until 1981) classification for Touring car racing, applied to standard touring cars. Comparable to modern FIA Group N * Group On ...
mGluR The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs. Like all glutamate rece ...
s. In addition, it inhibits glutamine transporters and
glutamate transporter Glutamate transporters are a family of neurotransmitter transporter proteins that move glutamate – the principal excitatory neurotransmitter – across a membrane. The family of glutamate transporters is composed of two primary subclasses: the ex ...
s, and thus blocks the
reuptake Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal (i.e., the pre-synaptic neuron at a synapse) or glial cell after it has performed its function of transm ...
of glutamine and glutamate. Lastly, theanine elicits
umami Umami ( from ja, 旨味 ), or savoriness, is one of the five basic tastes. It has been described as savory and is characteristic of broths and cooked meats. People taste umami through taste receptors that typically respond to glutamates and ...
taste, and this effect has been found to be a consequence of the fact that it directly binds to and activates the T1R1 +
T1R3 Taste receptor type 1 member 3 is a protein that in humans is encoded by the ''TAS1R3'' gene. The ''TAS1R3'' gene encodes the human homolog of mouse Sac taste receptor, a major determinant of differences between sweet-sensitive and -insensitive mo ...
heterodimer In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...
or umami (savory) taste receptor. Theanine increases
serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
,
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
and
glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
levels in various areas of the brain, as well as
BDNF Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the cano ...
and NGF levels in certain brain areas. 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. It has also been found that injecting spontaneously hypertensive mice with theanine significantly lowered levels of 5-hydroxy
indole Indole is an aromatic heterocyclic organic compound with the formula C8 H7 N. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indole is widely distributed in the natural environmen ...
s in the brain. Researchers also speculate that it may inhibit
glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
excitotoxicity In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate re ...
.


Effects

A 2014
Natural Standard Natural Standard is an international research collaboration that systematically reviews scientific evidence on complementary and alternative medicine. Together with the faculty of Harvard Medical School, Natural Standard provides consumer inform ...
monograph that reviewed 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. Natural Standard rates the evidence to support the usage of theanine 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. However 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. and other subsequent studies have also concluded that it has an effect on reducing anxiety. In 2011, the EFSA (European Food Safety Authority) intervened with a scientific opinion on the alleged properties of L-theanine (improvement of cognitive functions, alleviation of psychological stress, maintenance of normal sleep conditions, reduction of menstrual pain) and concluded that at present there is no scientific evidence of a cause-and-effect relationship between the intake of L-theanine and the indicated benefits.


Supplement use

A 2020 systematic review concluded that L-theanine supplementation between 200 and 400 mg per day may help reduce stress and anxiety acutely in people with acute stress, but there is insufficient evidence for treatment of chronic stress. It further concluded that longer term and larger clinical study is needed to clinically justify its use therapeutically. In 2003, the German Federal Institute for Risk Assessment (''Bundesinstitut für Risikobewertung'', BfR) objected to the addition of isolated theanine to beverages. 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 Green tea is a type of tea that is made from '' Camellia sinensis'' leaves and buds that have not undergone the same withering and oxidation process which is used to make oolong teas and black teas. Green tea originated in China, and since the ...
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 Pharmacology is a branch of medicine, biology and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemica ...
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 Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...
effects of alcohol and
hypnotics Hypnotic (from Greek ''Hypnos'', sleep), or soporific drugs, commonly known as sleeping pills, are a class of (and umbrella term for) psychoactive drugs whose primary function is to induce sleep (or surgical anesthesiaWhen used in anesthesia ...
. The combination of theanine and
caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of adenosine t ...
has been shown to promote faster simple reaction time, faster numeric working memory reaction time and improved sentence verification accuracy. Studies have also concluded that an L-theanine and caffeine combination have improved sustained attention, impulsivity and cognition in children diagnosed with ADHD. Theanine has been reported to raise levels of brain serotonin and dopamine, with possible improvement in specific memory and learning tasks.


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.


See also

* ''gamma''-Glutamylmethylamide *
Green tea Green tea is a type of tea that is made from '' Camellia sinensis'' leaves and buds that have not undergone the same withering and oxidation process which is used to make oolong teas and black teas. Green tea originated in China, and since the ...


References


Further reading

* * {{Glutamate metabolism and transport modulators AMPA receptor antagonists Anxiolytics Carboxamides Excitatory amino acid reuptake inhibitors Kainate receptor antagonists NMDA receptor agonists Non-proteinogenic amino acids Substances discovered in the 1940s