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Theanine Science
By David Tolson

Synonyms: Gamma-glutamylethylamide, 5-N-ethylglutamine

Introduction

Theanine, pronounced "tea-anene" (as in tea), is an amino acid found only in tea and a single species of mushroom (Xerocomus badius) in its free amino acid form. It was first identified and isolated as a major component of green tea in the late 1940's, and it was later found in other forms of tea as well [1-2]. Theanine constitutes around 50% of the amino acids in tea and makes up 1-2% of the dry weight of tea on average [2-3], although one source indicates that the number is closer to 1.5-3% [1]. This places the content in a normal cup of tea in the 20-60 mg range.

The amino acids, especially theanine, are one of the primary reasons for the taste of tea [2]. The amount of theanine in a cup of tea shows the highest correlation of any constituent with tea quality (as determined by tea tasters) [3]. The taste of theanine is described as "umami" or "brothy," which is separate from the four other basic tastes (sweet, sour, salty, bitter) [4]. About 20-25% of the population cannot distinguish this taste [5].

Theanine has been found to be involved in many of the effects of tea, which is known to have numerous benefits (see the green tea article).

Effects on Mood & Cognition

Theanine may have has shown to support mood. In human studies, oral administration of theanine has been reported to dose-dependently increase the production of alpha waves in the occipital and parietal regions of the brain [6-8]. According to one article, this signifies a state of being awake, alert, and relaxed at the same time. This effect occurs within 30-40 minutes of oral administration of 50-200 mg. It should be noted that the study population in this research consisted only of females 18-22 years of age, and this effect has not yet been confirmed in other human populations [8].

The behavioral effects of theanine on rodents have also been the subject of study. Theanine does not change activity level or exploration behavior in normal animals. However, it does improve performance on a number of tests of memory and learning, including the active avoidance test, the passive avoidance test, and the Morris water maze [9]. Using electroencephalography, it has also been determined that theanine antagonizes the effect of caffeine. If about eight times as much theanine than caffeine is given (on a per milligram basis), the effect of caffeine is completely blunted [2, 10]. It has been suggested that theanine is responsible for the relaxing effect of tea despite the caffeine content.

Animal studies have also explored the possible mechanism by which theanine leads to these effects. Theanine reliably causes a significant increase in CNS dopamine (DA) levels, especially in the striatum, hypothalamus, and hippocampus [2, 9, 11-12]. The effect theanine has on levels of other neurotransmitters is less well-established. It has been reported to both increase and decrease central serotonin levels [11-12]. One study indicated that it may decrease central norepinephrine [3]. Finally, a study in the early 70's reported that theanine may have an effect on the formation of gamma-aminobutyric acid (GABA) [13]. The direct mechanism for these changes is not clear, although it may be related to an effect at N-methyl-D-aspartate (NMDA) receptors [14].

Neuroprotection

Theanine has neuroprotective properties in experimental models. In animals, theanine has also been reported to increase the synthesis rate of nerve growth factor (NGF) [6].

The neuroprotective properties are thought to be primarily due to the fact that it is structurally similar to glutamate. Glutamate is an excitatory neurotransmitter, and in some instances it can cause excitotoxicity [14]. It has been traditionally thought that theanine prevents toxicity by acting as a competitive antagonist to glutamate at ionotropic glutamate receptors, of which there are three types, NMDA, alpha-amino-3-hydroxy-5-methylisoxazol-4-propionic acid (AMPA), and kainate (KA) [15]. In rat cortical neurons, theanine acted at all three subtypes, but had less binding affinity than glutamate. Also, the binding affinity to NMDA receptors was an order of magnitude lower than to AMPA and KA receptors [14]. It is possible that actions at all of the subtypes could play important roles in the activity of theanine.

Because the effective concentration in antagonizing ionotropic glutamate receptors is so low compared to glutamate, a more recent study hypothesized that the neuroprotective effect was related to an effect at metabotropic glutamate receptors instead [11]. This study found that inhibition of glutamate-induced neuronal death by theanine could be inhibited by an antagonist of group I metabotropic glutamate receptors. This indicates that this may be the mechanism for the neuroprotective effect of theanine. Given the current state of research, it is too early to draw any solid conclusions, as the effect of theanine could ultimately prove to be due to an action at any combination of these receptors. An effect on glutamate transporters may also be involved [14].

A final mechanism of neuroprotection is the antioxidant effect of theanine. One study suggested that one of the protective mechanisms was inhibition of lipid peroxidation. Vitamin E has also been found to inhibit ischemia induced by MCA occlusion [15].

Other Benefits

Tea drinking has been found to support the immune system in humans, and theanine and related compounds may be the reason. Theanine and its precursor ethylamine can act as antigens, which "prime" T cells and make them more able to respond effectively to challenges to the immune system by pathogens.

A final use for theanine is to hide the bitter taste of some foods or supplements. Although umami is not a strong taste, it effectively masks bitter tastes, such as the taste of caffeine, ginseng, some antioxidants, and bitter foods [13].

Suggested Use

After oral administration, theanine is absorbed in the intestine and then easily crosses into the brain from the bloodstream through an amino acid transporter [11, 15]. The increase in alpha wave activity in the brain is measurable within 30 minutes and maximized at the 40 minute point [8]. Although the pharmacokinetic profile in humans is not well-known, in rats, it is metabolized in the kidney to L-glutamate and ethylamine and is completely absent 24 hours after administration [1] [26].

No toxic effects of theanine have been reported, and green tea has a long history of safe use [1, 8]. Toxicology studies have failed to find any side effects or toxic effects associated with theanine, even in large amounts. In Japan, it underwent the 28 Day Subacute Toxicity Study, the 78 Week Evaluation of Toxicity and Carcinogenicity, the Acute Toxicity/LD50 Determination, and the Ames Salmonella Mutagenicity tests, and was subsequently approved for unlimited use as a food additive except in infant foods [13]. The LD50 is 5 g/kg [8].

The generally recommended dosage of theanine is 100-200 mg 2-3 times daily or as needed, although some sources recommend even higher doses. It can be used on a regular basis for general stress prevention and good health or saved for periods of high stress. Theanine does not have a strong taste and mixes easily in water.

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No part of this article may be reproduced in any form without the permission of David Tolson or Mike McCandless.


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References
1. Biochim Biophys Acta. 2003 Mar 17;1620(1-3):47-53. Theanine, gamma-glutamylethylamide, is metabolized by renal phosphate-independent glutaminase. Tsuge H, Sano S, Hayakawa T, Kakuda T, Unno T.

2. Rapid Commun Mass Spectrom. 2004;18(3):251-6. Analysis of derivatized and underivatized theanine enantiomers by high-performance liquid chromatography/atmospheric pressure ionization-mass spectrometry. Desai MJ, Armstrong DW.

3. J Chromatogr A. 2003 Sep 26;1013(1-2):183-9. Rapid analysis of amino acids in Japanese green tea by microchip electrophoresis using plastic microchip and fluorescence detection. Kato M, Gyoten Y, Sakai-Kato K, Toyo'oka T.

4. J Agric Food Chem. 2004 Feb 25;52(4):692-700. Metabolite profiling using (1)H NMR spectroscopy for quality assessment of green tea, Camellia sinensis (L.). Le Gall G, Colquhoun IJ, Defernez M.

5. Chem Senses. 2002 Feb;27(2):105-15. A new specific ageusia: some humans cannot taste L-glutamate. Lugaz O, Pillias AM, Faurion A.

6. Biochim Biophys Acta. 2003 Dec 5;1653(2):47-59. Theanine and glutamate transporter inhibitors enhance the antitumor efficacy of chemotherapeutic agents. Sugiyama T, Sadzuka Y.

7. J Agric Food Chem. 1999 Apr;47(4):1593-6. Metabolism of theanine, gamma-glutamylethylamide, in rats. Unno T, Suzuki Y, Kakuda T, Hayakawa T, Tsuge H.

8. Trends in Food Science & Technology. 1999;10(6-7):199-204. L-theanine – a unique amino acid of green tea and its relaxation effect in humans. Lekh Raj Jujena, Chu D, Okubo T, Nagato Y, and Yokogoshi H.

9. Nutrition. 2000 Sep;16(9):776-7. Effect of theanine, r-glutamylethylamide, on brain monoamines, striatal dopamine release and some kinds of behavior in rats. Yokogoshi H, Terashima T.

10. Biosci Biotechnol Biochem. 2000 Feb;64(2):287-93. Inhibiting effects of theanine on caffeine stimulation evaluated by EEG in the rat. Kakuda T, Nozawa A, Unno T, Okamura N, Okai O.

11. Biochem Biophys Res Commun. 2004 Jul 16;320(1):116-22. Possible involvement of group I mGluRs in neuroprotective effect of theanine. Nagasawa K, Aoki H, Yasuda E, Nagai K, Shimohama S, Fujimoto S.

12. Neurochem Res. 1998 May;23(5):667-73. Effect of theanine, r-glutamylethylamide, on brain monoamines and striatal dopamine release in conscious rats. Yokogoshi H, Kobayashi M, Mochizuki M, Terashima T.

13. Alternative & Complementary Therapies. 2001 April;7:91-95. 200 mg of Zen: L-theanine boosts alpha waves, promotes alert relaxation. Mason R.

14. Biosci Biotechnol Biochem. 2002 Dec;66(12):2683-6. Inhibition by theanine of binding of [3H]AMPA, [3H]kainate, and [3H]MDL 105,519 to glutamate receptors. Kakuda T, Nozawa A, Sugimoto A, Niino H.

15. Neurosci Lett. 2004 Jun 3;363(1):58-61. Neuroprotective effect of gamma-glutamylethylamide (theanine) on cerebral infarction in mice. Egashira N, Hayakawa K, Mishima K, Kimura H, Iwasaki K, Fujiwara M.

16. Biosci Biotechnol Biochem. 1995 Apr;59(4):615-8. Reduction effect of theanine on blood pressure and brain 5-hydroxyindoles in spontaneously hypertensive rats. Yokogoshi H, Kato Y, Sagesaka YM, Takihara-Matsuura T, Kakuda T, Takeuchi N.

17. Biosci Biotechnol Biochem. 2002 Apr;66(4):711-6. Effects of dietary powdered green tea and theanine on tumor growth and endogenous hyperlipidemia in hepatoma-bearing rats. Zhang G, Miura Y, Yagasaki K.

18. Exp Toxicol Pathol. 1997 Dec;49(5):329-35. Influence of green tea and its three major components upon low-density lipoprotein oxidation. Yokozawa T, Dong E.

19. Jpn J Cancer Res. 1999 Jul;90(7):775-80. Membrane transport and antitumor activity of pirarubicin, and comparison with those of doxorubicin. Sugiyama T, Sadzuka Y, Nagasawa K, Ohnishi N, Yokoyama T, Sonobe T.

20. Cancer Lett. 2000 Oct 1;158(2):119-24. Improvement of idarubicin induced antitumor activity and bone marrow suppression by theanine, a component of tea. Sadzuka Y, Sugiyama T, Sonobe T.

21. Cancer Lett. 1998 Nov 13;133(1):19-26. Enhancing effects of green tea components on the antitumor activity of adriamycin against M5076 ovarian sarcoma. Sugiyama T, Sadzuka Y.

22. Toxicol Lett. 2000 Apr 3;114(1-3):155-62. Efficacies of tea components on doxorubicin induced antitumor activity and reversal of multidrug resistance. Sadzuka Y, Sugiyama T, Sonobe T.

23. Proc Natl Acad Sci U S A. 2003 May 13;100(10):6009-14. Epub 2003 Apr 28.  Antigens in tea-beverage prime human Vgamma 2Vdelta 2 T cells in vitro and in vivo for memory and nonmemory antibacterial cytokine responses. Kamath AB, Wang L, Das H, Li L, Reinhold VN, Bukowski JF.

24. In Vivo. 2004 Jan-Feb;18(1):55-62. Anti-obesity effects of three major components of green tea, catechins, caffeine and theanine, in mice. Zheng G, Sayama K, Okubo T, Juneja LR, Oguni I.

25. Institute for Traditional Medicine (www.itmonline.org). Amino Acid Supplements IV: Theanine. Subhuti D. Referencing: Proceedings of the Nogei Kagaku Kai, Bioscience, Biotechnology, and Biochemistry. 2001;75:166. Theanine effects on premenstrual syndrome. Yokogoshi H, et al.

26. Biosci Biotechnol Biochem. 1999 Apr;63(4):615-8. Time-dependent changes of amino acids in the serum, liver, brain and urine of rats administered with theanine. Terashima T, Takido J, Yokogoshi H.






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