Theanine: a useful and a supplement, generally recognized as safe (GRAS)

What kinds of theanine do we get on the market?

There are two sorts of supplements available on the market:

1. a synthetic form, mostly branded under the name Suntheanine and consisting of  purified L-theanine which is derived from chemical, enzymatic synthesis and

2. a pure natural form, l-theanine, consisting of the natural aminoacid in tea leaves and produced by a natural fermentation process of these tea leaves.

The subject ingredient of tea leaves, the compound L-theanine, is an amino acid which is also known under different names,  y-glutamylethylamide or N-ethyl-L-glutamine.

L-theanine
occurs in tea-leaves and is soluble in hot water

L-Theanine is
naturally occurring at high concentrations in the leaves of the green tea
plant, Camellia sinensis.

L- Theanine
accounts for approximately I-2% of the dry weight of tea leaves and is
water-soluble. Steeping C. sinensis leaves in hot water creates tea, the most
commonly consumed beverage in the world. After steeping, the majority of
theanine is solubilized and can easily enter the body via the stomach and the
guts.

How to make
natural L-theanine

If we do not
want l-theanine via chemical synthesis, we can isolate l-theanine from tea
leaves. How does such an isolation takes place?

Theanine, which
as we saw is water soluble, can be naturally extracted from the leaves by
incubating the leaves with water at around sixty degrees Celsius for some
hours. The extract can then be concentrated, centrifuged, isolated and purified
through membrane ultrafiltration to a very high degree of purity.

L-theanine is
very stable and does not deteriorate after years

Once in a
capsule, l-theanine is a very stable compound, and even at high temperature it
does not become unstable or degrades. The so called shelf life of theanine has
been found to be at least 2 years.

Amount of
l-theanine intake each day and recommended dose

In the form of
tea, theanine is a widely consumed ingredient which has been a part of the
human diet for thousands of years. World tea production in 2001 has been
reported to be 3.02 million tons.

Based on a 2003
world population of about 6.2 billion, per capita consumption of 120 mL of tea
equates to daily consumption of nearly a million metric tons of tea. Thus, the
available evidence suggests that there is a common exposure to tea and to its
constituent, L-theanine. Despite this long history, no adverse effects due to
ingestion of tea or L-theanine have been reported. L-Theanine has also been
used as a dietary supplement in the US since the 1990s without any reports of
adverse effects.

Recent studies by Kat et al. (2003) and Ekborg-Ott et al. ( I997) found the average theanine concentration
among tea varieties was approximately 1.4%. A typical cup of tea uses 3 g of tea leaves, which contains about 30 mg of theanine.

Based on the typical
concentration of L-theanine in tea (1-2.5%), in the estimated daily intake of
L-theanine from tea was determined to be between 153 and 382 mg/person/day at the mean and between 330 and 825 mg/person/day at the 90th percentile.

These estimates indicate that the estimated daily intake of L-theanine
between 450-900 mg/day corresponds with the levels of L-theanine currently
consumed by the heaviest tea drinkers in the United States. Thus it is
perfectly safe to ingest each day 3 times 150 mg to 6 times 150 mg capsules.

How come theanine protects cells and even neurons in the brain?

Since L-theanine crosses the blood-brain
barrier, and is an analog of the major excitatory neurotransmitter glutamate, a
number of studies have examined the effects of L-theanine on neuraltissues.

Research has shown that L-theanine is
capable of binding to both glutamate receptors and glutamate transporters.

Glutamate receptors are mostly found in
the post-synaptic cells, and are responsible for transmitting the excitatory
glutamate signal. The glutamate transporters are mostly found in neuronal and
glial cells; they remove glutamate from the extracellular synaptic space and
help to regulate glutamate levels and thus neuronal signaling. In brain injury
and disease, an excess of glutamate causes oxidative damage, known as
excitotoxicity, which can ultimately lead to neuronal cell death.

Theanine appears to provide
neuroprotection by reducing levels of glutamate, thus inhibiting
glutamate-induced excitotoxicity.

Research studies have shown that theanine
binds to two glutamate receptors,  both
the so called ionotropic and metabotropic glutamate receptors. The first
receptor arranges ions to stream in and out off neurons, the second receptor
initiates metabolic activity in the cells.

The ionotropic glutamate receptors conduct
neuronal signals through ligand-gated ion channels.     

In an early study, Shinozaki and lshida
(1978) reported that theanine functions as a glutamate antagonist at the
crayfish neurom uscularj unction. Later, Kakuda et al. (2000) demonstrated that
theanine provided dose-dependent protection from ischemic delayed neuronal
death induced by glutamic acid in brainfield CAI of the gerbil hippocampus.

Theanine literature 

Blumberg, J. (2003). Introduction to the proceedings of the third international scientific symposium on tea and human

health:roleofflavonoidsinthediet. JNutr133(Suppl):3244s-3246s.

Borzelleca, J. F., D. Peters, Hall, W., 2006. A 13-week dietary toxicity and toxicokinetic study with I-theanine in rats. Food Chem Toxicol44(7): 1158-66.

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

Graham, H.N., 1992. Green tea composition, consumption, and polyphenol chemistry. Prev Med 21: 334-350. 

Kakuda,T.,Yanase,H.,Utsunomiya,K.,Nozawa,A.,Unno,T.,Kataoka,K.,2000. Protective effect of gamma- glutamylethylamide (theanine) on ischemic delayed neuronal death in gerbils. Neurosc iLett289(3):189-192. 

More literature 

1. Singal A, Kaur S, Tirkey N, Chopra K. Green tea extract and catechin ameliorate chronic fatigue-induced oxidative stress in mice. J Med Food. 2005;8(1):47-52.

2. Hossain SJ, Aoshima H, Koda H, Kiso Y. Fragrances in oolong tea that enhance the response of GABAA receptors. Biosci Biotechnol Biochem. 2004 Sep;68(9):1842-8.

3. Huang Y, Chan NW, Lau CW, et al. Involvement of endothelium/nitric oxide in vasorelaxation induced by purified green tea (-)epicatechin. Biochim Biophys Acta. 1999 Apr 19;1427(2):322-8.

4. Unno K, Takabayashi F, Kishido T, Oku N. Suppressive effect of green tea catechins on morphologic and functional regression of the brain in aged mice with accelerated senescence (SAMP10). Exp Gerontol. 2004 Jul;39(7):1027-34.

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

6. Quinlan PT, Lane J, Moore KL, et al. The acute physiological and mood effects of tea and coffee: the role of caffeine level. Pharmacol Biochem Behav. 2000 May;66(1):19-28.

7. Hintikka J, Tolmunen T, Honkalampi K, et al. Daily tea drinking is associated with a low level of depressive symptoms in the Finnish general population. Eur J Epidemiol. 2005;20(4):359-63.

8. Negishi H, Xu JW, Ikeda K, et al. Black and green tea polyphenols attenuate blood pressure increases in stroke-prone spontaneously hypertensive rats. J Nutr. 2004 Jan;134(1):38-42.

9. Davies MJ, Judd JT, Baer DJ, et al. Black tea consumption reduces total and LDL cholesterol in mildly hypercholesterolemic adults. J Nutr. 2003 Oct;133(10):3298S-3302S.

10. Casimir J, Jadot J, Renard M. Separation and characterization of N-ethyl-gamma-glutamine from Xerocomus badius. Biochim Biophys Acta. 1960 Apr 22;39:462-8.

11. Chilcott LA and Shapiro CM. The socioeconomic impact of insomnia. An overview. Pharmacoeconomics. 1996;10 Suppl 11-14.

12. George J, Murphy T, Roberts R, Cooksley WG, Halliday JW, Powell LW. Influence of alcohol and caffeine consumption on caffeine elimination. Clin Exp Pharmacol Physiol. 1986 Oct;13(10):731-6.

13. Broughton LJ, Rogers HJ. Decreased systemic clearance of caffeine due to cimetidine. Br J Clin Pharmacol. 1981 Aug;12(2):155-9.

14. Gilbert RM, Marshman JA, Schwieder M, Berg R. Caffeine content of beverages as consumed. Can Med Assoc J. 1976 Feb 7;114(3):205-8.

15. McCusker RR, Goldberger BA, Cone EJ. Caffeine content of specialty coffees. J Anal Toxicol. 2003 Oct;27(7):520-2.

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

17. Kimura R, Kurita M, Murata T. Influence of alkylamides of glutamic acid and related compounds on the central nervous system. III. Effect of theanine on spontaneous activity of mice (author’s transl). Yakugaku Zasshi. 1975 Jul;95(7):892-5.

18. Nicassio PM, Boylan MB, McCabe TG. Progressive relaxation, EMG biofeedback and biofeedback placebo in the treatment of sleep-onset insomnia. Br J Med Psychol. 1982 Jun;55(Pt 2):159-66.

19. Friedman L, Bliwise DL, Yesavage JA, Salom SR. A preliminary study comparing sleep restriction and relaxation treatments for insomnia in older adults. J Gerontol. 1991 Jan;46(1):1-8.

20. Coursey RD, Frankel BL, Gaarder KR, Mott DE. A comparison of relaxation techniques with electrosleep therapy for chronic, sleep-onset insomnia a sleep-EEG study. Biofeedback Self Regul. 1980 Mar;5(1):57-73.

21. Available at: http://nutraingredients.com/ news/news-ng.asp?id=50679-green-tea-lulls. Accessed October 12, 2005.

22. US Patent Application 20040171624; Japanese Patent Application 2001-253740.

23. Calabrese JR, Kling MA, Gold PW. Alterations in immunocompetence during stress, bereavement, and depression: focus on neuroendocrine regulation. Am J Psychiatry. 1987 Sep;144(9):1123-34.

24. Ou XM, Storring JM, Kushwaha N, Albert PR. Heterodimerization of mineralocorticoid and glucocorticoid receptors at a novel negative response element of the 5-HT1A receptor gene. J Biol Chem. 2001 Apr 27;276(17):14299-307.

25. Bhatia V, Tandon RK. Stress and the gastrointestinal tract. J Gastroenterol Hepatol. 2005 Mar;20(3):332-9.

26. Schleimer RP, Jacques A, Shin HS, Lichtenstein LM, Plaut M. Inhibition of T cell-mediated cytotoxicity by anti-inflammatory steroids. J Immunol. 1984 Jan;132(1):266-71.

27. Price LH, Cappiello A, Malison RT, et al. Effects of antiglucocorticoid treatment on 5-HT1A function in depressed patients and healthy subjects. Neuropsychopharmacology. 1997 Oct;17(4):246-57.

28. Janowsky DS, Risch SC, Huey LY, Judd LL, Rausch JL. Hypothalamic=pituitary-adrenal regulation, neurotransmitters and affective disorder. Peptides. 1983 Sep-Oct;4(5):775-84.

29. Gartside SE, Leitch MM, Young AH. Altered glucocorticoid rhythm attenuates the ability of a chronic SSRI to elevate forebrain 5-HT: implications for the treatment of depression. Neuropsychopharmacology. 2003 Sep;28(9):1572-8.

30. McEwen BS. Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism. 2005 May;54(5 Suppl 1):20-3.

31. Sapolsky RM. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry. 2000 Oct;57(10):925-35.

32. Reus VI, Wolkowitz OM. Antiglucocorticoid drugs in the treatment of depression. Expert Opin Investig Drugs. 2001 Oct;10(10):1789-96.

33. Murphy BE. Antiglucocorticoid therapies in major depression: a review. Psychoneuroendocrinology. 1997;22 Suppl 1S125-32.

34. Paul IA, Skolnick P. Glutamate and depression: clinical and preclinical studies. Ann NY Acad Sci. 2003 Nov;1003:250-72.

35. Sanacora G, Gueorguieva R, Epperson CN, et al. Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry. 2004 Jul;61(7):705-13.

36. Trullas R, Skolnick P. Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol. 1990 Aug 21;185(1):1-10.

37. Huber TJ, Dietrich DE, Emrich HM. Possible use of amantadine in depression. Pharmacopsychiatry. 1999 Mar;32(2):47-55.

38. Shinozaki H, Ishida M. Theanine as a glutamate antagonist in crayfish neuromuscular junction. Brain Res. 1978 Jul 28;151(1):215-9.

39. Danilczuk Z, Ossowska G, Lupina T, Cieslik K, Zebrowska-Lupina I. Effect of NMDA receptor antagonists on behavioral impairment induced by chronic treatment with dexamethsome. Pharmacol Rep. 2005 Jan-Feb;57(1):47-54.

40. Hinoi E, Takarada T, Tsuchihashi Y, Yoneda Y. Glutamate transporters as drug targets. Curr Drug Targets CNS Neurol Disord. 2005 Apr;4(2):211-20.

41. Kolb JE, Trettel J, Levine ES. BDNF enhancement of postsynaptic NMDA receptors is blocked by ethanol. Synapse. 2005 Jan;55(1):52-7.

42. Yamada KA, Covey DF, Hsu CY, et al. The diazoxide derivative IDRA 21 enhances ischemic hippocampal neuron injury. Ann Neurol. 1998 May;43(5):664-9.

43. Bao HY, Zhang J, Yeo SJ, et al. Memory enhancing and neuroprotective effects of selected ginsenosides. Arch Pharm Res. 2005 Mar;28(3):335-42.

44. Tyszkiewicz JP, Yan Z. Beta-Amyloid peptides impair PKC-dependent functions of metabotropic glutamate receptors in prefrontal cortical neurons. J Neurophysiol. 2005 Jun;93(6):3102-11.

45. Egashira N, Hayakawa K, Mishima K, et al. Neuroprotective effect of gamma-glutamylethylamide (theanine) on cerebral infarction in mice. Neurosci Lett. 2004 Jun 3;363(1):58-61.

46. Chen Z, Li Y, Zhao LC, et al. A study on the association between tea consumption and stroke. Zhonghua Liu Xing Bing Xue Za Zhi. 2004 Aug;25(8):666-70.

47. Sadzuka Y, Inoue C, Hirooka S, et al. Effects of theanine on alcohol metabolism and hepatic toxicity. Biol Pharm Bull. 2005 Sep;28(9):1702-6.

48. Sugiyama T, Sadzuka Y. Theanine, a specific glutamate derivative in green tea, reduces the adverse reactions of doxorubicin by changing the glutathione level. Cancer Lett. 2004 Aug 30;212(2):177-84.

49. Sadzuka Y, Sugiyama T, Suzuki T, Sonobe T. Enhancement of the activity of doxorubicin by inhibition of glutamate transporter. Toxicol Lett. 2001 Sep 15;123(2-3):159-67.

50. Levine JA, Lanningham-Foster LM, McCrady SK, et al. Interindividual variation in posture allocation: possible role in human obesity. Science. 2005 Jan 28;307(5709):584-6.

51. Scott D, Rycroft JA, Aspen J, Chapman C, Brown B. The effect of drinking tea at high altitude on hydration status and mood. Eur J Appl Physiol. 2004 Apr;91(4):493-8.

52. Dulloo AG, Geissler CA, Horton T, Collins A, Miller DS. Normal caffeine consumption: influence on thermogenesis and daily energy expenditure in lean and postobese human volunteers. Am J Clin Nutr. 1989 Jan;49(1):44-50.

53. Dulloo AG, Seydoux J, Girardier L, Chantre P, Vandermander J. Green tea and thermogenesis: interactions between catechin-polyphenols, caffeine and sympathetic activity. Int J Obes Relat Metab Disord. 2000 Feb;24(2):252-8.

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