L-Theanine

Scientific Name(s): Gamma-ethylamino-L-glutamic acid ; derived from Boletus badius and Camellia sinensis .

Common Name(s): L-theanine , Suntheanine

Uses

L-theanine may help relieve stress by inducing a relaxing effect without drowsiness and may also possess immunologic attributes. Theanine may also have effects on the cardiovascular system and play a preventative role in cancer; however, limited clinical information is available to support these claims.

Dosing

Data supporting a clinical role for theanine are weak. Studies reporting an anxiolytic effect used single doses of theanine 200 to 250 mg.

Contraindications

None well established.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

Few adverse reactions have been reported. Adverse reactions recorded in human pharmacokinetic studies using tea extracts include headache, dizziness, and GI symptoms.

Toxicology

Theanine is sold in the United States as a dietary supplement and has been granted GRAS (generally recognized as safe) status by the Food and Drug Administration (FDA).

Botany

Theanine is derived from the leaves of Camellia sinensis (tea) and 2 other Camellia species ( Camellia japonica and Camellia sasanqua ). C. sinensis is native to eastern Asia and is a member of the Theaceae family. This evergreen shrub or tree grows to over 9 m in height and is pruned from 60 cm to 1.5 m for cultivation. Its dark green, serrated-edged leaves are alternate and oval, while its white and fragrant blossoms appear singly or in clusters. 1 , 2

The chemical has also been isolated from the edible mushroom Boletus badius , although information is limited to a single 1960 publication. 3 The mushroom is commonly found in late summer and autumn in the United States, and is reddish brown to dark brick/brown in color with a 4 to 12 cm tall stem. The flesh is white to yellow in color, and becomes a light blue/green color when cut or bruised.

History

Second only to water, tea is the most widely consumed beverage in the world. L-theanine was discovered as a constituent of green tea in 1949 and was approved in Japan in 1964 for unlimited use in all foods, including chocolates, soft drinks, and herb teas, except infant foods. It also provides a unique umami (brothy or savory) taste and flavor to green tea infusion. 2 , 4

Chemistry

L-theanine (or L-gamma-glutamylethylamide) was discovered in 1949 and constitutes 1% to 2% of the dry weight of tea leaves. It exists only in the free (nonprotein) form. An enzymatic method for manufacturing synthetic L-theanine ( Suntheanine ) has been developed. 2 , 4 , 5

Uses and Pharmacology

Cancer

Limited studies evaluate the effects of L-theanine in the prevention of cancer. A Cochrane meta-analysis of the effects of green tea in cancer has found insufficient and conflicting evidence to support a preventative role. 6 The observed anticancer effects are largely attributed to the catechins found in tea, 6 while action on tumors may be due to an enhanced immune response. 7

Cardiovascular effects

A dose-dependent hypotensive effect was demonstrated in spontaneously hypertensive rats, but not in normotensive ones. The effect may have been related to reduction in central levels of dopamine and serotonin. 2 In healthy volunteers, synthetic theanine 200 mg muted the increase in heart rate response to an acute stress test, 8 while theanine has been observed to antagonize the hypertensive effect of caffeine. 9 L-theanine exerts a weak (compared with green tea) antioxidant action as measured by the inhibition of LDL oxidation. 2 , 10

CNS effects

Although the pharmacological effects of theanine are uncertain, several researchers have proposed a number of mechanisms by which it may act on the CNS. These include the inhibition of glutamate receptors, increasing the concentration of gamma-aminobutyric acid (GABA), increasing dopamine and serotonin in specific brain regions, and neuroprotective blockage of multiple glutamate receptor subtypes in the hippocampus, suggesting a potential role in Parkinson disease. 5 , 11 , 12

Clinical data

L-theanine is able to cross the blood-brain barrier, and most research has focused on its relaxing effect. Studies have evaluated the effect of theanine alone or in combination with caffeine in concentrations naturally found in tea, and use self-reporting measures of stress and electroencephalographic recordings of brain activity. However, study data are inconsistent in methodology and outcome measures, making comparisons difficult. 4 , 8 , 9 , 11 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20

An effect of wakeful relaxation of theanine alone is apparent in most published data. The effect is weak in comparison with benzodiazepines, and may differ with consumption of theanine in the relaxed state versus an already anxious state. Some studies suggest a positive contribution to cognitive performance. 5 , 11 , 17 , 21

Immune system functioning

A limited number of studies conducted primarily by 2 groups of researchers suggest L-theanine may enhance the action of immune system components.

Results of in vitro studies, a pilot study, and a small clinical trial suggest that the enhancement of gamma delta T lymphocytes may play a role in the observed decrease in cold and influenza symptoms. A combination preparation was used in the clinical trial. 7 , 22 , 23

Other researchers have evaluated the combined effect of L-cystine and L-theanine on the immunologic response to vaccinations in the elderly and to exercise in athletes, as well as in rats, and suggest an enhanced immunologic response. 8 , 24 , 25 , 26

Other effects

L-theanine showed no hepatoprotective effect in an in vitro study. 27

Dosage

L-theanine crosses the blood-brain barrier, with effects evident within 30 minutes and measurable up to 5 hours after administration. 5 , 15 , 19 The chemical is metabolized in the kidneys to glutamic acid and ethylamine. 28 Data supporting a clinical role for theanine are weak. Studies reporting an anxiolytic effect used single doses of theanine 200 to 250 mg. 8 , 9 , 16 , 17 , 20 No dosage of L-theanine is suggested for enhanced immune system functioning.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. 29

Interactions

Clinical data are limited. L-theanine counteracted the stimulatory effect of caffeine in rats, although at smaller doses excitatory effects were observed. 2

Adverse Reactions

Information regarding adverse reactions to theanine alone (versus combined with caffeine, as in tea) is lacking. Clinical trials used small numbers of participants and reported poorly on adverse events. One study among elderly participants recorded a higher number of reported headaches among those receiving 4 doses of theanine 250 mg. 16

There are no reports of clinical toxicity from daily tea consumption. Adverse reactions recorded in human pharmacokinetic studies using tea extracts include headache, dizziness, and GI symptoms. 6

Toxicology

Theanine is sold in the United States as a dietary supplement and has been granted GRAS status in doses up to 250 mg per serving by the FDA. 30

The median lethal dose (LD 50 ) of L-theanine is suggested to be 5 g/kg. Mutagenicity and acute and subacute toxicity tests have failed to show toxicity of synthetic L-theanine. 4

A toxicological study in rats showed no effect on behavior, morbidity, mortality, body weight, hematology, or urinalysis. An increased incidence of renal tubule adenomas in a small number of female rats given high dosages (400 mg/kg body weight per day) was attributed to genetic predisposition. 31

Bibliography

1. L-Theanine. USDA, NRCS. 2010. The PLANTS Database ( http://plants.usda.gov , 1 March 2010). National Plant Data Center, Baton Rouge, LA 70874-4490 USA.
2. L-theanine. Monograph. Altern Med Rev . 2005;10(2):136-138.
3. Casimir J, Jadot J, Rendard M. Separation and characterization of N-ethyl-gamma-glutamine from Xerocomus badius [in French]. Biochim Biophys Acta . 1960;39:462-468.
4. Juneja LR, Chu D-C, Okubo T, Nagato Y, Yokogoshi H. L-theanine-a unique amino acid of green tea and its relaxation effect in humans. Trends Food Sci Technol . 1999;10:199-204.
5. Bryan J. Psychological effects of dietary components of tea: caffeine and L-theanine. Nutr Rev . 2008;66(2):82-90.
6. Boehm K, Borrelli F, Ernst E, et al. Green tea ( Camellia sinensis ) for the prevention of cancer. Cochrane Database Syst Rev . 2009;(3):CD005004.
7. Percival SS, Bukowski JF, Milner J. Bioactive food components that enhance gammadelta T cell function may play a role in cancer prevention. J Nutr . 2008;138(1):1-4.
8. Kimura K, Ozeki M, Juneja LR, Ohira H. L-Theanine reduces psychological and physiological stress responses. Biol Psychol . 2007;74(1):39-45.
9. Rogers PJ, Smith JE, Heatherley SV, Pleydell-Pearce CW. Time for tea: mood, blood pressure and cognitive performance effects of caffeine and theanine administered alone and together. Psychopharmacology (Berl) . 2008;195(4):569-577.
10. Bolling BW, Chen CY, Blumberg JB. Tea and health: preventive and therapeutic usefulness in the elderly? Curr Opin Clin Nutr Metab Care . 2009;12(1):42-48.
11. Lu K, Gray MA, Oliver C, et al. The acute effects of L-theanine in comparison with alprazolam on anticipatory anxiety in humans. Hum Psychopharmacol . 2004;19(7):457-465.
12. Cho HS, Kim S, Lee SY, Park JA, Kim SJ, Chun HS. Protective effect of the green tea component, L-theanine on environmental toxins-induced neuronal cell death. Neurotoxicology . 2008;29(4):656-662.
13. Kobayashi K, Nagato Y, Aoi N, et al. Effects of L-theanine on the release of alpha-brain waves in human volunteers. Nippon Nogeikagaku Kaishi . 1998:72:153-157.
14. Kelly SP, Gomez-Ramirez M, Montesi JL, Foxe JJ. L-theanine and caffeine in combination affect human cognition as evidenced by oscillatory alpha-band activity and attention task performance. J Nutr . 2008;138(8):1572S-1577S.
15. Nobre AC, Rao A, Owen GN. L-theanine, a natural constituent in tea, and its effect on mental state. Asia Pac J Clin Nutr . 2008;17(suppl 1):167-168.
16. Haskell CF, Kennedy DO, Milne AL, Wesnes KA, Scholey AB. The effects of L-theanine, caffeine and their combination on cognition and mood. Biol Psychol . 2008;77(2):113-122.
17. Gomez-Ramirez M, Kelly SP, Montesi JL, Foxe JJ. The effects of L-theanine on alpha-band oscillatory brain activity during a visuo-spatial attention task. Brain Topogr . 2009;22(1):44-51.
18. Dimpfel W, Kler A, Kriesl E, Lehnfeld R. Theogallin and L-theanine as active ingredients in decaffeinated green tea extract: I. electrophysiological characterization in the rat hippocampus in-vitro. J Pharm Pharmacol . 2007;59(8):1131-1136.
19. Dimpfel W, Kler A, Kriesl E, Lehnfeld R. Theogallin and L-theanine as active ingredients in decaffeinated green tea extract: II. Characterization in the freely moving rat by means of quantitative field potential analysis. J Pharm Pharmacol . 2007;59(10):1397-1403.
20. Dimpfel W, Kler A, Kriesl E, Lehnfeld R, Keplinger-Dimpfel IK. Source density analysis of the human EEG after ingestion of a drink containing decaffeinated extract of green tea enriched with L-theanine and theogallin. Nutr Neurosci . 2007;10(3-4):169-180.
21. Owen GN, Parnell H, De Bruin EA, Rycroft JA. The combined effects of L-theanine and caffeine on cognitive performance and mood. Nutr Neurosci . 2008;11(4):193-198.
22. Kamath AB, Wang L, Das H, Li L, Reinhold VN, Bukowski JF. Antigens in tea-beverage prime human Vgamma 2Vdelta 2 T cells in vitro and in vivo for memory and nonmemory antibacterial cytokine responses. Proc Natl Acad Sci U S A . 2003;100(10):6009-6014.
23. Bukowski JF, Percival SS. L-theanine intervention enhances human gammadeltaT lymphocyte function. Nutr Rev . 2008;66(2):96-102.
24. Miyagawa K, Hayashi Y, Kurihara S, Maeda A. Co-administration of l-cystine and l-theanine enhances efficacy of influenza vaccination in elderly persons: nutritional status-dependent immunogenicity. Geriatr Gerontol Int . 2008;8(4):243-250.
25. Kurihara S, Shibahara S, Arisaka H, Akiyama Y. Enhancement of antigen-specific immunoglobulin G production in mice by co-administration of L-cystine and L-theanine. J Vet Med Sci . 2007;69(12):1263-1270.
26. Murakami S, Kurihara S, Koikawa N, et al. Effects of oral supplementation with cystine and theanine on the immune function of athletes in endurance exercise: randomized, double-blind, placebo-controlled trial. Biosci Biotechnol Biochem . 2009;73(4):817-821.
27. Lee SI, Kim HJ, Boo YC. Effect of green tea and (-)-epigallocatechin gallate on ethanol-induced toxicity in HepG2 cells. Phytother Res . 2008;22(5):669-674.
28. Desai MJ, Gill MS, Hsu WH, Armstrong DW. Pharmacokinetics of theanine enantiomers in rats. Chirality . 2005;17(3):154-162.
29. Ernst E. Herbal medicinal products during pregnancy: are they safe? BJOG . 2002;109(3):227-335.
30. US Food and Drug Administration. Division of Biotechnology and GRAS Notice Review (HFS-255). Office of Premarket Approval. Center for Food Safety and Applied Nutrition. Determination of the GRAS Status of Suntheanine ¯ L-Theanine for Use in Food. February 2006. http://www.accessdata.fda.gov/scripts/fcn/gras_notices/615880A.pdf . Accessed March 1, 2010.
31. Borzelleca JF, Peters D, Hall W. A 13-week dietary toxicity and toxicokinetic study with l-theanine in rats. Food Chem Toxicol . 2006;44(7):1158-1166.

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