Description
L-theanine is a non-protein amino acid mainly found naturally in the green tea plant (Camellia sinensis). It is also found naturally in only one other known source, the edible mushroom Boletus badius, commonly known as the Bay bolete. L-theanine is the predominant amino acid in green tea and makes up 50% of the total free amino acids in the plant. The amino acid constitutes between 1% and 2% of the dry weight of green tea leaves. L-theanine is considered the main component responsible for the taste of green tea, which in Japanese is called umami. Umami, which was first described by a Japanese scientist over a hundred years ago, is now considered one of the five basic tastes: sweet, salty, sour, bitter and umami. Umami is the Japanese term for savory. L-theanine has been marketed in Japan for several years as a nutritional supplement for mood modulation and entered the United States dietary supplement marketplace a few years ago.
L-theanine is a derivative of L-glutamic acid. It is a water-soluble solid substance with the molecular formula C7H14O3 N and a molecular weight of 160.19 daltons. L-theanine is also known as gamma-ethylamino-L-glutamic acid, gamma-glutamylethylamide, r-glutamylethylamide, L-glutamic acid gamma-ethylamide and L-N-ethylglutamine. The chemical structure is:
Chemical Structure
L-theanine
Actions & Pharmacology
Actions
L-theanine may have activity in modulating the metabolism of cancer chemotherapeutic agents and ameliorating their side effects. It may also have mood-modulating activity and neuroprotective and immunoprotective effects.
Mechanism of Action
In animal tumor models, L-theanine has been found to increase the antitumor activity of some anthracyline agents (doxorubicin, idarubicin) and to ameliorate some of the side effects of these agents. It appears that L-theanine inhibits the efflux of these agents from tumor cells, increasing the inhibitory concentration of the drugs in the target cells. At the same time, L-theanine appears to decrease the oxidative stress caused by these agents on normal cells. Most of the side effects of these agents are due to oxidative stress. The mechanism by which L-theanine inhibits the efflux of such cancer chemotherapeutic agents as doxorubicin is unclear. L-theanine appears to have modest antioxidant activity, and this may explain, in part, L-theanine's ability to ameliorate some of the side effects of the chemotherapeutic agents. Further, L-theanine, by an unclear mechanism, appears to inhibit the influx of chemotherapeutic normal cells.
The mechanism of L-theanine's possible mood-modulating activity is also unclear. The amino acid might affect the metabolism and the release of some neurotransmitters in the brain, such as dopamine.
Human gamma-delta T cells are known to mediate innate immunity to microbes through T cell receptor-dependent recognition of unprocessed antigens with conserved molecular patterns. The nonpeptide alkylamine antigens are shared by bacteria fungi, parasites, tumor cells and edible plant substances, including mushrooms, apples and green tea. It has been shown that L-theanine, a precursor of the nonpeptide antigen ethylamine, primed peripheral blood gamma-delta T cells to mediate a memory response on reexposure to ethylamine and to secrete interferon (IFN)-gamma in response to bacteria. Such priming may enhance innate immunity to bacteria and tumor cells and may account for some of the health benefits of green tea.
Pharmacokinetics
Little is known about the pharmacokinetics of L-theanine in humans. From animal studies, it appears that L-theanine is absorbed from the small intestine via a sodium-coupled active transport process and appears to cross the blood-brain barrier. It has been found in rat studies that the D-enantiomer of theanine may decrease the absorption of L-theanine, the L-enantiomer. It is unclear if D-theanine possesses any of the actions found with L-theanine. Not much is known beyond that. However, research is ongoing.
Indications & Usage
L-theanine has exhibited anticancer effects and an ability to favorably modulate the activity of some anticancer drugs in in vitro and animal experiments. It has also demonstrated hypotensive effects in animal work. It has inhibited LDL-cholesterol oxidation in preliminary in vitro tests. It was recently reported to enhance learning ability in animals and to induce relaxation in human subjects, possibly through its effects on serotonin, dopamine and other neurotransmitters. It has also been shown to inhibit caffeine stimulation in another preliminary animal study. It demonstrates some neuroprotective and immunoprotective effects.
Dosage
L-theanine supplements have been available in Japan for some time for promotion of relaxation and modulation of mood. Doses used are between 50 and 200 mg, as necessary. L-theanine supplements are now available in the United States.
L-theanine is also available in some green tea preparations. The amino acid constitutes between 1% and 2% of the dry weight of green tea leaves. Two to three cups of green tea contain approximately 30-50 milligrams of the amino acid. Matcha, a variety of fine, powdered green tea used in the Japanese tea ceremony, has a higher amount of L-theanine when compared to other green tea varieties.
Literature
Bryan J. Psychological effects of dietary components of tea: caffeine and L-theanine. Nutr Rev. 2008;66(2):82-90.Bukowski JF, Percival SS. L-theanine intervention enhances human gammadeltaT lymphocyte function. Nutr Rev. 2008;66(2):96-102.Desai MJ, Gill MS, Hsu WH, et al. Pharmacokinetics of theanine enantiomers in rats. Chirality. 2005;17(3):154-162.Egashira N, Hayakawa K, Mishima K, et al. Neuroprotective effect of gamma-glutamylethylamide (theanine) on cerebral infarction in mice. Neurosci Lett. 2004;363(1):58-61.Egashira N, Hayakawa K, Osajima M, et al. Involvement of GABA(A) receptors in the neuroprotective effect of theanine on focal cerebral ischemia in mice. J Pharmacol Sci. 2007;105(2):211-214.Egashira N, Ishigami N, Pu F, et al. Theanine prevents memory impairment induced by repeated cerebral ischemia in rats. Phytother Res. 2008;22(1):65-68.Eschenauer G, Sweet BV. Pharmacology and therapeutic uses of theanine. Am J Health Syst Pharm. 2006;63(1):26,28-30.Haskell CF, Kennedy DO, Milne AL, et al. The effects of L-theanine, caffeine and their combination on cognition and mood. Biol Psychol. 2008;77(2):113-122.Juneja LR, Chu D-C, Okubo T, et al. L-Theanine—a unique amino acid of green tea and its relaxation effect in humans. Trends Food Sci Tech. 1999;10:199-204.Kakuda T. Neuroprotective effects of the green tea components theanine and catechins. Biol Pharm Bull. 2002;25(12):1513-1518.Kakuda T, Nozawa A, Unno T, et al. Inhibiting effects of theanine on caffeine stimulation evaluated by EEG in the rat. Biosci Biotechnol Biochem. 2000;64:287-293.Kamath AB, Wang L, Das H, et al. 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 USA. 2003;100(10):6009-6014.Kimura K, Ozeki M, Juneja LR, et al. L-Theanine reduces psychological and physiological stress responses. Biol Psychol. 2007;74(1):39-45.Kitaoka S, Hayashi H, Yokogoshi H, et al. Transmural potential changes associated with the in vitro absorption of theanine in the guinea pig intestine. Biosci Biotechnol Biochem. 1996;60:1768-1771.Nathan PJ, Lu K, Gray M, et al. The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent. J Herb Pharmacother. 2006;6(2):21-30.Owen GN, Parnell H, De Bruin EA, et al. The combined effects of L-theanine and caffeine on cognitive performance and mood. Nutr Neurosci. 2008;11(4):193-198.Sadzuka Y, Inoue C, Hirooka S, et al. Effects of theanine on alcohol metabolism and hepatic toxicity. Biol Pharm Bull. 2005;28(9):1702-1706.Sadzuka Y, Sugiyama T, Miyagishima A, et al. The effects of theanine, as a novel biochemical modulator, on the antitumor activity of adriamycin. Cancer Lett. 1996;105;203-209.Sadzuka Y, Sugiyama T, Sonobe T. Efficacies of tea components on doxorubicin induced antitumor activity and reversal of multidrug resistance. Toxicology Lett. 2000;113:155-162.Sugiyama T, Sadzuka Y. Combination of theanine with doxorubicin inhibits hepatic metastasis of M5076 ovarian sarcoma. Clin Cancer Res. 1999;5:413-416.Sugiyama T, Sadzuka Y. Enhancing effects of green tea components on the antitumor activity of adriamycin against M5076 ovarian carcinoma. Cancer Lett. 1998;133:19-26.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;212(2):177-184.Sugiyama T, Sadzuka Y, Sonobe T. Theanine, a major amino acid in green tea, inhibits leukopenia and enhances antitumor activity induce by idarubicin. Proc Am Assoc Cancer Res. 1999;40:10(Abstract 63).Yamada T, Terashima T, Honma H, et al. Effects of theanine, a unique amino acid in tea leaves, on memory in a rat behavioral test. Biosci Biotechnol Biochem. 2008;72(5):1356-1359.Yamada T, Terashima T, Kawano S, et al. Theanine, gamma-glutamylethylamide, a unique amino acid in tea leaves, modulates neurotransmitter concentrations in the brain striatum interstitium in conscious rats. Amino Acids. Epub: 2008 Jan 15.Yokogoshi H, Kato Y, Sagesaka YM, et al. Reduction effect of theanine on blood pressure and brain 5-hydroxyindoles in spontaneous hypertensive rats. Biosci Biotechnol Biochem. 1995;59:615-618.Yokogoshi H, Kobayashi M. Hypotensive effect of gamma-glutamylmethylamide in spontaneously hypertensive rats. Life Sci. 1998;62:1065-1068.Yokogoshi H, Kobayashi M, Mochizuki M, et al. Effect of theanine, r-glutamylethylamide on brain monoamines and striatal dopamine release in conscious rats. Neurochem Res. 1998;23:667-673.Research & Summary
L-theanine has been shown to enhance the anticancer activity of doxorubicin and idarubicin in in vitro and animal studies. In an in vitro study, L-theanine increased doxorubicin's inhibition of Ehrlich ascites carcinoma more than two-fold and increased nearly three-fold the concentration of doxorubicin in the tumor compared with treatment with doxorubicin alone.
Subsequently, L-theanine, in combination with doxorubicin, was shown to significantly reduce tumor weight (to 62% of the control level) in M5076 ovarian sarcoma-bearing mice. The doxorubicin dose used in this combination was ineffective by itself in inhibiting tumor growth. L-theanine was reported to increase doxorubicin concentration in the tumor by two- to seven-fold while simultaneously decreasing doxorubicin concentrations in normal tissues.
A combination of L-theanine and doxorubicin significantly inhibited both primary ovarian sarcoma and hepatic metastasis of the tumor. L-theanine was credited in this study with enhancing the activity of doxorubicin.
In another study, L-theanine was used in conjunction with idarubicin, an anthracycline derivative used clinically to treat acute myelocytic leukemia. The use of idarubicin has been limited due to the frequency with which it produces severe leukopenia. Combined with idarubicin in the treatment of P388 leukemia-bearing mice, L-theanine significantly inhibited suppression of bone marrow cells and leukopenia, while simultaneously enhancing the antitumor activity of idarubicin.
L-theanine, in combination with doxorubicin, was further shown to have the ability to significantly inhibit even doxorubicin-resistant leukemia in mice.
In an in vitro test, L-theanine showed some ability to inhibit LDL peroxidation. The polyphenol component of a green-tea extract was more potent in this regard than the L-theanine component. The caffeine component, on the other hand, was less effective than L-theanine.
L-theanine has also exhibited hypotensive effects in spontaneously hypertensive rats but not in Wistar kyoto rats. Recently, L-theanine, at certain doses, was shown to inhibit caffeine stimulation, measured by electroencephalography in rats.
L-theanine, previously shown to penetrate the blood-brain barrier through the leucine-preferring transport system, has been demonstrated to produce significant increases in serotonin and/or dopamine concentrations in the brain, principally in the striatum, hypothalamus and hippocampus.
These findings led to recent studies investigating the possibility that L-theanine might enhance learning ability, induce relaxation and relieve emotional stress. Memory and learning ability were said to be improved in young male Wistar rats given 180 mg of L-theanine daily for four months. Performance was assessed using a test for learning ability and passive and active avoidance tests for memory.
In another recent study, rats fed L-theanine for three weeks ad libitum showed some signs of improved memory and learning. In a double-blind, randomized, placebo-controlled trial, the cognitive mood effects of L-theanine (250 mg) and caffeine (150 mg) were investigated both in isolation and in combination. The combination was found to improve some measures of mood and cognition. The mental effects of L-theanine were tested in a small group of volunteers divided into two groups defined as ""high-anxiety'' and ""low-anxiety'' groups. The volunteers were females aged 18 to 22. Their level of anxiety was assessed by a manifest anxiety scale. Subjects received water, 50 mg of L-theanine or 200 mg of L-theanine solution once a week. Brain waves were measured 60 minutes after administration. The 200 mg dose (dissolved in 100 ml of water) resulted in significantly greater production of alpha waves than was observed in subjects receiving water. Greatest production was consistently seen about 40 minutes after L-theanine intake. The effect was dose-dependent. The researchers regarded the significantly increased production of alpha-brain wave activity as an index of increased relaxation. More rigorous follow-up is needed.
A neuroprotective effect of L-theanine was observed in mice following middle cerebral artery occlusion. Size of cerebral infarct was reduced.
Recently, L-theanine was credited with enhancement of peripheral blood T cells, boosting immunologic memory. More research is indicated.
Contraindications, Precautions & Adverse Reactions
Contraindications
L-theanine is contraindicated in those who are hypersensitive to any component of an L-theanine-containing product.
Precautions
Pregnant women and nursing mothers should avoid L-theanine supplements. Use of L-theanine supplements concomitantly with cancer chemotherapeutic agents must be done under medical supervision.
Adverse Reactions
There are no known adverse reactions.
Interactions
Drugs
Doxorubicin and Idarubicin: L-theanine may enhance the antitumor effects of these drugs and may ameliorate some of their side effects.
