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AMINO ACID SUPPLEMENTS IV: THEANINE
Theanine (l-theanine; see Figure 1) is an amino acid found in ordinary tea leaves from Camellia sinensis (also known as Thea sinensis, hence the name theanine, pronounced like tea-anene). It is also found in other species of Camellia and in the edible bay boletes mushroom Xerocomus badius (see Figure 2), but is otherwise rare in nature. L-theanine has the reputation for promoting mental and physical relaxation-decreasing stress and anxiety-without inducing drowsiness. In the beverage tea, it has an influence on taste (reducing bitterness) and is said to counteract some of the nervous agitation that can come with caffeine.
Preliminary research, which needs to be carried much further before more specific claims for benefits can be properly made, suggests that l-theanine may be helpful for the following applications:
It has been indicated by laboratory studies that theanine produces these effects by increasing the level of GABA (gamma-amino-butyric acid), an important inhibitory neurotransmitter in the brain. GABA serves a sedative function that brings balance to excitability that can lead to restlessness, insomnia, and other disruptive conditions. Theanine also appears to increase levels of dopamine, another brain chemical with mood-enhancing effects, which can reduce blood pressure.
To get adequate quantities efficiently, l-theanine is synthesized, based on the way it is synthesized in the tea plant (1-3). The main manufacturer is Taiyo Kagaku Company of Japan, which produces a 99% pure amino acid. Theanine is a modification of the amino acid glutamine (see: Amino acid supplements I: Glutamine); with an ethyl group added. It is simply made from glutamate as starting material:
Reaction: ATP + l-glutamate + ethylamine yields: ADP + phosphate + l-theanine
This reaction takes place in tea roots; the theanine thus produced is transported to the plant tops. The same reaction is used to synthesize l-theanine on a commercial scale, using an enzymatic catalyst.
Theanine research began in the 1960s, and by 1964 the Japanese government approved use of theanine as a food additive for all foods except baby food. There are now more than 50 different food items that contain theanine sold in Japan, including soft drinks and chewing gum. It is included in these "functional food" products to provide an anti-stress effect.
The most active researcher investigating the pharmacology and applications of l-theanine is Hidehiko Yokogoshi, professor at the Food and Nutritional Sciences Department, University of Shizuoka. He has summarized the results of theanine effects this way:
Of all amino acids found in green tea, l-theanine is the most prevalent. L-theanine is known as the umami component [a taste component, see next page] within green tea. When l-theanine is administered to rats, it is absorbed in the intestinal tract and delivered to each organ. It is also delivered concentration-dependently to the brain. Increase of dopamine levels and changes of serotonin levels by l-theanine have been observed. In various behavioral tests, including discrimination learning test, passive avoidance test, active avoidance test, Morris water maze test, elevated plus maze test, and locomotion tests, improvements in memory and learning performance with the administration of l-theanine have been observed. In human subjects, the activity of the parasympathetic nervous system increased. Also, alpha waves in the brain increased significantly, inducing relaxation. In addition to the relaxation, administration of l-theanine was found to alleviate the symptoms of premenstrual syndrome (PMS), especially the mental conditions associated with PMS
The research on PMS was conducted at the University of Shizuoka; the comparison between l-theanine and placebo effects on the severity of symptoms has been displayed in the following graph:
Department of Food and Nutritional Sciences
at University of Shizuoka (Mt. Fuji in the background)
Another important area of research is the potential of theanine to protect neurons from excesses of glutamate. Glutamate is an essential brain chemical that may be released in excess amounts with some disease conditions (e.g., ALS and cerebrovascular dementia) and with brain injuries (as occurs with strokes or physical injuries). Theanine may protect against this damage by blocking glutamine entrance to cells due to the similarity in stereochemical structures of theanine and glutamine. In studies of isolated neuron cells and in gerbil studies, this protective effect is demonstrated. A leader in this research, and other studies of theanine neurological effects, is Dr. Takami Kakuda, formerly working at the Food and Nutrition Department with Dr. Yokogoshi, and now with the Central Research Institute, of Ito En, Ltd., in Shizuoka.
Umami is the term for a taste that is imparted to foods by amino acids, especially the widely used food additive monosodium glutamate. The concept of this taste was first promulgated more than 90 years ago in Japan and is of such interest that there is a Society for Research on Umami Taste in Japan (founded in 1982). The taste is pictorially displayed in relation to the standard taste groups (bitter, sweet, salty, sour) as follows (the three dimensional distribution indicates the relationships between the tastes; umami is depicted here as a receptor that fits most closely to the sweet and salty taste and is opposite the bitter taste):
In the case of theanine in tea, it is thought that this amino acid makes a significant contribution to the flavor of the beverage, which is dominated by the bitter taste of the polyphenols and caffeine, but is mellowed and broadened by the umami taste. As tea is brewed longer, the umami taste is overcome by both the bitter taste and an astringent quality of the polyphenols; so, it is important to use a proper brewing time.
In the description of Oriental herbs and foods, there are five tastes traditionally listed, including the four that are usually described in relation to taste receptors plus the taste described interchangeably as acrid, pungent, or spicy. Flavor researchers generally place this quality not as a taste, but as a general impact on the tongue (and mouth), that produces a tingly, numbing, or hot sensation. Further, in the herbal system, the sour quality is sometimes broadened to include astringency as a general feature, but the astringent quality can be given a separate designation. The astringent nature of the non-sour items (like pomegranate rind) is an effect on the tongue and mouth rather than an actual taste.
Meats, and other foods high in glutamine and related amino acids, are classified in the traditional system as having a sweet taste. This designation indicates that the taste is pleasant and desirable. Humans and animals are naturally attracted to foods that have the pleasant tastes, which include sweet and umami tastes, as these food substances play critical nutritional roles (by contrast, bitter tastes are often avoided, as they signal the potential for toxicity). The sweet and umami taste receptors have similar subunits. Only about 3 of 4 adults can distinguish the umami taste, based on glutamate, the others having weak receptor function.
The umami receptors of the tongue have been isolated in rats. They respond most strongly to glutamate but also demonstrate response to each of the 20 amino acids, suggesting that they function as amino acid taste receptors that are most sensitive to glutamate (and amino acids of similar structure). Amino acid tastes range from bland to umami to sweet, depending on the particular amino acid.
There has been a developing interest, with accelerated research that is still in the laboratory stage, into the potential of theanine as an adjunct to cancer chemotherapy. The lead researcher in this field is Yasuyuki Sadzuka, working at the School of Pharmaceutical Sciences, University of Shizuoka. In an abstract of one of his recent articles, examples of the application for theanine was presented with a description of the proposed mechanism:
We have confirmed that theanine, a major amino acid in green tea, enhances the antitumor activity of doxorubicin (DOX) without an increase in DOX-induced side effects. We believe that the action of theanine is due to decreases in glutamate uptake via inhibition of the glutamate transporter and reduction of glutathione and DOX export from the cell....To increase our knowledge of the potential clinical usefulness of theanine, we examined its effects on the antitumor activity of cisplatin and irinotecan (CPT-11), which is known to be transported out of tumor cells by the [same system]. Cisplatin decreased tumor volume in M5076 tumor-bearing mice. Furthermore, the combination of theanine with cisplatin enhanced the decrease in tumor volume as compared with the cisplatin-alone group. Tumor volume in the CPT-11-alone group did not show a decrease, but the combination of theanine with CPT-11 significantly reduced tumor volume. The concentration of cisplatin in the tumor was significantly increased by combination with theanine, and thus we assume that it correlated with the enhancement on the antitumor activity by theanine. On the other hand, changes in drug concentrations with theanine were not observed in normal tissues, but rather it is indicated that theanine tends to reduce their concentrations. Therefore, theanine enhances the antitumor activity not only of DOX but also of cisplatin or CPT-11.
In essence, Sadzuka has found that theanine could block the export of doxorubicin (Adriamycin) (see Figure 6) from cancer cells by blocking the glutamate and glutathione transporter mechanisms; the elevated level of the drug within cancer cells strongly inhibits the tumor. At the same time, non-cancerous cells treated with the chemotherapy drug plus theanine did not accumulate the drug. There have been several studies of this nature, and if confirmed, it suggests that by either consuming green tea (several cups per day) or taking supplemental l-theanine, the anticancer effects of at least some of the chemotherapy drugs may be improved. Doxorubicin also poses some threat to the cardiac tissue, for which coenzyme Q10 is a recommended protective therapy.
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3. Sasaoka K, Kito M, and Onishi Y, Some properties of the theanine synthesizing enzyme in tea seedlings, Agricultural Biology and Chemistry 1965; (29): 984-988.
4. Yokogoshi H, et al., Reduction effect of theanine on blood pressure and brain 5-hydroxyindoles in spontaneously hypertensive rats, Bioscience, Biotechnology, and Biochemistry 1995; 59: 615-618.
5. Terashima T, Takido J, and Yokogoshi H, Time-dependent changes of amino acids in the serum, liver, brain and urine of rats administered with theanine, Bioscience, Biotechnology, and Biochemistry 1999. 63(4): 615-618.
6. Yokogoshi H, Mochizuki M, and Saitoh K, Theanine-induced reduction of brain serotonin concentration in rats, Bioscience, Biotechnology, and Biochemistry 1998; 62(4): 816-817.
7. Yokogoshi H, et al., Effect of theanine on brain monoamines and striatal dopa-mine release in conscious rats, Neurochemical Research 1998; 23(5): 667-673.
8. Yokogoshi H, and Terashima T, Effect of theanine on brain monoamines, striatal, dopamine release and some kinds of behavior in rats, Nutrition 2000; 16(9): 776-777.
9. Kobayashi K, et al., Effects of l-theanine on the release of alpha-brain waves in human volunteers, Nippon Noegikagako Kaishi 1998; 72 (2): 153-157.
10. Kakuda T, et al., Inhibiting effect of theanine on caffeine stimulation evaluated by EEG in the rat, Bioscience, Biotechnology, and Biochemistry 2000; 64: 287-293.
11. Yokogoshi H, et al., Theanine effects on premenstrual syndrome, Proceedings of the Nogei Kagaku Kai, Bioscience, Biotechnology, and Biochemistry 2001; 75: 166.
12. Yokogoshi H and Kobayashi M, Hypotensive effect of gamma-glutamylmethylamide (theanine) in spontaneously hypertensive rats, Life Sciences 1998; 62 (12): 1065-1068.
13. Lekh RJ, et al., L-theanine-a unique amino acid of green tea and its relaxation effect in humans, Trends in Food Science & Technology 1999; 10 (6-7): 199-204.
14. Kakuda T, et al., Protective effect of gamma-glutamylethylamide (theanine) on ischemic delayed neuronal death in gerbils, Neuroscience Letters 2000; 289(3): 189-192.
15. Li X, et al., Human receptors for sweet and umami taste, Proceedings National Academy of Sciences USA 2002; 99(7): 4692-4696.
16. Nelson G, et al., An amino acid taste receptor, Nature 2002; 416(6877): 199-202.
17. Lugaz O, Phillias AM, Faurion A, A new specific ageusia: some humans cannot taste l-glutamate, Chemical Senses 2002 27(2): 105-115.
18. Sadzuka Y, et al., The effects of theanine, as a novel biochemical modulator, on the antitumor activity of adriamycin, Cancer Letters 1996; 105(2): 203-209.
19. Sadzuka Y, Sugiyama T, and Hirota S, Modulation of cancer chemotherapy by green tea, Clinical Cancer Research 1998; 4(1): 153-156.
20. Sadzuka Y, et al., Efficacies of tea components on doxorubicin induced antitumor activity and reversal of multidrug resistance, Toxicology Letters 2000; 114 (1-3): 155-162.
21. Sadzuka Y, et al., Improvement of idarubicin induced antitumor activity and bone marrow suppression by theanine, a component of tea, Cancer Letters 2000;158(2): 119-24.
22. Sadzuka Y, et al., Enhancement of the activity of doxorubicin by inhibition of glutamate transporter, Toxicol Letters 2001; 123(2-3):159-67.
23. Sadzuka Y, et al., Effect of dihydrokainate on the antitumor activity of doxorubicin, Cancer Letters 2002; 179(2): 157-163.
24. Sugiyama T, et al., Inhibition of glutamate transporter by theanine enhances the therapeutic efficacy of doxorubicin, Toxicology Letters 2001; 121(2): 89-96.
25. Sugiyama T and Sadzuka Y, Combination of theanine with doxorubicin inhibits hepatic metastasis of M5076 ovarian sarcoma, Clinical Cancer Research 1999; 5(2): 413-4166.
26. Sugiyama T and Sadzuka Y, Enhancing effects of green tea components on the antitumor activity of adriamycin against M5076 ovarian sarcoma, Cancer Letters 1998; 133(1): 19-26.
27. Zhang G, Miura Y, and Yagasaki K, Effects of dietary powdered green tea and theanine on tumor growth and endogenous hyperlipidemia in hepatoma-bearing rats, Bioscience, Biotechnology, and Biochemistry 2002; 66(4): 711-716.
Note: This article is part of a series of reports on amino acids used as supplements. The previous three reports in the Amino Acid Series are:
I. Glutamine (with reference to glutamate)
II. SAM-e (with reference to methionine)
III. Carnitine (with reference to taurine)
Figure 7. Central Research Institute, of Ito En, Ltd., in Shizuoka, Japan
where several studies of theanine and other tea leave constituents are carried out.