L-Theanine: The Essence of Mellow in a Capsule

by Ed Sharpe

Sometimes even the most familiar of products holds the capacity to surprise us. Case in point is green tea and the wealth of nutrients it contains.

Informed consumers – and all of my readers are informed consumers – know that green tea is good for you because it is rich in polyphenols known as catechins. The catechins are potent antioxidants that can also prevent cancer, retard atherosclerosis, improve mood, and inhibit the growth of bacteria and other pathogens. All this you’ve probably heard before.

But there’s another natural component in tea that’s at least as beneficial as the catechins and is finally getting some long-deserved attention. Although not an antioxidant, it provides many of the same health benefits as the catechins – and more. It’s the amino acid L-theanine, which shows tremendous potential for calming, protecting and restoring the brain, stimulating the immune system, and even making cancer chemotherapy more effective with fewer side effects.

Theanine is an analog of glutamate, although it can be equally well considered an analog of glutamine. Its two chemical names (gamma-glutamylethylamide and 5-N-ethyl-glutamine) refer to one and the same molecule. The fact that theanine can resemble either glutamate or glutamine turns out to be key for understanding its usefulness in human nutrition, as we’ll see shortly. Theanine is by far the most predominant free amino acid found in tea, where it typically occurs in amounts estimated as 1 to 2% by dry weight. The relatively high content means that theanine must play an important role in the plant. Besides being a major source of transportable nitrogen in the root tips, theanine is also a precursor for part of the catechin ring system during catechin biosynthesis.

The fact that theanine resembles glutamic acid might lead one to suspect that ingested theanine can interact with the body’s glutamatergic (glutamate signaling) system. Such is indeed the case, as anyone who’s ever let a tea bag sit too long in hot water knows. Overbrewing results in tea that is bitter and astringent. The unpleasant taste arises because tea leaves soaking in water are continually releasing tannins and other astringent molecules. That being the case, why doesn’t tea taste bitter from the start? The answer is that theanine is also being released – at least initially – and it masks the bitterness and astringency of the tea polyphenols. The mellowing effect of the theanine blunts the harsher tea flavors, at least until the leaves supply of theanine runs out.

Theanine is able to enhance flavors the same way as MSG (monosodium glutamate), because theanine plugs into the same taste receptor on the tongue that MSG does, although with none of the reported side effects of MSG. Glutamate – and therefore MSG – is potentially neurotoxic, whereas theanine is exactly the opposite. Theanine activates the fifth taste sense in the tongue, known in Japanese as umami, which roughly translates as deliciousness or brothiness. (The other four tastes are the usual sweet, sour, salty and bitter.) For this reason theanine has been used for decades as a safe and reliable flavoring additive in Japan, where it is incorporated into beverages, chewing gum and other processed foods.

Given the humble history of theanine, it’s all the more surprising to find it suddenly elevated from food additive to the rank of nutraceutical superstar. The recent prominence of theanine is largely the result of a series of research papers published by Japanese scientists during the last decade. These papers demonstrated that not only does theanine have a mellowing effect on taste sensations – it also has a mellowing effect on consciousness!

For example, researchers found that theanine can induce deep states of relaxation without sedation, calm both PMS and menopausal symptoms, increase focused attention and improve learning, relieve nicotine addiction and promote sleep. It’s also been shown to lower blood pressure in spontaneously hypertensive rats, although the effect is small and large doses seem to be required. All these effects appear to be mediated by the interaction of theanine with various neurotransmitters (signaling molecules in the nervous system). The irony is that for centuries in Japan green tea has been associated with states of meditation and relaxation, but until the research of the 1990s no one suspected that the flavor of tea might be responsible for so many of its cognitive effects.

How does theanine work? Once ingested, theanine takes advantage of its resemblance to glutamine to hitch a ride on one of the body’s amino acid transporters, a sodium-dependent system that carries theanine across the intestine. A similar transporter ultimately carries theanine across the blood brain barrier as well. After getting into the central nervous system, theanine reverts back to its guise as a glutamate mimic and binds to a number of different types of glutamate receptor on nerve cells, albeit with considerably less affinity than glutamate itself.

A quick word about glutamate: When glutamate binds a receptor on a nerve cell, it excites the cell into greater activity. As one of the body’s major excitatory neurotransmitters, glutamate is indispensable for normal brain functioning, including long term memory formation. But too much glutamate can also kill nerve cells. This is exactly what happens in certain neurological disorders, including Alzheimer’s, Parkinson’s and Huntington’s diseases and epilepsy, stroke and amyotrophic lateral sclerosis as well.

The good news is that theanine appears capable of blocking cell death caused by kainic acid, a neurotoxin known to bind to a particular set of glutamate receptors, as well as by an excess of glutamate itself. Furthermore, theanine is effective at protecting nerve cells from injury caused by low levels of oxygen, a condition known as ischemia that is also characterized by excessive glutamate release. Although the research on brain ischemia has thus far been conducted only in animals, theanine holds promise for protecting human brain cells from stroke and from other diseases of glutamate toxicity such as Alzheimer’s and Parkinson’s. Incidentally, no neurotoxicity of theanine itself has been found either in cultured brain cells or intact animals, confirming theanine’s centuries-old record of safety as a food ingredient.

Theanine has also been reported to stimulate the release of nerve growth factor (NGF), a protein needed by cholinergic brain cells for survival. (Cholinergic cells are the ones that use acetylcholine for signaling.) When fed to cultured neurons, NGF increases the formation of neurites, extensions of the cell that are essential for making connections with other neurons. In animal models, NGF reverses the age-related atrophy of cholinergic cells of the basal forebrain. These cells are also the same ones that atrophy in Alzheimer’s. Thus, maintaining NGF synthesis may be crucial for keeping a youthful brain and for slowing or avoiding Alzheimer’s disease. NGF can also be deficient in other neurological conditions as well, such as diabetic neuropathy. In my view theanine should be part of a daily nutritional prescription for maintaining neurological health, either alone or combined with other NGF inducers such as acetyl-L-carnitine and idebenone or with an NGF potentiator such as DHA (docosahexaenoic acid).

The relaxing effects of theanine partly depend on its ability to interact with the brain’s glutamatergic system. For example, theanine has been reported to induce the release of gamma-amino butyric acid (GABA), the main inhibitory neurotransmitter known for counterbalancing the stimulatory effects of glutamate. Just as glutamate excites nerve cells into greater activity, GABA (which is produced in the brain from glutamate) quiets them down. Unfortunately, it’s difficult to supplement with GABA because it doesn’t cross the blood-brain barrier readily. Theanine, on the other hand, crosses the blood-brain barrier with relative ease. This makes theanine rather than GABA itself the supplement of choice for relieving anxiety and stress.

Speaking of anxiety, theanine also has a reputation for counteracting the anxious jitters associated with caffeine without interfering with its ability to fight fatigue or sharpen mental focus. In fact, that’s why drinking tea has always been a mellower experience than drinking coffee. You might get a comparable dose of caffeine from drinking either one, but with theanine present in the tea you’re much less likely to notice a caffeine buzz.

I’m a prime example of someone who can’t tolerate caffeine except in very small doses because it increases my anxiety levels. As an experiment I’ve been taking two 100 mg theanine capsules half an hour before drinking 8 ounces of caffeinated coffee. I’ve noticed that while I still retain a heightened sense of mental stimulation, the tension and anxiety I usually feel after drinking coffee just aren’t there. After around five hours the effects of the theanine starts to wear thin and I’ve had to boost my theanine intake by another two capsules, for a total of 400 mg, to quiet my system. Because I am not a habitual drinker of caffeine, I’m ultra sensitive to it and my results may not be exactly typical. Nevertheless I’d guess that a dose of 1 or 2 capsules of theanine before a cup of coffee (with an equal amount sometime after, if necessary) should be enough to neutralize any case of the caffeine jitters.

To me, this represents nothing less than the redemption of caffeine. For too long we’ve been excoriated by nutritional faddists for not eliminating caffeine from our diets. The fact is, caffeine is a potent antioxidant with many benefits, including an ability to increase the effectiveness of cancer chemotherapy (a characteristic it shares with theanine, by the way). The ability of theanine to block caffeine-induced anxiety while preserving the positive effects of caffeine means that people like me who are caffeine-intolerant can finally take advantage of this unfairly maligned nutrient.

Returning to the subject of theanine’s benefits for the brain, theanine has also been reported to trigger dopamine release in the striatum via an interaction with glutamate receptors. Dopamine is the brain’s master regulator of reward and pleasure, and the release of dopamine probably contributes to the sense of well being associated with theanine intake (or with drinking green tea). Theanine likewise stimulates norepinephrine release, perhaps through its effect of increasing GABA levels, since GABA has been reported to increase norepinephrine release in the brain. Because dopamine and norepinephrine are the neurotransmitters released by drugs such as Ritalin which are used to treat ADHD (attention deficit hyperactivity disorder), theanine has the potential to become a natural alternative to Ritalin for treating ADHD.

The effect of theanine on serotonin metabolism is more ambiguous, however. One study indicated that theanine had no effect on serotonin levels, whereas two other studies showed that theanine decreased brain serotonin. A fourth study (by the same author as the previous two) reported that theanine increased serotonin levels in some regions of the brain. In view of this uncertainty, anyone being treated with a serotonin reuptake inhibitor for depression should consult with a health care professional before taking theanine. Normal individuals – i.e., people without serotonin deficiency or serotonin-dependent depression – who are concerned that theanine could possibly decrease their brain serotonin levels may want to consider supplementing concurrently with St. John’s wort. Note that taking 5-HTP (5-hydroxytryptophan, a serotonin precursor) along with theanine may not be especially useful; theanine has been reported to inhibit the formation of serotonin from tryptophan and the same could be true for 5-HTP.

If its cognitive and mood-enhancing effects were the whole story, theanine would be impressive enough. In fact, however, theanine does even more. For one thing, it has antibacterial activity against Staphylococcus aureus and E. coli by acting as antagonist (antimetabolite) of glutamate. It inhibits the copper-catalyzed oxidation of low density lipoprotein (LDL), suggesting that theanine contributes to the protective effects of green tea against atherosclerosis. And it also prevents liver injury induced by D-galactosamine, a model of experimental hepatitis which mimics the macroscopic and microscopic features of viral hepatitis in animals. Does this mean that theanine can assist recovery from viral hepatitis in humans, such as hepatitis C? While such a possibility remains intriguing, there’s no direct evidence for or against it as yet.

Perhaps even more important, theanine has some surprising, recently documented effects on priming the immune system. When theanine gets catabolized in the liver or kidney, it breaks down into two components, glutamic acid and ethylamine. The glutamic acid is recycled or used as a cellular fuel, while any ethylamine not excreted or catabolized continues to circulate. Now ethylamine also happens to be a member of a family of bacterial products (alkylamines) that are recognized by a specific set of T lymphocytes, the gamma delta cells. T cells of this class ordinarily make up only 2-5% of all T cells in circulation, but they expand their population by up to 50 times within days of infection by a wide variety of bacteria, viruses and parasites. They similarly increase their numbers when they’re primed with alkylamines – including ethylamine derived from tea – and exposed in vitro to heat-killed bacteria and parasites or to virus-infected cells. The activated T cells also produce an abundance of antimicrobial cytokines, including interferon gamma and tumor necrosis factor alpha.

What all this means is that regular consumption of theanine can boost the body’s defenses against infection by many different pathogenic organisms – and, as it turns out, against tumors as well. Tumors also secrete antigens to which gamma delta  cells respond. Once the gamma delta cells have been primed by circulating ethylamine, they can provide enhanced immune surveillance against cancer. In this way theanine can help the body stamp out tumors before they get established and conceivably even shrink existing tumors. The concept is reminiscent of the mechanism behind Coley’s toxins, a bacterial vaccine first used over 100 years ago by a pioneering New York surgeon to treat inoperable cancer. The bacterial alkylamines, endotoxins and other antigens in Coley’s toxins produced an enhanced immune response that caused tumors to regress or even disappear in a number of cases. There’s reason to think that theanine may be able to do something similar during the process of ratcheting up the body’s immune responsiveness.

Finally, theanine has at least two more characteristics of interest to anyone dealing with cancer. One is that both theanine and green tea can shrink liver tumors (hepatomas), at least in rats. Although the significance of this finding for human health is not yet known, the study confirms that the catechins aren’t the only component of green tea with anticancer effects. Also unknown is whether the mechanism involves a direct cytotoxic action of theanine on tumor cells or a systemic enhancement of antitumor immunity as discussed in the preceding paragraph. The same study also showed that theanine could decrease the elevated levels of serum cholesterol and triglycerides (fats) associated with this kind of tumor.

In addition, data collected both in vitro and in animal studies show that theanine potentiates the tumor-killing properties of various chemotherapy drugs, including cisplatin, Adriamycin (generically known as doxorubicin) and similar drugs related to it. Theanine does so while decreasing the toxic effects of these drugs on normal cells. The mechanism has to do with a tumor-specific effect of theanine on glutamate transporters in the cell membrane. By binding to tumor cell glutamate transporters, theanine prevents the uptake of glutamate and the subsequent synthesis of glutathione, the body’s main detoxifying agent.

Tumor cells typically have high levels of glutathione and the ones with the highest levels are the most resistant to killing with cytotoxic drugs. A tumor cell will attempt to dispose of such a drug by fusing it enzymatically (“conjugating” it) with glutathione and then excreting the resulting glutathione-drug conjugate. By inhibiting glutathione synthesis in tumor cells only, theanine raises the intracellular concentration and tumor-killing effectiveness of doxorubicin and other drugs. The dose of theanine typically administered in the chemotherapy studies is a relatively modest 10 mg per kg body weight, which would translate to 700 mg of theanine per day for a 154 pound human.

Glutamate transporters on normal cells are of a different type from the ones on tumor cells and hence theanine does not inhibit glutamate uptake, glutathione synthesis or the disposal of cancer drugs in normal cells. Consequently a noncancerous heart, liver or bone marrow cell can get rid of the toxic drug much more effectively than a cancer cell. The net result is to widen the therapeutic window for cancer chemotherapy. When administered with theanine, smaller, less toxic doses of cancer drugs can be as effective (or even superior to) larger doses without theanine. Theanine can increase the antitumor activity of chemotherapy even in drug-resistant tumors without increasing side effects. Furthermore, the combination of theanine with doxorubicin can not only shrink existing tumors, it can also inhibit metastases more effectively than doxorubicin alone. Interestingly enough, caffeine has likewise been shown to potentiate tumor killing by doxorubicin while leaving normal cells unharmed. The combination of theanine and caffeine might be especially useful for this purpose, since the theanine will quiet a case of “caffeine nerves” while at the same time adding to the caffeine-induced enhancement of doxorubicin antitumor activity.

A few sensible words of caution: It has been suggested that theanine could provide considerable clinical benefit to patients receiving cancer chemotherapy. To date, however, no such studies have been conducted in humans. Theanine appears to be an exceptionally safe nutrient, since it was impossible to find a lethal oral dose even when mice were fed as much as 2 grams per kilogram of body weight (that would translate to 140 grams or 5 ounces of theanine for a human weighing 70 kg, i.e., 154 pounds). Nevertheless, anyone being treated for cancer, autoimmune disease or any other serious illness should supplement with theanine only under the supervision of a health care professional. Likewise, as previously mentioned, theanine should be used with caution by anyone undergoing treatment for depression with a serotonin reuptake inhibitor, since according to some reports theanine can decrease brain levels of this neurotransmitter.

1 Comment

  1. AMAZING Article!!!!! You summed up exactly what I was trying to find out regarding the use of Theanine in combination with Concerta (Ridalin), 5-HTP, caffeine, St. John’s Wort, etc and explained it in terms thatI can actually understand!!! Not to mention all the other info related to anti cancer, pro chemo effects – info like that needs to be more readily available to folks. Thanks again for taking the time to write this.

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