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GABA: Gamma-Amino Butyric Acid

 

INTRODUCTION:

Gamma-Amino Butyric acid (GABA) is an amino acid which acts as a neurotransmitter in the central nervous system. It inhibits nerve transmission in the brain, calming nervous activity. As a supplement it is sold and promoted for these neurotransmitter effects as a natural tranquilizer. It is also touted as increasing Human Growth Hormone levels and is popular among body builders. The published research supporting any of these promotional claims is weak. Current medical opinion says that GABA taken as a supplement does not reach the brain and has no effect or benefit aside from being a benign placebo.

 

Many websites claim that the neurotransmitter GABA was discovered in Berlin in 1863, which is an outlandish claim. The concept of neurotransmitters had yet to be conceived of. It is more likely that GABA was isolated and identified as an amino acid in 1863. It was 87 years later, in 1950, that Eugene Roberts and J. Awapara discovered that GABA acted as an inhibitory neurotransmitter.

 

NEUROTRANSMITTER REVIEW

The nervous system is made up of individual nerve cells called neurons. They serve as the body's wiring. Nerve signals are transmitted through the length of a neuron as an electrical impulse. When a nerve impulse reaches the end of the neuron it can jump over to the next cell using chemical messengers called neurotransmitters.

 

In the central nervous system, which consists of the brain and the spinal cord, neurotransmitters pass from neuron to neuron. In the peripheral nervous system, which is made up of the nerves that run from the central nervous system to the rest of the body, the chemical signals pass between a neuron and an adjacent muscle or gland cell.

 

Glutamate and GABA are the most abundant neurotransmitters in the central nervous system, and especially in the cerebral cortex, which is where thinking occurs and sensations are interpreted.

 

Tiny sacs filled with neurotransmitters are stored at the end of each neuron. When a nerve impulse reaches the cell's end it triggers these sacs to dump the neurotransmitters into the gaps that separate one nerve cell from another. These spaces are called synapses. The neurotransmitters float across the synapse. When they reach the neighboring neuron, the neurotransmitters click into specialized receptor sites much as a key fits into a lock. When enough neurotransmitters attach to the receptors, the neuron “fires,” sending an electrical impulse down its length.

 

GABA'S ROLE IN THE BRAIN

GABA is made in brain cells from glutamate, and functions as an inhibitory neurotransmitter – meaning that it blocks nerve impulses. Glutamate acts as an excitatory neurotransmitter and when bound to adjacent cells encourages them to “fire” and send a nerve impulse. GABA does the opposite and tells the adjoining cells not to “fire”, not to send an impulse.

 

 

Without GABA, nerve cells fire too often and too easily. Anxiety disorders such as panic attacks, seizure disorders, and numerous other conditions including addiction, headaches, Parkinson's syndrome, and cognitive impairment are all related to low GABA activity. GABA hinders the transmission of nerve impulses from one neuron to another. It has a calming or quieting influence. A good example to help understand this effect is caffeine. Caffeine inhibits GABA release. The less GABA, the more nerve transmissions occur. Think what too much coffee feels like: that is the sensation of glutamate without enough GABA.

 

The reason caffeine does this is that other molecules can bind to the neuron near the GABA binding site and influence GABA's effect. This is how tranquilizing drugs such as Benzodiazepines and barbiturates work. They increase or imitate GABA's effect, inhibiting nerve transmission.

 

Research on GABA

In the half century since GABA was identified as a neurotransmitter there has been an enormous amount of research published directed toward its role in both animals and humans. Most of this has focused on the mechanics of GABA action and the drugs and chemicals which affect its action along with GABA's role in various disease states. A search on the term GABA on PubMed today ( October 7, 2004 ) brings up a list of 43,859 published papers. Only a handful of these papers focus on using GABA orally as a nutritional supplement. Some nutritional writers suggest a conspiracy on the part of the drug industry to suppress GABA research so as to promote their drugs such as Valium. [1] A more likely explanation rests in the fact that the common belief among scientists is that GABA will not cross the blood brain barrier. If GABA does not reach the brain, it will have no effect. Although I have found no direct published evidence proving that oral GABA changes brain levels of GABA, some scientists assume that with large enough doses some may cross over. [2] This amount may vary from person to person, their nutritional status, physical conditioning and activity level.

 

This lack of research caught me by surprise. With most nutritional and herbal supplements these days there is ample research to argue in support of their therapeutic use. This is an unusual situation in modern nutritional medicine. Few of the websites which sell GABA list references for the scientifically proven benefits attributed to its use. This is unsatisfactory and discredits the bona fide claims made for other products. Instead of garnering uses directly from clinical research, we are left to look elsewhere.

 

Possible Uses of GABA:

The best information I have on clinical use comes from the writing of Eric Braverman and Carl Pfeiffer. [3] Their 1987 book on the clinical use of amino acids is a classic treatise for the practice of nutritional medicine.

Anxiety:

If oral GABA reaches the brain in any significant amount it should act as a tranquilizer. GABA as a neurotransmitter, blocks nerve impulses and slows neuronal transmission. It should make you feel the opposite of a double espresso.

Braverman and Pfeiffer write an anecdotal account of the successful treatment of a forty year old woman suffering from anxiety with 800 mg of GABA a day. They also gave her an undisclosed amount of inositol which we now know is an effective anxiolytic used in treating obsessive compulsive disorder. Was it the GABA or the inositol that helped this patient? Perhaps the combination.

Though this anecdote is inconclusive, using GABA to treat anxiety is the most common and reasonable use.

Will the brain adapt to supplemental GABA? There are no answers to this as no one has proven GABA reaches the brain. Looking at the brain's capacity to change GABA receptor response and its tendency to build up tolerance to drugs which modify GABA, it is possible that a tolerance to oral GABA might develop and withdrawal symptoms might occur. None are reported in the literature to my knowledge.

Depression:

There is a well proven tendency for depressed and bipolar patients to have lower levels of GABA in their blood plasma. These low levels are thought to reflect lower brain levels. Both Braverman, Pfeifer and Robert Atkins in their books suggest using GABA to treat depression. The theory is that oral GABA will bring up plasma levels. Unfortunately this theory is too simplistic and possibly dangerous.

The current theory of GABA and depression is that low plasma levels of GABA may identify an inheritable tendency for mood disorders such as depression or bipolar disease. [4] Today's view is that things which increase GABA in these people may trigger a depressive episode. It isn't until time or treatment restores GABA to its former low level that these people feel better. [5] This information suggests a situation that is far more complex than what was once thought and certainly argues for caution in using GABA in patients with depressive or bipolar disorders. Will excess GABA from oral supplementation stimulate a depressive episode in susceptible patients? There is no data to answer this question. Until proven safe, GABA should be used with caution in this population.

Again recall the biochemistry, GABA is an inhibitory neurotransmitter. Give it to people who look or feel like they've drunk too much coffee, not people who look like they need a cup.

Premenstrual Syndrome

Women who become depressed with hormonal changes during their menstrual cycle have lower plasma GABA levels than women whose moods are unaffected by menstrual changes. Dr. Atkins suggests that GABA supplementation will “lift spirits.” [6]

The study Dr Atkins cites in support of his suggestion [7] suggests that it is this same inheritable tendency for low GABA levels that underlie their depressive tendencies and their premenstrual depression. More recent research suggests a more complicated interaction between sex hormones and GABA in the brain. In healthy women, brain GABA activity decreases through the menstrual cycle, especially the luteal phase. In women with premenstrual depression, brain GABA activity actually increases during the luteal phase. [8] Giving GABA to women with premenstrual depression may aggravate their problem and drop their spirits.

Male Contraceptive

Braverman and Pfeiffer suggest GABA as a possible male contraceptive because it decreases sperm motility but don't count on this. The reference they cite is referring to monosodium glutamate, a distant relative of GABA. [9] Newer studies say GABA makes sperm cells hyperactive. [10] In other words GABA might be useful for treating male infertility rather than as a contraceptive No clinical trials have been published but this is not something one would want to make a mistake with.

Seizures

Dr. Atkin's mentions Taurine's apparent effect of suppressing seizures because it increases GABA effect in the brain. At this time the research on Taurine and epileptic seizures is mixed. The effect of Taurine varies with the time it is administered, sometimes preventing and sometime precipitating seizures. [11] In other carefully designed animal models, no benefit was demonstrated. [12] GABA should thus be used with caution with anyone who has a seizure history.

Blood sugar and Diabetes:

Braverman and Pfeifer suggest that 2-4 grams of GABA may stimulate insulin production and lower blood sugar levels. [13] This idea is supported by the newer Human Growth Hormone studies which also see an increase in insulin levels with oral GABA.

 

CAN IT WORK?

GABA supplements are promoted as an alternative to these tranquilizing drugs. There's a problem. There is scant evidence that it does anything. Current medical belief is that GABA will not pass the blood brain barrier.

The blood brain barrier is a biologic firewall between the body's general blood circulation and the blood circulation that supplies the brain. It prevents many of the chemicals and drugs which circulate in the blood from reaching the brain. GABA can not cross from the body into the brain. If GABA doesn't reach the brain, can it work? Common medical wisdom says it can't.

So why are so many people buying and taking GABA insisting that it is helpful for its tranquilizing action?

First, it may simply be a placebo. If our thoughts affect our chemistry and physiology, what more susceptible part of our chemistry can there be than the neurotransmitters in our brain that carry thoughts?

Second, it may have some affect that hasn't been reported yet. If taking GABA makes a person feel calmer and more relaxed, perhaps some of it crosses into the brain. Studies on Human Growth Hormone suggest that it can.

HUMAN GROWTH HORMONE

There is evidence that getting extra GABA into the brain increases Human Growth Hormone. Injections of GABA directly into the brain increase Growth Hormone in rats. Baclofin, a drug analog of GABA that does reach the brain, increases HGH [14] so it makes sense that GABA would do the same.

Several studies support the notion that taking oral GABA increases Human Growth Hormone (HGH). Two of the studies were published almost 25 years ago. They used a small number of test subjects. Yet they produced significant increases, HGH levels increased 500%. [15] [16] No studies replicated this effect for years bringing the initial results into question. In May of 2003, a new study confirmed the results of the early studies. The new study measured GABA and HGH in body builders. Three grams doses of GABA increased HGH levels, but only if taken just before exercise. Without exercise, the GABA had no effect on HGH. [17] We should clarify the term exercise, test subjects were body builders; we are talking about a strenuous workout. If GABA can raise HGH levels, some of it may cross the blood brain barrier, perhaps only after exhausting exercise.

The HGH studies raise some concerns. Oral GABA also affects the pancreas increasing insulin production. [18] Of course with all the concern about Syndrome X and hyperinsulinemia, making more insulin might not desirable. Yet a diabetic might find the insulin stimulating effect contributes to better blood sugar control. Besides increasing insulin and HGH, oral GABA increases prolactin, a finding not emphasized in the promotional literature. Prolactin is the hormone that stimulates the breasts to produce milk. Although body builders want to build up their chest size, they probably don't want to do it this way. Although there is no research on taking GABA during pregnancy or nursing, pregnant or nursing mothers should not take this information to suggest that GABA might increase their milk supply. It might, but it also might stimulate early breast development and lactation in their infants.

There are other amino acids besides GABA that increase HGH. [19] Whether they are more effective is unknown.

 

Side Effects:

Although the newer studies with body builders report using high doses of GABA with little side effect, these results may not reflect the experience of a more sedentary person. Carl Pfeiffer devotes a full page in his book to describing an unpleasant experience he had after taking a 10 gram dose of GABA:

“About ten minutes after taking the GABA, I started to wheeze and my breath rate increased to 45 a minute. Five minutes later, my heart rate peaked at 140 and my blood pressure at 180/100. I was choking, fidgeting and could not sit still. I had a massive anxiety attack, thinking I was going to die…….I vomited into the waste basket. Over the next half hour, this anxiety attack let up, but I continued to be nauseous for the next two hours.

“This dose of GABA also caused a constant flush sensation, like that of niacin, although my skin was not red. I had a tingling in my hands and over my entire body. This effect occurred even at the lesser dose of 3 g of GABA and is likely neuralgic, unlike the effect of niacin which is primarily vascular……” [20]

 

Home Experimentation:

Probably the only way you will figure out if GABA works for you is to try it. GABA is nontoxic and appears generally safe to take. There is nothing stopping you from testing these contradictory claims for yourself. Below are suggested doses for treating various conditions.

I personally had never taken GABA before reviewing this research and then stalled experimenting on it until I wrote this article. Once done with the preliminary drafts I experimented using 750 mg. capsules of GABA. I began taking them at 12 hour intervals. After the second dose I began to experience the tingling sensations reported by Pfeifer. I too thought them reminiscent of a niacin flush without the surface heat from vasodilatation. It was very noticeable for about five minutes and then only slightly noticeable if I paid attention and looked for it. I did not feel particularly calm during my normal activity but did wonder if something was different while driving, especially while merging onto the freeway, an experience where I typically notice some agitation. Interesting to note, it was just after getting on the highway while driving that I noticed the tingling.

 

Suggested Dosages:

I would consider suggesting GABA to patients who are over anxious or who complain of insomnia due to “too many thoughts which I can't shut off.” Again I like the coffee analogy: If they look or feel like they drank too much coffee, GABA may help.

Research no longer supports using GABA for depression, bipolar disease or PMS: if it looks like they need a cup of coffee, don't use GABA

For increasing Human Growth Hormone production the studies used between 3 and 18 grams. Keep in mind that at these doses expect tingling.

CAUTIONS

GABA may cause sleepiness, that is if it works: Do not operate or drive heavy machinery while taking GABA, at least until you know what effect it has on you. Do not take GABA if you have been diagnosed with bipolar or unipolar depressive disorders. If taking doses greater than 3-4 grams do not be surprised if you experience a flushed tingling sensation; this appears to be a common experience. Caution should also be taken in combining GABA with any drug which affects GABA pathways in the brain. These drugs include but are not limited to barbiturates, benzodiazepines, and alcohol. GABA has not been tested in pregnant or breast-feeding women, children, or people with liver or kidney disease.

GHB

Gamma-hydroxybutyric acid (GHB) has a similar name but is a different chemical. It is made within the brain from GABA. GHB has been researched for treating alcohol, opiate and other drug dependencies and for treating withdrawal symptoms. [21] [22] [23] [24] GHB unfortunately can also be abused [25] and employed as a ‘date rape drug'. [26] It has gone from a promising new treatment for addictions to an addictive and dangerous drug in its own right. [27] Instead of touting potential benefits recent articles focus on how to treat overdoses [28] and the withdrawal syndrome associated with GHB. [29] Don't mix these two names up.

Other ways to skin the cat: other ways to increase GABA effect

Another approach is to look at substances which change GABA action in the brain. There seems to be more and better clinical research on the use of many of these substances in humans than there is on GABA. There are numerous natural substances which affect GABA. In fact understanding GABA helps explain the action of many commonly used herbs, vitamins and minerals.

 

Valerian root has a long history of use as a tranquilizer and works by increasing the effect of GABA on its receptors [30] American Ginseng also acts on the GABA receptors. [31] So does Kava Kava. [32]

All sorts of other unexpected things change GABA activity; the chemicals formed by aging whiskey in oak barrels increase GABA effect. Aging really does make whiskey mellower literally based on what it does to brain neurotransmitters. [33] These chemicals are released from the alcohol as a fragrance and appear to reach the brain by inhalation. [34] The fragrance of Oolong tea has a similar effect, increasing GABA action. [35] Extracts of green tea, black tea and oolong tea elicit a GABA response in test models. [36] Epigallocatechin gallate extracts from tea had the opposite effect, inhibiting the GABA response. Coffee extracts also inhibit GABA response. [37] Magnesium binds to GABA sites and increases effect. [38] Taurine protects against glutamate overstimulation. [39] [40] Its inhibitory effect may act as anxiolytic. [41]

 

Serotonin is another neurotransmitter and it enhances GABA. Therefore, as precursors to serotonin, Tryptophan and 5-HTP increase GABA action.

 

Theanine is an amino acid found in large amounts in tea. It is why a cup of tea can be calming despite the fact it contains caffeine. Theanine may increase glutamate transport [42] and increase GABA levels.

The vitamin B6 derivative pyridoxal phosphate is a cofactor in the synthesis of GABA. Some people have trouble converting Vitamin B-6 to pyridoxal phosphate and for those people taking this active B-6 may increase GABA levels.

 

While these other supplements alter or potentiate the GABA receptor, they do not add any GABA to the system. Many companies add one or more of these other materials to capsules containing GABA. The idea may be to amplify the effect of any GABA that crosses the Blood Brain Barrier into the brain. These other ingredients may work independently and be the active ingredient in the product.

 

At this point GABA is more interesting for the understanding it provides of the mechanics of the mind than it is as a nutritional supplement. Although small amounts of orally taken GABA may reach the brain and have a tranquilizing effect in certain individuals, there are many other alternatives which have both a longer history of safe use and better research support for their use. There are unanswered questions about the safety of the long term high doses promoted by some supplement companies. Although I can say as others do that there is no evidence of harm from oral doses, there are no long term clinical trials published.

Try GABA if you want. If it provides a suitable tranquilizing effect, you are probably safe to use it for short term, low dose intervention.

 

References:

 

[1] Atkins, Robert. Dr. Atkins' Vita-nutrient solution. Simon & Schuster. Page 176

[2] Private communication with F. Petty MD October 7, 2004

[3] Braverman, E. Pfeiffer, C. The Healing Nutrients Within. [Keats Publishing, New Canaan , Connecticut . 1987. pgs 191-210

[4] Petty F, Kramer GL, Fulton M, Moeller FG, Rush AJ. Low plasma GABA is a trait-like marker for bipolar illness. Neuropsychopharmacology. 1993 Sep;9(2):125-32.

[5] Petty F. GABA and mood disorders: a brief review and hypothesis. J Affect Disord. 1995 Aug 18;34(4):275-81.

[6] Atkins page 177

[7] Am J Psychiatry. 1996 May;153(5):718-20.

Low plasma gamma-aminobutyric acid levels during the late luteal phase of women with premenstrual dysphoric disorder.

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Cortical gamma-aminobutyric acid levels across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder: a proton magnetic resonance spectroscopy study.

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[9] Neurobehav Toxicol. 1979 Spring;1(1):1-4.

Reproductive dysfunction in male rats following neonatal administration of monosodium L-glutamate.Pizzi WJ, Barnhart JE, Unnerstall JR.

[10] Mol Hum Reprod. 1996 Oct;2(10):733-8.

Effects of gamma-aminobutyric acid on human sperm motility and hyperactivation.

Calogero AE, Hall J, Fishel S, Green S, Hunter A, D'Agata R.

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Kainic acid (KA)-induced seizures in Sprague-Dawley rats and the effect of dietary taurine (TAU) supplementation or deficiency.

Eppler B, Patterson TA, Zhou W, Millard WJ, Dawson R Jr.

[12] Can J Physiol Pharmacol. 1978 Jun;56(3):497-500.   

The effect of taurine on kindled seizures in the rat.

Burnham WM, Albright P, Racine RJ.

[13] pg 203

[14] J Clin Endocrinol Metab. 1982 Jun;54(6):1145-9.

A possible role of gamma-aminobutyric acid in the control of the endocrine pancreas.

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[15] Acta Endocrinol (Copenh). 1980 Feb;93(2):149-54

Effect of acute and repeated administration of gamma aminobutyric acid (GABA) on growth hormone and prolactin secretion in man.

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Effect of gamma-aminobutyric acid on growth hormone and prolactin secretion in man: influence of pimozide and domperidone.

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[17] Medicine & Science in Sports & Exercise: Volume 35(5) Supplement 1 May 2003 p S271

THE EFFECTS OF GAMMA AMINOBUTYRIC ACID ON GROWTH HORMONE SECRETION AT REST AND FOLLOWING EXERCISE

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[19] DI LUIGI, L., L. GUIDETTI, F. PIGOZZI, C. BALDARI, A. CASINI, M. NORDIO, and F. ROMANELLI. Acute amino acids supplementation enhances pituitary responsiveness in athletes. Med. Sci. Sports Exerc., Vol. 31, No. 12, pp. 1748-1754, 1999.

[20] The Healing Nutrients Within page 206

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Gamma-hydroxybutyric acid in the treatment of alcohol and heroin dependence.

Gallimberti L, Spella MR, Soncini CA , Gessa GL.

[22] Acta Med Austriaca. 2003;30(3):83-6.

Gamma-hydroxybutyric acid in the treatment of alcohol withdrawal syndrome in patients admitted to hospital.

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[23] Lancet. 1989 Sep 30;2(8666):787-9.

Gamma-hydroxybutyric acid for treatment of alcohol withdrawal syndrome.

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Alcohol. 2000 Apr;20(3):271-6

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Alcohol. 2000 Apr;20(3):217-22

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Eur Arch Psychiatry Clin Neurosci. 1994;244(3):113-4

Clinical efficacy of gamma-hydroxybutyric acid in treatment of opiate withdrawal.

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[25] Alcohol. 2000 Apr;20(3):263-9.   

Abuse and therapeutic potential of gamma-hydroxybutyric acid.

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[26] Trends Pharmacol Sci. 2004 Jan;25(1):29-34.

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[27] Am J Addict. 2001 Summer;10(3):232-41.   

Gamma-hydroxybutyric acid: patterns of use, effects and withdrawal.

Miotto K, Darakjian J, Basch J, Murray S, Zogg J, Rawson R.

[28] Acad Emerg Med. 2002 Jul;9(7):730-9. Comment in:

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Comment in:

J Emerg Med. 2001 May;20(4):418-20.

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[30] Anesth Analg. 2004 Feb;98(2):353-8, table of contents.

The gamma-aminobutyric acidergic effects of valerian and valerenic acid on rat brainstem neuronal activity.

Yuan CS, Mehendale S, Xiao Y, Aung HH, Xie JT, Ang-Lee MK.

[31] J Ethnopharmacol. 1998 Oct;62(3):215-22.   

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[32] Planta Med. 2002 Dec;68(12):1092-6.

Kavalactones and dihydrokavain modulate GABAergic activity in a rat gastric-brainstem preparation.

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[33] J Agric Food Chem. 2003 Aug 27;51(18):5238-44.

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Koda H, Hossain SJ, Kiso Y, Aoshima H.

[34] J Agric Food Chem. 2003 Aug 27;51(18):5238-44.

Aging of whiskey increases the potentiation of GABA(A) receptor response.

Koda H, Hossain SJ, Kiso Y, Aoshima H.

[35] Biosci Biotechnol Biochem. 2004 Sep;68(9):1842-8.   

Fragrances in Oolong Tea That Enhance the Response of GABA(A) Receptors.

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Magnesium potentiation of the function of native and recombinant GABA(A) receptors.

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[39] FASEB J. 2004 Mar;18(3):511-8.

Taurine prevents the neurotoxicity of beta-amyloid and glutamate receptor agonists: activation of GABA receptors and possible implications for Alzheimer's disease and other neurological disorders.

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[40] FASEB J. 2004 Mar;18(3):511-8.

Taurine prevents the neurotoxicity of beta-amyloid and glutamate receptor agonists: activation of GABA receptors and possible implications for Alzheimer's disease and other neurological disorders.

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[41] Life Sci. 2004 Aug 6;75(12):1503-11

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[42] Biochim Biophys Acta. 2003 Dec 5;1653(2):47-59.

Theanine and glutamate transporter inhibitors enhance the antitumor efficacy of chemotherapeutic agents.

Sugiyama T, Sadzuka Y.

 

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