Does Oral GABA Make It Into the Brain?
Think of glutamic acid (GA), glutamine (GAM) and gamma-aminobutyric acid (GABA) as three members of a close-knit family with three very different personalities. Glutamic acid is a non-essential amino acid (the body can manufacture it when things are working right) that's also an excitatory neurotransmitter.1
Its cousin GABA has an opposite personality - it calms our nerves and relaxes us. Glutamine is the source for both of them - the body can make either glutamic acid or GABA from glutamine. This is a special family ... the members can change into each other from time to time.
GABA and glutamine are both available over the counter in health food stores. Glutamine is usually found labeled "l-glutamine". (The "l-" stands for the direction the molecule "turns". All amino acids are either "d-" or "l-", but the body only accepts and works with molecules spun in the "l-" direction.)
In conventional medical circles it's thought that GABA will not pass through the blood-brain barrier, and so taking it orally shouldn't have much effect on mood. Nevertheless, many people report that taking GABA has an anti-anxiety action, and at least one study provides evidence that it does.2 This could be the power of suggestion ... ie: a placebo effect ... but it's also the case that due to malnutrition or inflammation the blood-brain barrier can weaken. A blood-brain barrier that's not fully functional can contribute to anxiety and depression, so it's possible that there is a physiological basis for reports of oral GABA's calming action.
Alternatively, one can take the amino acid theanine instead. Theanine is converted to several useful calming and mood-elevating substances in the brain, including GABA.3,4 So one can use theanine as a kind of "bank shot" to get around the blood brain barrier issue with respect to GABA.
Glutamic acid is the second most abundant amino acid in the brain.5 It's particularly abundant in the part of the brain where memory lives, the hippocampus. Glutamine (GAM) is critical to DNA synthesis. Glutamate, a salt made from glutamic acid, is the most common neurotransmitter in the body, found literally everywhere but especially in the brain.
GABA is the most abundant calming (inhibiting) neurotransmitter in the body. It's also found throughout the brain and many internal organs. Valium and other benzodiazepines mimic GABA's action in the central nervous system (CNS.) Again,formed by enzymatic action from glutamic acid,6,7 GABA is a specific for anxiety.8-11 The body makes sleep-inducing gamma-hydroxybutyrate (GHB) from GABA.12
So glutamate and GABA play opposite roles in the CNS - glutamate wakes us up, GABA calms us down. Too much glutamate can destroy nerve cells through overstimulation (this is the reason some argue against the use of MSG-monosodium glutamate.) GABA, its gentle twin, exerts its effects by calming overactive hypothalami and amygdalae. This lifts depression and soothes jangled nerves.
Glutamine is a principal source of energy for the whole body but especially the brain. There's three times more glutamine than any other amino acid in blood and it's 10-15 times more concentrated in cerebrospinal fluid than it is in blood.
Glial cells surround neurons in the brain. They drink in glutamate and GABA and secrete glutamine, which seeps out into the neurons and resupplies them with glutamate and GABA; these only to be absorbed again by the glial cells once their working day as neurotransmitters is over and recycled back into glutamine.13
As we get older it gets harder and harder for the brain to form the enzyme necessary to make GABA from glutamic acid; manganese can correct this.14-16 Supplementation with GABA and glutamine has also been shown to raise intelligence.17,18 GABA modulates aggression.19 GABA's also been used to treat schizophrenia.
Overstimulation of specific brain regions has been connected to predictable psychological syndromes ranging from cognitive inflexibility as well as anxiety and depression. Imbalances of GA/GAM/GABA metabolism can easily contribute to this excessive stimulation given glutamic acid and GABA's complementary roles. Usually seizure disorders are characterized by low GABA levels. Oral GABA inhibits seizures20 and tremors. Some studies show that excesses of glutamic acid are associated with seizures21 but since MSG breaks down into glutamic acid in the body there are a number of contradictory studies.
GABA receptors are easily damaged by free radicals.22 Autistics have reduced numbers of these receptors.23,24
Seizures and autism represent the extreme end of nervous system over-stimulation. What Amen's studies and those of other imaging investigators suggest is that levels of overexcitation not extreme enough to result in seizures or completely disabling neuropathology still characterize many psychiatric conditions. Higher levels of glutamate in the brain increase excitotoxicity especially if there's any problem with energy metabolism.25
Hibernating animals have high levels of GABA in their brains. Depressed patients can show disrupted GABA metabolism.26 Insulin pushes sugar out of the bloodstream and into cells where it's either burned for energy, stored or becomes destructive. Cells sometimes reach a point where they no longer accept sugar so easily; this is called insulin resistance. Diabetic blood sugar levels are lowered by GABA, decreasing insulin resistance.
When the body (or brain) resists insulin's action the body has to pump out extra to get the same reduction of blood sugar levels. If the kidneys and liver have any trouble clearing this extra insulin promptly it can increase appetite. It appears that by lowering the body's need for insulin GABA can reduce appetite in some people.
Excessive GABA levels appear to contribute to migraine, cerebrovascular disease and other brain diseases.27 GABA breakdown byproducts inhibit sperm action; GABA may have application as a male contraceptive.28 Large doses of GABA are probably not a good idea. Doses in excess of 1,000 mg may be dangerous because they'd be too sedating.29
Thiamin (B1) deficiency results in a loss of thiamin-containing nerve endings, changing the balance of neurotransmitters in the brain including GABA.30-32 Manganese is also essential to the synthesis of glutamine. Glutamine, in turn, is essential for the synthesis of niacin (B3.) GABA is involved in glucose metabolism36 as well as that of vitamin C.33,34 Lysine enhances GABA's action in the brain, while aspartate inhibits glutamic acid. A number of food additives inhibit GABA receptors, while many perfumes enhance their responsiveness.35 Taurine, another amino acid, helps break glutamate down to GABA, and it too seems to act as a CNS sedative.
Glutamic acid is common in food, but glutamine and GABA are nonexistent there. Wheat gluten is close to half glutamic acid. A quarter of the most common protein in milk is glutamic acid.
Some studies suggest that taking GABA by mouth may not raise brain GABA levels much.36,37 But oral GABA does have some sympatholytic activity because it can lower blood pressure.38,39 And in one study of GABA and pyridoxine, fully half of 699 epileptics taking it showed improvement.40 It's been my experience that oral GABA is often, but not always effective at calming anxiety and lifting depression.
When GABA doesn't work I'll often turn to theanine, instead. Theanine is found in abundance in green tea.
Librium, a pharmaceutical that raises GABA, helps alcoholics go straight. This might explain the long history of l-glutamine as helpful for people who want to let go of their addictions to alcohol and sugar.
The liver and kidney break glutamate down. It's not wise to supplement with glutamic acid or l-glutamine when those organs may be compromised by medical conditions or other medications. In any event l-glutamine is absorbed much better than glutamic acid. GABA won't be problematic in this situation, and may even be helpful.
1. Braverman, E. 1987. The Healing Nutrients Within. New Canaan: Keats. 191-200.
2. Abdou, AM, Higashiguchi, S., et al. 2006. Relaxation and immunity enhancement effects of gamma-aminobutyric acid (GABA) administration in humans. Biofactors. 26(3):201-208.
3. Cross, DR, Kellenrmann, G., et al. 2011. A randomized targeted amino acid therapy with behaviourally at-risk adopted children. Child Care Health and Development 37(5):671-8.
4. Nathan, PJ, Lu, K. et al. 2006. The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent. Journal of Herbal Pharmacotherapy 6(2):21-30.
5. Aspartic acid is #1.
6. Lipton, M. A., C. B. Nemeroff, and R. B. Mailman. 1979. Hyperkinesis and food additives. In Nutrition and The Brain. vol. 4, Wurtman and Wurtman, eds. New York: Raven Press. 1-27.
7. Blass, J. P. 1989. Vitamin and nutritional deficiencies. In: Basic Neurochemistry: Molecular, Cellular, and Medical Aspects, 4th ed., Siegel, G.J. et al., eds. New York: Raven Press. 671-684
8. Gerra G. et al. 1998. GABAergic function in detoxified heroin addicts: relationship to anxiety disorders. Psychiatry Research. 77(2):89-96.
9. Roy-Byrne, P.P. 2005. The GABA-benzodiazepine receptor complex: structure, function, and role in anxiety. Journal of Clinical Psychiatry. 66 Suppl. 2:14-20.
10. Jain, N.S., Hirani, K., Chopde, CT. 2005. Reversal of caffeine-induced anxiety by neurosteroid 3-alpha-hydroxy-5-alpha-pregnane-20-one in rats. Neuopharmacology. 48(5):627-638.
11. Chiu, C.S. et al. 2005. GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum. The Journal of Neuroscience. 25(12)3234-3245.
12. GHB gained notoriety in the 1990s as the infamous "date rape" drug.
13. Hertz, L. et al. 1988. Energy metabolism in glutamatergic neurons, GABAergic neurons and astrocytes in primary cultures. Neurochemical Research. 13(605).
14. Denman, R.B., Wedler, F.C. 1984. Association-dissociation of mammalian brain glutamine synthetase: effects of metal ions and other ligands. Archives of Biochemistry and Biophysics. 232(2):427-440.
15. Rajeswari, T.S., Radha, E. 1984. Metabolism of the glutamate group of amino acids in rat brain as a function of age. Mechanisms of Ageing and Development. 24(2):139-150.
16. Lai et al., 1984. Ibid.
17. Pfeiffer, 1984. Ibid.
18. Ebert, A.G. 1979. The dietary administration of L-monosodium glutamate, DL-monosodium glutamate and L-glutamic acid to rats. Toxicology Letters. 3:71-78.
19. Siegel, A. 1999. Neuropharmacology of brain-stimulation-evoked aggression. Neuroscience and Biobehavioral Reviews. 23(3):359-389.
20. Balcar, V. et al. 1978. GABA-mediated inhibition in the epleptogenic focus, a process which may be involved in the mechanism of the cobalt-induced epilepsy. Brain Research. 154:182.
21. Owen, G. 1978. The feeding of diets containing up to 4 percent monosodium glutamate to rats for 2 years. Toxicology Letters. 1:221-226.
22. Sah, R. et al. 2002. Modulation of the GABA(A)-gated chloride channels by reactive oxygen species. Journal of Neurochemistry. 80:383-391.
23. Blatt, G.J. 2001. Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study. Journal of Autism and Developmental Disorders. 31:537-543.
24. Buxbaum, J.D. 2002. Association between a GABRB(3) polymorphism and autism. Molecular Psychiatry. 7:311-316.
25. Siegel, G.J., et al eds. 1998. Basic Neurochemistry: Molecular, Cellular and Medical Aspects, 6th ed.. Philadelphia: Lippman Williams and Wilkins.
26. Perry, T.L 1973. Huntington's chorea: deficiency of gamma-aminobutric acid in brain. New England Journal of Medicine. 288(2):337-342.
27. Brenner, H.J. et al. 1981. Disturbance of Amino Acid Metabolism: Clinical Chemistry and Diagnosis. Baltimore, MD: Urban and Schwarzenberg, Inc.
28. Pizzi, W.J., Barnhart, J.E., and Fanslow, D.J. 1977. Monosodium glutamate administration to the newborn reduces reproductive ability in female and male mice. Science. 196(4):452-454.
29. Braverman, 1987. Ibid. 205-206.
30. Kanarek, R., Marks-Kaufman, R. 1991. Nutrition and Behavior. New York: Van Nostrand Reinhold. 41-43.
31. Siegel, G.J., et al eds. 1998. Basic Neurochemistry: Molecular, Cellular and Medical Aspects, 6th ed. Philadelphia: Lippman Williams and Wilkins.
32. Durlach, J. et al. 2000. Physiopathology of symptomatic and latent forms of central nervous hyperexcitability due to magnesium deficiency: a current general scheme. Magnesium Research. 13(4):293-302.
33. Bigelow et al. 1984. Gamma-aminobutyric acid stimulates the release of endogenous ascorbic acid from rat striatal tissue. Journal of Neurochemistry. 42(2):412-419.
34. Christensen, J.C., Wang, Z., Rebec, G.V. 2000. gamma-Aminobutyric acid infusion in substantia nigra pars reticulata in rats inhibits ascorbate release in ipsilateral striatum. Neuroscience Letters. 280(3):191-194.
35. Aoshima, H., Tenpaku, Y. 1997. Modulation of GABA receptors expressed in Xenopus oocytes by 13-L-hydroxylinoleic acid and food additives. Bioscience, Biotechnology, and Biochemistry. 61(12):2051-2057.
36. Loschef and Siemes, 1984, Ibid.
37. Sytinsky, I.A., Soldatenkov, A.T. 1978. Neurochemical basis of the therapeutic effect of gamma-aminobutyric acid and its derivatives. Progress in Neurobiology. 10:89-133.
38. Antonaccio, 1984. Ibid.
39. Gillis, R.A., et al. 1984. Central gamma-aminobutyric acid involvement in blood pressure control. Federation Proceedings. 43(1):32-38.
40. Kamrin, R.P., Kamrin, A.A. 1961. The effects of pyridoxine antagonists and other convulsive agents on amino acid concentrations of the mouse brain. Journal of Neurochemistry. 6:219-225.