Symptoms Associated with Abnormal GABA Levels

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Gamma-aminobutyric acid (GABA) plays a major role in neuronal inhibition. It occurs naturally in several foods, but it is found in higher levels in fermented food products.[1] In Japan, it is used deliberately as a functional food ingredient for health benefits. Research on the safety of using GABA as a supplement has shown that taking 18 grams per day for 4 days or 120 mg per day for 12 weeks does not produce adverse events.[2] Some studies have shown that a moderate drop in blood pressure has occurred with GABA intake. The ubiquity of GABA within the central nervous system makes it difficult to delineate its specific effects.

See Paredes and Agmo for deeper information on most of the following.

Affective Disorders and Mood[edit]

Anxiety. GABA has a clear role in fear and anxiety disorders.[3][4][5][6] GABA administration has been shown to reduce anxiety and worry and to induce relaxation in humans.[1][7] At the same time, negative modulators of GABA receptors are known to have anxiogenic-like effects.[4] The specific mechanism by which GABA mediates fear appears to be gender dependent.[8]

One way GABA may impact anxiety is via its impact on fear memory.[9] Drugs that facilitate the transmission of GABA have been shown to interrupt fear memory formation and storage.[9]

Depression. GABA appears to play a role in depression.[4][10][11][12] The GABA hypothesis of depression posits that modulators of the α2/α3 GABAA receptor may be valuable antidepressants.[5] Reduced GABAergic functioning is generally associated with depression, and thus antidepressants that leverage the GABA system aim to increase GABA.[4]

Mood. Emrich first postulated a role for GABA in mood in 1980.[13] GABA has since been shown to play a role in mood and to be capable of stabilizing mood.[1][4][14] For instance, sodium valproate, which blocks GABA transmission, is used to treat bipolar disorder.[15]

Stress. Stress is known to deplete GABA and requires replacement of the metabolite through, for instance, enriched functional foods.[1] Thus unsurprisingly, the administration of GABA is known to reduce stress.[3]

Psychosis. Psychosis may be influenced by GABA functioning.[16]

Autism. GABA inhibition is implicated in autism spectrum disorder as well as other developmental disorders.[17]

Cognition[edit]

Cognition. Altered GABA transmission is linked to cognitive functions.[18] Specifically, whereas lowered GABA is associated with reduced cognitive control, GABA has been shown to enhance memory.[3][19]

Attention. GABA is implicated in scattered attention and difficulty in focusing on one task.[17][19] For instance, altered levels of GABA have been observed in children with attention-deficit/hyperactivity disorder, ADHD, potentially owing to its impact on dopaminergic transmission in the striatum.[19][20] Specifically, children with ADHD have lower GABA concentrations than those without the disorder.[17]

Behavior[edit]

Different GABA receptor subtypes have distinct impacts on behavior.[21]

Impulsivity. GABA is implicated in self-control and behavioral inhibition.[19][22][23] Low GABA levels are associated with increased impulsivity, as well as impaired response inhibition.[19]

GABA levels have been shown to be lower in patient groups – like those with Prader-Willi syndrome – who display significant behavioral disturbances that may be related to lack of self-control and a tendency toward impulsivity.[24] These behavioral problems include temper outbursts, social interaction difficulties, skin-picking, and a tendency to be self-absorbed.

Compulsivity. GABA levels in the orbitofrontal cortex of those with obsessive-compulsive disorder (OCD) is significantly lower than what is observed in those without the disorder.[25]

Sleep. It is well established that GABA enhances sleep and is involved in circadian rhythm.[3] It is also implicated in insomnia and other sleep disturbances.

Physical Symptoms[edit]

Pain. GABA is implicated in pain, though activation of GABA can enhance or minimize pain, depending on the location of activation.[3][7][26][27]

However, generalized activation of GABA appears to reduce the overall response to painful stimuli.[7][26] As such, therapeutic strategies aimed at leveraging the GABA system are developed to increase GABA synthesis.[27] Agonists for both GABAA and GABAB receptors act as analgesics.[21][28]

Headaches. Headaches are one of the manifestations related to changes in GABA transmission that involves pain.[29]

Immunity. GABA administration may bolster immunity through its anxiolytic effects.[1] It may also have antimicrobial and anti-allergy effects.[30] Additionally, GABA appears to have anti-inflammatory properties that may provide health benefits.[2][30]

Cardiovascular function. GABA regulates cardiovascular functions and can impact heart rate.[1][31][32][33][34][35] Research into its ability to combat hypertension is ongoing.[2][30]

Respiration. GABA is found not only in the brain but also in peripheral tissues and in other locations, such as the lungs. Baclofen (a GABAB agonist) has been shown preclinically to inhibit neurally mediated bronchoconstriction.[36]

Motility. Administration of GABA leads to hypomotility, reduced ambulatory activity, and sedation. [21] On the other hand, reduced GABA in the motor cortex is associated with muscle rigidity and spasms, as seen in stiff-person syndrome.[37][38] 

Cancer. GABA may provide antioxidant effects and has been shown to contribute to inhibiting cancer cell metastasis.[1][2][30][16][21]

Renal function. GABA appears to play a role in renal function.[1][12]

References[edit]

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Abdou, Adham M.; Higashiguchi, S.; Horie, K.; Kim, Mujo; Hatta, H.; Yokogoshi, H. (2008). "Relaxation and immunity enhancement effects of γ-Aminobutyric acid (GABA) administration in humans". BioFactors. 26 (3): 201–208. doi:10.1002/BIOF.5520260305. ISSN 0951-6433.
  2. ↑ 2.0 2.1 2.2 2.3 Oketch-Rabah, Hellen A.; Madden, Emily F.; Roe, Amy L.; Betz, Joseph M. (2021). "United States Pharmacopeia (USP) Safety Review of Gamma-Aminobutyric Acid (GABA)". Nutrients. 13 (8): 2742. doi:10.3390/nu13082742. ISSN 2072-6643. PMC PMC8399837 Check |pmc= value (help). PMID 34444905 Check |pmid= value (help).CS1 maint: PMC format (link)
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Hepsomali, Piril; Groeger, John A.; Nishihira, Jun; Scholey, Andrew (2020). "Effects of Oral Gamma-Aminobutyric Acid (GABA) Administration on Stress and Sleep in Humans: A Systematic Review". Frontiers in Neuroscience. 14: 923. doi:10.3389/fnins.2020.00923. ISSN 1662-453X. PMC PMC7527439 Check |pmc= value (help). PMID 33041752 Check |pmid= value (help).CS1 maint: PMC format (link)
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Kalueff, Allan V.; Nutt, David J. (2007). "Role of GABA in anxiety and depression". Depression and Anxiety. 24 (7): 495–517. doi:10.1002/da.20262.
  5. ↑ 5.0 5.1 Möhler, Hanns (2012). "The GABA system in anxiety and depression and its therapeutic potential". Neuropharmacology. 62 (1): 42–53. doi:10.1016/j.neuropharm.2011.08.040.
  6. ↑ Nuss, Philippe (2015). "Anxiety disorders and GABA neurotransmission: a disturbance of modulation". Neuropsychiatric Disease and Treatment: 165. doi:10.2147/NDT.S58841. ISSN 1178-2021. PMC 4303399. PMID 25653526. Missing |author1= (help)CS1 maint: PMC format (link)
  7. ↑ 7.0 7.1 7.2 Jasmin, L.; Wu, M.; Ohara, P. (2004). "GABA Puts a Stop to Pain". Current Drug Target -CNS & Neurological Disorders. 3 (6): 487–505. doi:10.2174/1568007043336716.
  8. ↑ Adkins, Jordan M.; Lynch, Joseph; Gray, Michael; Jasnow, Aaron M. (2021). "Presynaptic GABAB receptor inhibition sex dependently enhances fear extinction and attenuates fear renewal". Psychopharmacology. 238 (8): 2059–2071. doi:10.1007/s00213-021-05831-w. ISSN 0033-3158. PMC PMC8295214 Check |pmc= value (help). PMID 33855580 Check |pmid= value (help).CS1 maint: PMC format (link)
  9. ↑ 9.0 9.1 Makkar, Steve R; Zhang, Shirley Q; Cranney, Jacquelyn (2010). "Behavioral and Neural Analysis of GABA in the Acquisition, Consolidation, Reconsolidation, and Extinction of Fear Memory". Neuropsychopharmacology. 35 (8): 1625–1652. doi:10.1038/npp.2010.53. ISSN 0893-133X. PMC 3055480. PMID 20410874.CS1 maint: PMC format (link)
  10. ↑ Brambilla, P; Perez, J; Barale, F; Schettini, G; Soares, J C (2003). "GABAergic dysfunction in mood disorders". Molecular Psychiatry. 8 (8): 721–737. doi:10.1038/sj.mp.4001362. ISSN 1359-4184.
  11. ↑ Leung, Justin; Xue, Hong (2003). "GABAergic Functions and Depression: From Classical Therapies to Herbal Medicine". Current Drug Target -CNS & Neurological Disorders. 2 (6): 363–373. doi:10.2174/1568007033482715.
  12. ↑ 12.0 12.1 Tunnicliff, G.; Malatynska, E. (2003). "Central GABAergic systems and depressive illness". Neurochemical Research. 28 (6): 965–976. doi:10.1023/A:1023287729363.
  13. ↑ Emrich, H. M.; Zerssen, D.; Kissling, W.; Möller, H. -J.; Windorfer, A. (1980). "Effect of sodium valproate on mania: The GABA-hypothesis of affective disorders". Archiv für Psychiatrie und Nervenkrankheiten. 229 (1): 1–16. doi:10.1007/BF00343800. ISSN 0003-9373.
  14. ↑ Krystal, J H; Sanacora, G; Blumberg, H; Anand, A; Charney, D S; Marek, G; Epperson, C N; Goddard, A; Mason, G F (2002). "Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments". Molecular Psychiatry. 7 (S1): S71–S80. doi:10.1038/sj.mp.4001021. ISSN 1359-4184.
  15. ↑ Sekhon, S., & Gupta, V. (2021). Mood disorder. 2021 May 8. StatPearls. Treasure Island (FL): StatPearls Publishing. Accessed April 17, 2022. https://www.ncbi.nlm.nih.gov/books/NBK558911/
  16. ↑ 16.0 16.1 Kegeles, Lawrence S. (2016). "Brain GABA Function and Psychosis". American Journal of Psychiatry. 173 (5): 448–449. doi:10.1176/appi.ajp.2016.16020165. ISSN 0002-953X.
  17. ↑ 17.0 17.1 17.2 Edden, Richard A. E.; Crocetti, Deana; Zhu, He; Gilbert, Donald L.; Mostofsky, Stewart H. (2012). "Reduced GABA Concentration in Attention-Deficit/Hyperactivity Disorder". Archives of General Psychiatry. 69 (7). doi:10.1001/archgenpsychiatry.2011.2280. ISSN 0003-990X. PMC 3970207. PMID 22752239.CS1 maint: PMC format (link)
  18. ↑ Prévot, Thomas; Sibille, Etienne (2021). "Altered GABA-mediated information processing and cognitive dysfunctions in depression and other brain disorders". Molecular Psychiatry. 26 (1): 151–167. doi:10.1038/s41380-020-0727-3. ISSN 1359-4184.
  19. ↑ 19.0 19.1 19.2 19.3 19.4 Bollmann, S; Ghisleni, C; Poil, S-S; Martin, E; Ball, J; Eich-Höchli, D; Edden, R A E; Klaver, P; Michels, L; Brandeis, D; O'Gorman, R L (2015). "Developmental changes in gamma-aminobutyric acid levels in attention-deficit/hyperactivity disorder". Translational Psychiatry. 5 (6): e589–e589. doi:10.1038/tp.2015.79. ISSN 2158-3188. PMC 4490289. PMID 26101852.CS1 maint: PMC format (link)
  20. ↑ Tritsch, Nicolas X.; Ding, Jun B.; Sabatini, Bernardo L. (2012). "Dopaminergic neurons inhibit striatal output through non-canonical release of GABA". Nature. 490 (7419): 262–266. doi:10.1038/nature11466. ISSN 0028-0836. PMC 3944587. PMID 23034651.CS1 maint: PMC format (link)
  21. ↑ 21.0 21.1 21.2 21.3 Paredes, Raul G.; Ågmo, Anders (1992). "GABA and behavior: The role of receptor subtypes". Neuroscience & Biobehavioral Reviews. 16 (2): 145–170. doi:10.1016/S0149-7634(05)80177-0.
  22. ↑ Silveri, Marisa M.; Sneider, Jennifer T.; Crowley, David J.; Covell, Michael J.; Acharya, Deepa; Rosso, Isabelle M.; Jensen, J. Eric (2013). "Frontal Lobe γ-Aminobutyric Acid Levels During Adolescence: Associations with Impulsivity and Response Inhibition". Biological Psychiatry. 74 (4): 296–304. doi:10.1016/j.biopsych.2013.01.033. PMC 3695052. PMID 23498139.CS1 maint: PMC format (link)
  23. ↑ Boy, Frederic; Evans, C. John; Edden, Richard A.E.; Lawrence, Andrew D.; Singh, Krish D.; Husain, Masud; Sumner, Petroc (2011). "Dorsolateral Prefrontal γ-Aminobutyric Acid in Men Predicts Individual Differences in Rash Impulsivity". Biological Psychiatry. 70 (9): 866–872. doi:10.1016/j.biopsych.2011.05.030. PMC 3192031. PMID 21757187.CS1 maint: PMC format (link)
  24. ↑ Rice, Lauren J.; Lagopoulos, Jim; Brammer, Michael; Einfeld, Stewart L. (2016). "Reduced gamma-aminobutyric acid is associated with emotional and behavioral problems in Prader-Willi syndrome". American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 171 (8): 1041–1048. doi:10.1002/ajmg.b.32472.
  25. ↑ Zhang, Gensheng; Zhang, Kai; Cui, Wei; Hong, Yucai; Zhang, Zhongheng (2018). "The effect of early mobilization for critical ill patients requiring mechanical ventilation: a systematic review and meta-analysis". Journal of Emergency and Critical Care Medicine. 2: 9–9. doi:10.21037/jeccm.2018.01.04.
  26. ↑ 26.0 26.1 Enna SJ, McCarson KE. (2006) The role of GABA in the mediation and perception of pain. Adv Pharmacol. 54:1-27. https://doi.org/10.1016/S1054-3589(06)54001-3
  27. ↑ 27.0 27.1 Gwak, Young S.; Hulsebosch, Claire E. (2011). "GABA and central neuropathic pain following spinal cord injury". Neuropharmacology. 60 (5): 799–808. doi:10.1016/j.neuropharm.2010.12.030. PMC 3285561. PMID 21216257.CS1 maint: PMC format (link)
  28. ↑ Sawynok, Jana (1987). "GABAergic mechanisms of analgesia: An update". Pharmacology Biochemistry and Behavior. 26 (2): 463–474. doi:10.1016/0091-3057(87)90148-1.
  29. ↑ Farmakidis, Constantine; Inan, Seniha; Milstein, Mark; Herskovitz, Steven (2015). "Headache and Pain in Guillain-Barré Syndrome". Current Pain and Headache Reports. 19 (8): 40. doi:10.1007/s11916-015-0508-x. ISSN 1531-3433.
  30. ↑ 30.0 30.1 30.2 30.3 Ngo, Dai-Hung; Vo, Thanh Sang (2019). "An Updated Review on Pharmaceutical Properties of Gamma-Aminobutyric Acid". Molecules. 24 (15): 2678. doi:10.3390/molecules24152678. ISSN 1420-3049. PMC 6696076. PMID 31344785.CS1 maint: PMC format (link)
  31. ↑ Bentzen, Bo Hjorth; Grunnet, Morten (2011). "Central and Peripheral GABA A Receptor Regulation of the Heart Rate Depends on the Conscious State of the Animal". Advances in Pharmacological Sciences. 2011: 1–10. doi:10.1155/2011/578273. ISSN 1687-6334. PMC 3226329. PMID 22162673.CS1 maint: PMC format (link)
  32. ↑ Zhang, Jing; Mifflin, Steven W. (1998). "Receptor subtype specific effects of GABA agonists on neurons receiving aortic depressor nerve inputs within the nucleus of the solitary tract". Journal of the Autonomic Nervous System. 73 (2–3): 170–181. doi:10.1016/S0165-1838(98)00140-4.
  33. ↑ Gozlinska, B.; Czyzewska-Szafran, H. & Plaznik, A.(1999). Blood pressure and hypothalamic NA-GABA interaction in spontaneously hypertensive rats (SHR): effect of administration DSP-4. Acta poloniae pharmaceutica, 56, 245-248.
  34. ↑ Gordon, Frank J; Sved, Alan F (2002). "Neurotransmitters In Central Cardiovascular Regulation: Glutamate And Gaba". Clinical and Experimental Pharmacology and Physiology. 29 (5–6): 522–524. doi:10.1046/j.1440-1681.2002.03666.x. ISSN 0305-1870.
  35. ↑ Shizuka, F.; Kido, Y.; Nakazawa, T.; Kitajima, H.; Aizawa, C.; Kayamura, H.; Ichijo, N. (2004). "Antihypertensive effect of γ-amino butyric acid enriched soy products in spontaneously hypertensive rats". BioFactors. 22 (1–4): 165–167. doi:10.1002/biof.5520220133.
  36. ↑ Dicpinigaitis, Peter V.; Nierman, David M.; Miller, Albert (1993). "Baclofen-Induced Bronchoconstriction". Annals of Pharmacotherapy. 27 (7–8): 883–884. doi:10.1177/106002809302700713. ISSN 1060-0280.
  37. ↑ Levy, Lucien M.; Dalakas, Marinos C.; Floeter, Mary Kay (1999). "The Stiff-Person Syndrome: An Autoimmune Disorder Affecting Neurotransmission of γ-Aminobutyric Acid". Annals of Internal Medicine. 131 (7): 522. doi:10.7326/0003-4819-131-7-199910050-00008. ISSN 0003-4819.
  38. ↑ Devlin CL, Schlosser W. (1999) Gamma-aminobutyric acid modulation of acetylcholine-induced contractions of a smooth muscle from an echinoderm (Sclerodactyla briareus). Invert Neurosci. 4(1):1-8. https://doi.org/10.1007/PL00022363
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