J Clin Neurol.  2018 Jul;14(3):291-295. 10.3988/jcn.2018.14.3.291.

Safety and Efficacy of Gamma-Aminobutyric Acid from Fermented Rice Germ in Patients with Insomnia Symptoms: A Randomized, Double-Blind Trial

• Byun JI
• Shin YY
• Chung SE
• Shin WC

• KMID: 2415043
• DOI: http://doi.org/10.3988/jcn.2018.14.3.291

Abstract

BACKGROUND AND PURPOSE
This study aimed to determine the subjective and objective improvements in sleep quality after treatment with gamma-aminobutyric acid (GABA; 300 mg daily) extracted from unpolished rice germ.
METHODS
This study was a prospective, randomized, double-blind, and placebo-controlled trial. In total, 40 patients who complained of insomnia symptoms were enrolled and randomly assigned to the GABA treatment group (n=30) or the placebo group (n=10). Polysomnography was performed, and sleep questionnaires were administered before treatment and after 4 weeks of treatment.
RESULTS
After 4 weeks of treatment the sleep latency had decreased [13.4±15.7 min at pretreatment vs. 5.7±6.2 min at posttreatment (mean±SD), p=0.001] and the sleep efficacy had increased (79.4±12.9% vs. 86.1±10.5%, p=0.018) only in the GABA treatment group. Adverse events occurred in four subjects (10%).
CONCLUSIONS
This study shows that treatment with unpolished-rice-germ-derived GABA improved not only the subjective sleep quality but also the objective sleep efficacy without severe adverse events.

Keyword

gamma-aminobutyric acid; fermented rice germ extract; insomnia; treatment

MeSH Terms

gamma-Aminobutyric Acid*
Humans
Polysomnography
Prospective Studies
Sleep Initiation and Maintenance Disorders*
gamma-Aminobutyric Acid

Reference

1. Riemann D, Nissen C, Palagini L, Otte A, Perlis ML, Spiegelhalder K. The neurobiology, investigation, and treatment of chronic insomnia. Lancet Neurol. 2015; 14:547–558. PMID: 25895933.

2. Winkelman JW. Clinical practice. insomnia disorder. N Engl J Med. 2015; 373:1437–1444. PMID: 26444730.

3. Gottesmann C. GABA mechanisms and sleep. Neuroscience. 2002; 111:231–239. PMID: 11983310.

4. Ashton H. The diagnosis and management of benzodiazepine dependence. Curr Opin Psychiatry. 2005; 18:249–255. PMID: 16639148.

5. Ancoli-Israel S. Insomnia in the elderly: a review for the primary care practitioner. Sleep. 2000; 23(Suppl 1):S23–S30. PMID: 10755805.

6. Ford ES, Cunningham TJ, Giles WH, Croft JB. Trends in insomnia and excessive daytime sleepiness among U.S. adults from 2002 to 2012. Sleep Med. 2015; 16:372–378. PMID: 25747141.

7. Abdou AM, Higashiguchi S, Horie K, Kim M, Hatta H, Yokogoshi H. Relaxation and immunity enhancement effects of gamma-aminobutyric acid (GABA) administration in humans. Biofactors. 2006; 26:201–208. PMID: 16971751.

8. Diana M, Quílez J, Rafecas M. Gamma-aminobutyric acid as a bioactive compound in foods: a review. J Funct Foods. 2014; 10:407–420.

9. Li H, Qiu T, Huang G, Cao Y. Production of gamma-aminobutyric acid by Lactobacillus brevis NCL912 using fed-batch fermentation. Microb Cell Fact. 2010; 9:85. PMID: 21070676.

10. Dhakal R, Bajpai VK, Baek KH. Production of gaba (γ-Aminobutyric acid) by microorganisms: a review. Braz J Microbiol. 2012; 43:1230–1241. PMID: 24031948.

11. Hong KB, Park Y, Suh HJ. Sleep-promoting effects of a GABA/5-HTP mixture: behavioral changes and neuromodulation in an invertebrate model. Life Sci. 2016; 150:42–49. PMID: 26921634.

12. Mabunga DF, Gonzales EL, Kim HJ, Choung SY. Treatment of GABA from fermented rice germ ameliorates caffeine-induced sleep disturbance in mice. Biomol Ther. 2015; 23:268–274.

13. Shell W, Bullias D, Charuvastra E, May LA, Silver DS. A randomized, placebo-controlled trial of an amino acid preparation on timing and quality of sleep. Am J Ther. 2010; 17:133–139. PMID: 19417589.

14. Boonstra E, de Kleijn R, Colzato LS, Alkemade A, Forstmann BU, Nieuwenhuis S. Neurotransmitters as food supplements: the effects of GABA on brain and behavior. Front Psychol. 2015; 6:1520. PMID: 26500584.

15. Sohn SI, Kim DH, Lee MY, Cho YW. The reliability and validity of the Korean version of the Pittsburgh Sleep Quality Index. Sleep Breath. 2012; 16:803–812. PMID: 21901299.

16. Cho YW, Song ML, Morin CM. Validation of a Korean version of the insomnia severity index. J Clin Neurol. 2014; 10:210–215. PMID: 25045373.

17. Kook MC, Seo MJ, Cheigh CI, Pyun YR, Cho SC, Park H. Enhanced production of gamma-aminobutyric acid using rice bran extracts by Lactobacillus sakei B2-16. J Microbiol Biotechnol. 2010; 20:763–766. PMID: 20467250.

18. Shin YY, Byun JI, Chung SE, Seong MJ, Cho HA, Cha HK, et al. [Effect of low and high-dose GABA from unpolished rice-germ on timing and quality of sleep: a randomized double-blind placebo-controlled trial]. J Sleep Med. 2016; 13:60–66.

19. Berry RB, Brooks R, Gamaldo CE, Harding SM, Lloyd RM, Marcus CL, et al. The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications, Version 2.3. Darien (IL): American Academy of Sleep Medicine;2015.

20. Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol. 2003; 13:176–181. PMID: 12903007.

21. Nauta WJ. Hypothalamic regulation of sleep in rats; an experimental study. J Neurophysiol. 1946; 9:285–316. PMID: 20991815.

22. Luppi PH, Peyron C, Fort P. Not a single but multiple populations of GABAergic neurons control sleep. Sleep Med Rev. 2017; 32:85–94. PMID: 27083772.

23. Schneider E, Ziegler B, Maxion H. Gamma-aminobutyric acid (GABA) and sleep. the influence of di-n-propylacetic acid on sleep in man. Eur Neurol. 1977; 15:146–152. PMID: 192556.

24. Kuriyama K, Sze PY. Blood-brain barrier to H3-gamma-aminobutyric acid in normal and amino oxyacetic acid-treated animals. Neuropharmacology. 1971; 10:103–108. PMID: 5569303.

25. Al-Sarraf H. Transport of 14C-gamma-aminobutyric acid into brain, cerebrospinal fluid and choroid plexus in neonatal and adult rats. Brain Res Dev Brain Res. 2002; 139:121–129. PMID: 12480126.

26. Shyamaladevi N, Jayakumar AR, Sujatha R, Paul V, Subramanian EH. Evidence that nitric oxide production increases gamma-amino butyric acid permeability of blood-brain barrier. Brain Res Bull. 2002; 57:231–236. PMID: 11849830.

27. Ohayon MM, Roth T. Place of chronic insomnia in the course of depressive and anxiety disorders. J Psychiatr Res. 2003; 37:9–15. PMID: 12482465.

28. Sutton EL. Psychiatric disorders and sleep issues. Med Clin North Am. 2014; 98:1123–1143. PMID: 25134876.

29. Brambilla P, Perez J, Barale F, Schettini G, Soares JC. GABAergic dysfunction in mood disorders. Mol Psychiatry. 2003; 8:721–737. PMID: 12888801.

30. Ator NA. Contributions of GABAA receptor subtype selectivity to abuse liability and dependence potential of pharmacological treatments for anxiety and sleep disorders. CNS Spectr. 2005; 10:31–39. PMID: 15618945.

31. Möhler H. The GABA system in anxiety and depression and its therapeutic potential. Neuropharmacology. 2012; 62:42–53. PMID: 21889518.

32. Brunner DP, Dijk DJ, Münch M, Borbély AA. Effect of zolpidem on sleep and sleep EEG spectra in healthy young men. Psychopharmacology. 1991; 104:1–5. PMID: 1881993.

33. Aeschbach D, Dijk DJ, Trachsel L, Brunner DP, Borbély AA. Dynamics of slow-wave activity and spindle frequency activity in the human sleep EEG: effect of midazolam and zopiclone. Neuropsychopharmacology. 1994; 11:237–244. PMID: 7857498.