Effects of L-theanine on Motor Cortex Excitability in Healthy Subjects: A Paired-Pulse TMS Study

Summary

Major depressive disorder (MDD) is a serious mental illness and the leading cause of disability worldwide. New pharmacotherapeutic agents with complementary neurobiological mechanism and better side effect profile are of great needs. In addition to the monoamine system, the glutamatergic system plays a crucial role in MDD. L-theanine (N5-ethyl-L-glutamine) is the primary psychoactive component uniquely in green tea. Preclinical studies have demonstrated anti-depressant effect of L-theanine in rodents and provided evidences for its pharmacological properties of N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA) agonism. Yet these effects have not been proven in humans. Only one open-label clinical trial has studied and supported antidepressant effects of L-theanine in MDD patients. We propose using pair-pulse transcranial magnetic stimulation (ppTMS) to probe how L-theanine may manipulate the glutamatergic and GABA systems in the frontal region by changing cortical excitability first in healthy subjects. We plan to investigate the neurobiological effects of L-theanine in healthy subjects first. Granted that the first phase pilot trial provides neurophysiological evidence of L-theanine on motor cortex excitability in human subjects, next phases of studies on L-theanine in MDD patients cortical excitability could be justified.

Timeline

Start

2020-06-09

Primary completion

2021-05-31

Completion

2021-05-31

Publications

• Background Vuong QV, Bowyer MC, Roach PD. L-Theanine: properties, synthesis and isolation from tea. J Sci Food Agric. 2011 Aug 30;91(11):1931-9. doi: 10.1002/jsfa.4373. Epub 2011 Mar 29.
• Background Kim J, Kim J. Green Tea, Coffee, and Caffeine Consumption Are Inversely Associated with Self-Report Lifetime Depression in the Korean Population. Nutrients. 2018 Sep 1;10(9):1201. doi: 10.3390/nu10091201.
• Background Hintikka J, Tolmunen T, Honkalampi K, Haatainen K, Koivumaa-Honkanen H, Tanskanen A, Viinamaki H. Daily tea drinking is associated with a low level of depressive symptoms in the Finnish general population. Eur J Epidemiol. 2005;20(4):359-63. doi: 10.1007/s10654-005-0148-2.
• Background Hozawa A, Kuriyama S, Nakaya N, Ohmori-Matsuda K, Kakizaki M, Sone T, Nagai M, Sugawara Y, Nitta A, Tomata Y, Niu K, Tsuji I. Green tea consumption is associated with lower psychological distress in a general population: the Ohsaki Cohort 2006 Study. Am J Clin Nutr. 2009 Nov;90(5):1390-6. doi: 10.3945/ajcn.2009.28214. Epub 2009 Sep 30.
• Background Wakabayashi C, Numakawa T, Ninomiya M, Chiba S, Kunugi H. Behavioral and molecular evidence for psychotropic effects in L-theanine. Psychopharmacology (Berl). 2012 Feb;219(4):1099-109. doi: 10.1007/s00213-011-2440-z. Epub 2011 Aug 23.
• Background Egashira N, Ishigami N, Pu F, Mishima K, Iwasaki K, Orito K, Oishi R, Fujiwara M. Theanine prevents memory impairment induced by repeated cerebral ischemia in rats. Phytother Res. 2008 Jan;22(1):65-8. doi: 10.1002/ptr.2261.
• Background Lardner AL. Neurobiological effects of the green tea constituent theanine and its potential role in the treatment of psychiatric and neurodegenerative disorders. Nutr Neurosci. 2014 Jul;17(4):145-55. doi: 10.1179/1476830513Y.0000000079. Epub 2013 Nov 26.
• Background Hidese S, Ota M, Wakabayashi C, Noda T, Ozawa H, Okubo T, Kunugi H. Effects of chronic l-theanine administration in patients with major depressive disorder: an open-label study. Acta Neuropsychiatr. 2017 Apr;29(2):72-79. doi: 10.1017/neu.2016.33. Epub 2016 Jul 11.
• Background Paulus W, Classen J, Cohen LG, Large CH, Di Lazzaro V, Nitsche M, Pascual-Leone A, Rosenow F, Rothwell JC, Ziemann U. State of the art: Pharmacologic effects on cortical excitability measures tested by transcranial magnetic stimulation. Brain Stimul. 2008 Jul;1(3):151-63. doi: 10.1016/j.brs.2008.06.002. Epub 2008 Jun 30.
• Background Radhu N, de Jesus DR, Ravindran LN, Zanjani A, Fitzgerald PB, Daskalakis ZJ. A meta-analysis of cortical inhibition and excitability using transcranial magnetic stimulation in psychiatric disorders. Clin Neurophysiol. 2013 Jul;124(7):1309-20. doi: 10.1016/j.clinph.2013.01.014. Epub 2013 Feb 26.
• Background Bajbouj M, Lisanby SH, Lang UE, Danker-Hopfe H, Heuser I, Neu P. Evidence for impaired cortical inhibition in patients with unipolar major depression. Biol Psychiatry. 2006 Mar 1;59(5):395-400. doi: 10.1016/j.biopsych.2005.07.036. Epub 2005 Sep 28.
• Background Lefaucheur JP, Lucas B, Andraud F, Hogrel JY, Bellivier F, Del Cul A, Rousseva A, Leboyer M, Paillere-Martinot ML. Inter-hemispheric asymmetry of motor corticospinal excitability in major depression studied by transcranial magnetic stimulation. J Psychiatr Res. 2008 Apr;42(5):389-98. doi: 10.1016/j.jpsychires.2007.03.001. Epub 2007 Apr 20.
• Background Levinson AJ, Fitzgerald PB, Favalli G, Blumberger DM, Daigle M, Daskalakis ZJ. Evidence of cortical inhibitory deficits in major depressive disorder. Biol Psychiatry. 2010 Mar 1;67(5):458-64. doi: 10.1016/j.biopsych.2009.09.025. Epub 2009 Nov 17.
• Background Jeng JS, Li CT, Lin HC, Tsai SJ, Bai YM, Su TP, Chang YW, Cheng CM. Antidepressant-resistant depression is characterized by reduced short- and long-interval cortical inhibition. Psychol Med. 2020 Jun;50(8):1285-1291. doi: 10.1017/S0033291719001223. Epub 2019 Jun 3.
• Background Ziemann U, Chen R, Cohen LG, Hallett M. Dextromethorphan decreases the excitability of the human motor cortex. Neurology. 1998 Nov;51(5):1320-4. doi: 10.1212/wnl.51.5.1320.
• Background Schwenkreis P, Witscher K, Janssen F, Addo A, Dertwinkel R, Zenz M, Malin JP, Tegenthoff M. Influence of the N-methyl-D-aspartate antagonist memantine on human motor cortex excitability. Neurosci Lett. 1999 Aug 6;270(3):137-40. doi: 10.1016/s0304-3940(99)00492-9.
• Background Di Lazzaro V, Oliviero A, Saturno E, Dileone M, Pilato F, Nardone R, Ranieri F, Musumeci G, Fiorilla T, Tonali P. Effects of lorazepam on short latency afferent inhibition and short latency intracortical inhibition in humans. J Physiol. 2005 Apr 15;564(Pt 2):661-8. doi: 10.1113/jphysiol.2004.061747. Epub 2005 Feb 17.
• Background Ritsner MS, Miodownik C, Ratner Y, Shleifer T, Mar M, Pintov L, Lerner V. L-theanine relieves positive, activation, and anxiety symptoms in patients with schizophrenia and schizoaffective disorder: an 8-week, randomized, double-blind, placebo-controlled, 2-center study. J Clin Psychiatry. 2011 Jan;72(1):34-42. doi: 10.4088/JCP.09m05324gre. Epub 2010 Nov 30.
• Background Borzelleca JF, Peters D, Hall W. A 13-week dietary toxicity and toxicokinetic study with l-theanine in rats. Food Chem Toxicol. 2006 Jul;44(7):1158-66. doi: 10.1016/j.fct.2006.03.014. Epub 2006 Apr 26.
• Background Taylor JJ, Borckardt JJ, George MS. Endogenous opioids mediate left dorsolateral prefrontal cortex rTMS-induced analgesia. Pain. 2012 Jun;153(6):1219-1225. doi: 10.1016/j.pain.2012.02.030. Epub 2012 Mar 22.
• Background Health Quality Ontario. Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Ont Health Technol Assess Ser. 2016 Mar 1;16(5):1-66. eCollection 2016.
• Background Carpenter LL, Janicak PG, Aaronson ST, Boyadjis T, Brock DG, Cook IA, Dunner DL, Lanocha K, Solvason HB, Demitrack MA. Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice. Depress Anxiety. 2012 Jul;29(7):587-96. doi: 10.1002/da.21969. Epub 2012 Jun 11.
• Background Levkovitz Y, Isserles M, Padberg F, Lisanby SH, Bystritsky A, Xia G, Tendler A, Daskalakis ZJ, Winston JL, Dannon P, Hafez HM, Reti IM, Morales OG, Schlaepfer TE, Hollander E, Berman JA, Husain MM, Sofer U, Stein A, Adler S, Deutsch L, Deutsch F, Roth Y, George MS, Zangen A. Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial. World Psychiatry. 2015 Feb;14(1):64-73. doi: 10.1002/wps.20199.
• Background Rossi S, Hallett M, Rossini PM, Pascual-Leone A; Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol. 2009 Dec;120(12):2008-2039. doi: 10.1016/j.clinph.2009.08.016. Epub 2009 Oct 14.
• Background McClintock SM, Reti IM, Carpenter LL, McDonald WM, Dubin M, Taylor SF, Cook IA, O'Reardon J, Husain MM, Wall C, Krystal AD, Sampson SM, Morales O, Nelson BG, Latoussakis V, George MS, Lisanby SH; National Network of Depression Centers rTMS Task Group; American Psychiatric Association Council on Research Task Force on Novel Biomarkers and Treatments. Consensus Recommendations for the Clinical Application of Repetitive Transcranial Magnetic Stimulation (rTMS) in the Treatment of Depression. J Clin Psychiatry. 2018 Jan/Feb;79(1):16cs10905. doi: 10.4088/JCP.16cs10905.
• Background Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Electroencephalogr Clin Neurophysiol. 1998 Jan;108(1):1-16. doi: 10.1016/s0168-5597(97)00096-8.
• Background Gomez-Ramirez M, Kelly SP, Montesi JL, Foxe JJ. The effects of L-theanine on alpha-band oscillatory brain activity during a visuo-spatial attention task. Brain Topogr. 2009 Jun;22(1):44-51. doi: 10.1007/s10548-008-0068-z. Epub 2008 Oct 9.
• Background Gomez-Ramirez M, Higgins BA, Rycroft JA, Owen GN, Mahoney J, Shpaner M, Foxe JJ. The deployment of intersensory selective attention: a high-density electrical mapping study of the effects of theanine. Clin Neuropharmacol. 2007 Jan-Feb;30(1):25-38. doi: 10.1097/01.WNF.0000240940.13876.17.
• Yuan S, Brown JC, Gold M, Tirrell E, Jones RN, Carpenter LL. Effects of single-dose L-theanine on motor cortex excitability. Clin Neurophysiol. 2021 Sep;132(9):2062-2064. doi: 10.1016/j.clinph.2021.07.003. Epub 2021 Jul 10. No abstract available.

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Indications