Clinical trial NCT04749745: Effects of L-theanine on Motor Cortex Excitability in Healthy Subjects: A Paired-Pulse TMS Study
Official title: Effects of Single-dose L-theanine on Motor Cortex Excitability in Healthy Subjects: A Double-blinded, Randomized Order, Cross-over Paired-Pulse Transcranial Magnetic Stimulation Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Cortical Excitability
Psychiatric Disorder
Keywords: L-theanine
Cortical Excitability
NMDA
GABA
Paired-Pulse TMS
Lead sponsor: Butler Hospital
Sponsor class: OTHER
First posted: 2021-02-11
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This is a pilot study, investigating the effects of single dose L-theanine in Healthy subjects, to further assess the validity and feasibility to study this compound in patient population.
Primary purpose: OTHER

Brief 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.

Detailed description: Background and Significance:

Major depressive disorder (MDD) is a serious mental illness and the leading cause of disability worldwide. Although many antidepressants acting on synaptic monoamine levels have been used as the first-line drug treatment for MDD, around one third of MDD are pharmacologically resistant. Side effects of these medications impose additional hardship on adherence and further affect treatment outcome. 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. Epidemiological studies support that green tea consumption is an independent factor associated with lower prevalence of depression. 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. ppTMS is a well-established technique to investigate frontal motor cortical excitability mediated by the inter-neuron NMDA and GABA receptors. Specific changes of ppTMS measures, including impaired short-term and long-term intracortical inhibition (SICI, mediated by GABA-A receptor; LICI, mediated by GABA-B receptor) and intracortical facilitation (ICF, mediated by NMDA receptor), have been demonstrated in MDD. Using this technique, 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. This will lay foundation for further exploration of L-theanine's potential as an augmenting agent for MDD in a placebo- controlled design.

Aims and Hypothesis:

Given the potential NMDA and GABA agonistic effects of L-theanine, we hypothesize that it increases intracortical inhibition and facilitation through enhancement of NMDA- and GABA-receptor mediated neurotransmission, in healthy subjects (N=10 to complete study).

Study Procedures:

Double-blinded, Randomized-order, Cross-over placebo-controlled to evaluate acute effect of single-dose L-theanine on motor cortex excitability by ppTMS in 10 healthy subjects.

Dose of L-theanine or placebo is 400mg. At baseline, subjects will be randomized to L- theanine or placebo group, then receive ppTMS protocol before drug administration. The ppTMS protocol is repeated after 30min of administration. Then subjects will return to clinic after 1 week free of any medications and repeat the above protocol with the second drug condition. Visual analog scale will be used to evaluate psychosomatic symptoms and wellbeing of the subjects pre- and post-each drug administration.

Data Analytic Plan:

Wilcoxon test will be used to compare the baseline-to-post-drug means of SICI, LICI and ICF measures. Prespecified covariates include age, sex, handedness, level of fatigue will be analyzed in linear regression model. The time-condition relationship with continuous dependent variables of ICI and ICF values will be evaluated by Mixed Effect Model. Two- sided P value \< 0.05 is considered statistically significant.

Eligibility criteria: Inclusion Criteria:

1. Adult, aged between 18 and 65 years old;
2. Able to read/speak English and give informed consent
3. No current or history of Axis I psychiatric disorders by DSM-5.
4. Free of psychotropic medication use

Exclusion Criteria:

1. History of significant acute or chronic neurological or medical disorder or condition that increases risk for seizure with TMS;
2. History of alcohol use disorder, nicotine dependence, adjustment disorder;
3. History of allergic reactions to L-theanine or green tea;
4. Pregnancy;
5. Unable/unwilling to abstain from nutraceutical supplements and psychotropic agents during participation in the study
6. Unable/ unwillingness to refrain from recreational substance use (e.g. alcohol or marijuana) during participation in the study;
7. Meet criteria for exclusion from TMS or MRI procedures, including intracranial metal implants or nonremovable ferromagnetic items in the head/neck.

Primary outcomes:
measure: The Change of Motor Cortex Excitability Measures by ppTMS
timeFrame: Before and 30 minutes after each drug administration (no long-term follow up as this is a study on acute effect of a single-dose agent).
Secondary outcomes:
measure: The Change of Visual Analog Scale (VAS)
timeFrame: Throughout each session; each session lasts up to 3 hours; 2 sessions for each subject. The 2 sessions are 3-7 days apart.
Other outcomes:
Locations:
city: Providence
country: United States
facility: Butler Hospital
state: Rhode Island
Study officials:
affiliation: Brown University-Butler Hospital
name: Linda Carpenter, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.