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

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ClinicalTrials.gov Identifier: NCT04749745
Recruitment Status : Recruiting
First Posted : February 11, 2021
Last Update Posted : February 11, 2021
Sponsor:
Information provided by (Responsible Party):
Butler Hospital

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.


Condition or disease Intervention/treatment Phase
Cortical Excitability Psychiatric Disorder Drug: L-theanine Drug: Placebo Early Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
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.
Masking: Double (Participant, Investigator)
Primary Purpose: Other
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
Actual Study Start Date : June 9, 2020
Estimated Primary Completion Date : May 31, 2021
Estimated Study Completion Date : May 31, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Theanine

Arm Intervention/treatment
Active Comparator: L-Theanine
Subject will receive 400mg single dose of L-theanine, by oral ingestion with water. The capsules are prepared and dispensed by hospital pharmacy, with the investigator and participant both blinded.
Drug: L-theanine
The subject will receive paired-pulse TMS (ppTMS) procedure before and 30min after taking the drug orally, to assess motor cortex excitability, measured by surface electromyogram (EMG). The ppTMS procedure is administered by a TMS stimulator controlled a program software named Signal. The coil of the stimulator is placed above the scalp where the stimulation would activate the left primary motor cortex region that controls the right thumb. When a pulse stimulation is delivered by the coil, the EMG over a thumb muscle (abductor pollicis brevis) will record a motor-evoked potential on the tracing. Cross-over with placebo in two separate sessions at least 72 hours apart.

Drug: Placebo
The subject will receive paired-pulse TMS (ppTMS) procedure before and 30min after taking the drug orally, to assess motor cortex excitability, measured by surface electromyogram (EMG). The ppTMS procedure is administered by a TMS stimulator controlled a program software named Signal. The coil of the stimulator is placed above the scalp where the stimulation would activate the left primary motor cortex region that controls the right thumb. When a pulse stimulation is delivered by the coil, the EMG over a thumb muscle (abductor pollicis brevis) will record a motor-evoked potential on the tracing. Cross-over with L-theanine in two separate sessions at least 72 hours apart.

Placebo Comparator: Placebo
Subject will receive 400mg single dose of matching Placebo, by oral ingestion with water. The capsules are prepared and dispensed by hospital pharmacy, with the investigator and participant both blinded.
Drug: L-theanine
The subject will receive paired-pulse TMS (ppTMS) procedure before and 30min after taking the drug orally, to assess motor cortex excitability, measured by surface electromyogram (EMG). The ppTMS procedure is administered by a TMS stimulator controlled a program software named Signal. The coil of the stimulator is placed above the scalp where the stimulation would activate the left primary motor cortex region that controls the right thumb. When a pulse stimulation is delivered by the coil, the EMG over a thumb muscle (abductor pollicis brevis) will record a motor-evoked potential on the tracing. Cross-over with placebo in two separate sessions at least 72 hours apart.

Drug: Placebo
The subject will receive paired-pulse TMS (ppTMS) procedure before and 30min after taking the drug orally, to assess motor cortex excitability, measured by surface electromyogram (EMG). The ppTMS procedure is administered by a TMS stimulator controlled a program software named Signal. The coil of the stimulator is placed above the scalp where the stimulation would activate the left primary motor cortex region that controls the right thumb. When a pulse stimulation is delivered by the coil, the EMG over a thumb muscle (abductor pollicis brevis) will record a motor-evoked potential on the tracing. Cross-over with L-theanine in two separate sessions at least 72 hours apart.




Primary Outcome Measures :
  1. The Change of Motor Cortex Excitability Measures by ppTMS [ Time Frame: 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). ]

    The changes of Short-interval Intracortical Inhibition (SICI), Intracortical Facilitation (ICF), and Long-interval Intracortical Inhibition (LICI) before and 30 minutes after each drug administration.

    SICI, ICF and LICI are paired-pulse TMS (ppTMS)-EMG outcome measures that assess the activity of motor cortex GABA-A, NMDA and GABA-B interneurons, respectively. They are measured by the ratio between the peak-to-peak amplitude of motor-evoked potential (MEP) elicited by a testing TMS pulse (120% of the intensity of the resting motor threshold, following a conditioning pulse at different inter-stimuli interval, 2-5 milliseconds for SICI, 10-20 milliseconds for ICF, 100-200 milliseconds for LICI) and the peak-to-peak MEP amplitude elicited by a single pulse (120% of the intensity of the resting motor threshold).



Secondary Outcome Measures :
  1. The Change of Visual Analog Scale (VAS) [ Time Frame: Throughout each session; each session lasts up to 3 hours; 2 sessions for each subject. The 2 sessions are 3-7 days apart. ]
    VAS is a quick scale to assess and track how the participant subjectively feels through out each study session, e.g. anxiety, depression, excitement, etc. The score for each word ranges from "0" being the least in your life and "100" being the most in your life. It takes 3-4 minutes to complete each VAS, and there are 4 takes of VAS during each session. The outcome measure is the change of VAS throughout the 4 time points: 1) before the baseline ppTMS procedure; 2) before drug administration; 3) 30 minutes after drug administration; 4) before discharge from the session, during the session.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04749745


Contacts
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Contact: Shiwen Yuan, MD 401-455-6373 ext 26127 shiwen_yuan@brown.edu
Contact: Linda Carpenter, MD 4014556533349 Linda_Carpenter_MD@brown.edu

Locations
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United States, Rhode Island
Butler Hospital Recruiting
Providence, Rhode Island, United States, 02906
Contact: Shiwen Yuan, MD    401-455-6373 ext 26127    shiwen_yuan@brown.edu   
Contact: Linda Carpenter, MD    4014556349    Linda_Carpenter_MD@brown.edu   
Sponsors and Collaborators
Butler Hospital
Investigators
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Principal Investigator: Linda Carpenter, MD Brown University-Butler Hospital
Publications:

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Responsible Party: Butler Hospital
ClinicalTrials.gov Identifier: NCT04749745    
Other Study ID Numbers: 202006-003
First Posted: February 11, 2021    Key Record Dates
Last Update Posted: February 11, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: To protect subject confidential information.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Butler Hospital:
L-theanine
Cortical Excitability
NMDA
GABA
Paired-Pulse TMS
Additional relevant MeSH terms:
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Mental Disorders
Problem Behavior
Behavioral Symptoms