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

NCT04749745 | Completed Early Phase 1 Results FDA Drug

• 1 other identifier: 202006-003
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

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.

Conditions

Cortical Excitability; Psychiatric Disorder

Keywords

L-theanine; Cortical Excitability; NMDA; GABA; Paired-Pulse TMS

Outcome Measures

Primary Outcomes (1)

• The Change of Motor Cortex Excitability Measures by ppTMS

  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). The baseline-to-post-drug change of SICI, ICF and LICI elicited by L-theanine will be compared to that elicited by placebo within each subject.

  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 (1)

• The Change of Visual Analog Scale (VAS)

  Throughout each session; each session lasts up to 3 hours; 2 sessions for each subject. The 2 sessions are 3-7 days apart.

Study Arms (2)

L-Theanine

ACTIVE COMPARATOR

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; Drug: Placebo

Placebo

PLACEBO COMPARATOR

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; Drug: Placebo

Interventions

L-theanine DRUG

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.

L-Theanine; Placebo

Placebo DRUG

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.

L-Theanine; Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• History of significant acute or chronic neurological or medical disorder or condition that increases risk for seizure with TMS;
• History of alcohol use disorder, nicotine dependence, adjustment disorder;
• History of allergic reactions to L-theanine or green tea;
• Pregnancy;
• Unable/unwilling to abstain from nutraceutical supplements and psychotropic agents during participation in the study
• Unable/ unwillingness to refrain from recreational substance use (e.g. alcohol or marijuana) during participation in the study;

Sponsors & Collaborators

• Butler Hospital: lead

Study Sites (1)

Butler Hospital

Providence, Rhode Island, 02906, United States

Location

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• 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.

  PMID: 34293527 DERIVED

MeSH Terms

Conditions

Mental Disorders

Interventions

theanine

Results Point of Contact

• Title: Dr. Shiwen Yuan
• Organization: Butler Hospital

shiwen_yuan@brown.edu

2025783000

Study Officials

• Linda Carpenter, MD

  Brown University-Butler Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: January 27, 2021
• First Posted: February 11, 2021
• Study Start: June 9, 2020
• Primary Completion: May 31, 2021
• Study Completion: May 31, 2021
• Last Updated: September 23, 2021
• Results First Posted: September 23, 2021

Record last verified: 2021-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)