Effects of L-theanine on Motor Cortex Excitability in Healthy Subjects: A Paired-Pulse TMS Study
Condition: Cortical Excitability; Psychiatric Disorder
MeSH terms: Mental Disorders; Problem Behavior
Study type: Interventional
Phase: Early Phase 1

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.
    

Intervention name(s): L-theanine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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.
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
Keywords: L-theanine; Cortical Excitability; NMDA; GABA; Paired-Pulse TMS