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
试验速览
- 阶段
- 早期 1 期
- 状态
- 已完成
- 入组人数
- 11
- 试验地点
- 1
- 主要终点
- The Change of Motor Cortex Excitability Measures by ppTMS
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Other
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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-
- •Free of psychotropic medication use
排除标准
- •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;
- •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;
- •Meet criteria for exclusion from TMS or MRI procedures, including intracranial metal implants or nonremovable ferromagnetic items in the head/neck.
研究组 & 干预措施
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.
干预措施: L-theanine (Drug)
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.
干预措施: Placebo (Drug)
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.
干预措施: L-theanine (Drug)
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.
干预措施: Placebo (Drug)
结局指标
主要结局
The Change of Motor Cortex Excitability Measures by ppTMS
时间窗: 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). 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.
次要结局
- 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.)