Introduction
l-theanine is a nonproteinogenic amino acid contained in green tea1 and mushrooms.2 Among the different tea varieties in Japan, gyokuro and matcha contain more l-theanine than sencha.3
l-theanine affects brain functions.4 Studies in mice indicate that it improves behavior under stress conditions,5 suppresses deterioration of learning ability under social stress,6 and improves memory impairment.7
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The epidemiologic Nakajima8 and Tsurugaya studies9 in Japan indicated that green tea may improve age-related cognitive impairment. In addition, the Hisayama study warned about a recent increase in the prevalence of Alzheimer's disease (AD).10,11 Prevention of AD is an important problem worldwide, and it is necessary to seek a solution.
Green tea contains several substances that affect cognitive function, including caffeine,12,13
l-theanine,7,14 and catechin.15,16 Caffeine transiently improves performance after intake17 and has a substantial benefit on cognitive function. Our previous study indicated that the regular intake of matcha may improve attention.18 However, in that study, subjects did not consume matcha on the day of the test, suggesting that the improvement in attention was not a transient effect of caffeine but involved other components of the tea. A further implication would be that the regular intake of the tea is also a factor responsible for the observed improvement in attention.
l-theanine has been previously reported to have a neuroprotective effect. Because it suppresses delayed neuronal cell death in the hippocampal Cornu Ammonis 1 area after transient ischemia,19 reduces excitotoxicity by suppressing the extracellular release of glutamate through inhibition of the glutamine transporter,20 and promotes neurogenesis,21
l-theanine can potentially reduce cognitive impairment. However, there are many uncertainties about the effects of l-theanine on human cognitive function.
The purpose of this study was to clarify whether the intake of l-theanine, which has a neuroprotective effect, affects the cognitive processes of attention, working memory, and executive function. In addition, to investigate whether the single response was associated with cognitive function after regular ingestion, we compared the results of a single-dose and regular ingestion.
Materials And Methods
The study was conducted at the Tokyo Skytree Station Medical Clinic (Tokyo, Japan) and was approved by the Research Ethics Committee of Nihonbashi Egawa Clinic (Tokyo, Japan; Approval No.: food-). The study was conducted in accordance with the Declaration of Helsinki from August 8, to December 6, . The study was registered with University Hospital Medical Information Network (Tokyo, Japan).
Test food
l-theanine (trade name: Suntheanine; Taiyo Kagaku Co., Ltd., Mie, Japan) was used as the test food. Suntheanine contains &#;98% l-theanine and was encapsulated into hard No. 1 porcine gelatin capsules and used for the test. A placebo was dispensed into the same type capsules as l-theanine, and corn starch was used as the excipient in both the theanine and placebo capsules. Each theanine capsule contained 100.6&#;mg of l-theanine. The test food was manufactured at Sunsho Pharmaceutical Co., Ltd. (Shizuoka, Japan).
Subjects
Sixty-nine Japanese men and women certified as healthy by a physician based on hematological and biochemical blood test results and with self-assessed declined cognitive function were initially enrolled.
Of these, subjects with a Mini Mental State Examination-Japanese version (MMSE-J) score &#;24 were included, while those who had food allergies or were taking medication or undergoing treatment were excluded.
The subjects participated in the study on their own initiative after receiving a full explanation of the study.
Study design
A double-blind, randomized placebo-controlled parallel group study was conducted. The primary end points were the results of MMSE-J and Cognitrax, and the secondary end points were blood levels of amyloid β 1&#;40 [Aβ (1&#;40)], Aβ 1&#;42 [Aβ (1&#;42)], secreted form of amyloid-β precursor protein α (sAPPα), amyloid-β precursor protein 770 (APP770), and brain-derived neurotrophic factor (BDNF). A computer-generated stratified randomized schema (Huma R&D Corp., Tokyo, Japan; Contract Research Organization) was used to assign the subjects to either the placebo or the l-theanine group, with matching based on age, sex, and MMSE-J score. The study flow diagram are shown in Figure 1.
Subjects took one capsule per day of placebo or l-theanine for 12 weeks. They took the test food after breakfast. When they did not eat breakfast, they took the test food in the morning. Subjects were required to enter into the web input system (Huma R&D Corp.), using a personal computer (PC), whether they had taken the test food. During the test period, the subjects were free to consume polyphenol-containing beverages (green tea, black tea, oolong tea, etc.), but subjects were restricted from taking any health foods, supplements, or medications that might affect cognitive function.
Evaluation items
The evaluation items are shown in Table 1. On the day of the single-dose study, the Cognitrax test was started &#;50&#;min after capsule intake. Except for taking the capsule before undergoing the tests, the tests were performed in the same order at week 12. Hematologic tests and biochemical blood parameter measurements were conducted at baseline and 12 weeks as a safety evaluation at SRL, Inc. (Tokyo, Japan).
Table 1.
&#;1 Week (baseline)
0 Week (single dose)
12 Weeks
Ingestion on test day
&#;
Medical interview
&#;
&#;
&#;
Height
&#;
Weight
&#;
&#;
&#;
Vital signs
&#;
&#;
&#;
Blood samplinga
&#;
&#;
MMSE-J
&#;
&#;
Cognitrax test
&#;
&#;
&#;
Mini Mental State Examination-Japanese version
MMSE-J (Nihon Bunka Kagakusha Co., Ltd., Tokyo, Japan) is a Japanese version of MMSE,22 and its validity and test&#;retest reliability have been confirmed in Japan.23 The test consists of 11 items: time orientation, location orientation, memorization, attention and calculation, recall, naming, repetition, three-stage command, reading, writing, and copying, and it is evaluated with the total score. Two tests of attention and calculation were used: the backward spelling task and the serial sevens task, respectively. The score for the backward spelling task was used for allocation of subjects into the placebo or theanine group.22,23
Cognitrax test
Cognitrax24 is a test to evaluate cognitive function, developed by the U.S. company CNS Vital Signs (Morrisville, NC, USA). It comprises 10 test items with accompanying instructions. It measures both reaction time and number of responses. Reaction time is measured in milliseconds. The test items were ordered as follows: verbal memory (VBM), visual memory (VIM), finger tapping test (FTT), symbol digit coding (SDC), Stroop test (ST), shifting attention test (SAT), continuous performance test (CPT), perception of emotions test (POET), nonverbal reasoning test (NVRT), four-part CPT (FPCPT), VBM, and VIM. These items assess various cognitive functions&#;VBM and VIM assess memory; ST, SAT, CPT, and FPCPT Parts 1 and 2 assess attention; POET assesses facial expression recognition; FPCPT Parts 3 and 4 assess working memory; SDC and NVRT assess visual information processing; and FTT assesses motor function.
The first VBM and VIM performed are indicative of immediate memory, while the last is indicative of delayed memory. There were &#;50&#;min between the first-performed VBM and VIM and the last-performed VBM and VIM. Details of the test are shown in Table 2.
Table 2.
Task
Approximate time required (min)
Overview
VBM
3
First, memorize 15 words. Then, from the 30 words that appear at random, select the word you remembered.
VIM
3
Graphic version of the VBM test
Finger Tapping
2
Quickly tap the key for 10&#;sec with your index finger. Do this with both right and left hands.
SDC
4
Enter the number corresponding to the symbol while referring to the symbol-to-number correspondence table.
Stroop
5
It consists of Parts 1&#;3. Part 1 is pressing the key when the character appears. (Red, yellow, blue, and green letters written in black are displayed.) Parts 2 and 3 display the letters red, yellow, blue, and green written in red, yellow, blue, and green. Part 2 is pressing the key when matches, letters, and colors match. Part 3 is pressing the key when letters and colors do not match.
Shifting attention
3
Follow the instructions on the screen and select the option that matches the color or shape. It is a combination of red, blue, yellow, and green letters and colors.
Continuous Performance
5
Random letters of the alphabet are displayed one by one. Press the key only when B is displayed.
Perception of Emotions
2
The photo of a face and a word describing facial expression are displayed. The word used may be &#;calm,&#; &#;happy,&#; &#;sad,&#; or &#;angry.&#; Press the key only if the photo and description match. We evaluated positive emotions (calm and happiness), negative emotions (sadness and anger), and their sums.
Nonverbal Reasoning
3
One of the four sections is blank and three have symbols. Five examples are displayed on the screen. Subjects look at the examples and choose the ones that are closest to the three symbols.
Four-Part Continuous Performance
7
It consists of Parts 1&#;4. Part 1 is pressing the key when the figure appears. Part 2 is pressing the key when a green circle appears. Part 3 is 1-back task. Part 4 is 2-back task. Shapes are displayed for Parts 3 and 4. Shapes are a combination of circles, triangles, squares, and star shapes and red, blue, yellow, and green colors.
Biomarkers related to dementia
On the day of the test, the subjects were restricted from eating from 6&#;h before arriving at the hospital until the completion of the test. Serum blood collection tubes were used to estimate BDNF levels, while ethylenediamine tetra-acetate disodium tubes were used for Aβ (1&#;40), Aβ (1&#;42), sAPPα, and APP770 measurements. The blood was centrifuged at &#;rpm (Kokusan Co., Ltd., Tokyo, Japan, H-19Ra). The measurement was performed using kits with the following dilutions: the blood sample for Aβ (1&#;40) was diluted 20 times with human Aβ (1&#;40) Full Length (FL) Assay Kit-IBL; the blood sample for Aβ (1&#;42) was diluted 4 times with human Aβ (1&#;42) (FL) Assay Kit-IBL; the blood sample for sAPPα was diluted four times with sAPPα (highly sensitive) Assay Kit-IBL; the blood sample for APP770 was diluted 50 times with human APP770 Assay Kit-IBL; and the blood sample for BDNF was diluted 20 times with human BDNF Enzyme-linked Immunosorbent Assay Kit (Quantikine-R&D Systems). Any measured value below the kit range was excluded due to inaccuracy. The measurement was carried out by Skylight Biotech, Inc. (Akita, Japan). The results are shown in Table 3.
Table 3.
Group
N
&#;1 Week (baseline)
12 Weeks
Amount of change from baseline
Plasma Aβ (1&#;40) (pg/mL)
&#;Placebo
22
219&#;±&#;56
210&#;±&#;65
&#;9.21&#;±&#;35
&#;Theanine
26
243&#;±&#;175
205&#;±&#;94
&#;38.6&#;±&#;105
Plasma Aβ (1&#;42) (pg/mL)
&#;Placebo
3
11.6&#;±&#;5.8
22.7&#;±&#;10.5
11.2&#;±&#;9.4
&#;Theanine
9
21.6&#;±&#;21
46.0&#;±&#;59
24.3&#;±&#;52
Aβ(1&#;42)/Aβ(1&#;40)
&#;Placebo
10
0.04&#;±&#;0.03
0.09&#;±&#;0.04
0.05&#;±&#;0.02
&#;Theanine
12
0.08&#;±&#;0.06
0.24&#;±&#;0.31
0.16&#;±&#;0.27
Plasma sAPPα (ng/mL)
&#;Placebo
25
8.07&#;±&#;4.1
9.82&#;±&#;3.1
1.75&#;±&#;2.4
&#;Theanine
22
8.38&#;±&#;3.3
10.2&#;±&#;4.7
1.80&#;±&#;4.7
Plasma APP770 (ng/mL)
&#;Placebo
23
29.2&#;±&#;13
28.9&#;±&#;9.1
&#;0.32&#;±&#;8.5
&#;Theanine
26
30.6&#;±&#;12
28.6&#;±&#;10
&#;1.95&#;±&#;11
Serum BDNF (ng/mL)
&#;Placebo
24
18.2&#;±&#;14
24.3&#;±&#;11
6.07&#;±&#;18
&#;Theanine
26
21.8&#;±&#;12
20.5&#;±&#;12
&#;1.30&#;±&#;18
Statistical analysis
The values are presented as mean&#;±&#;standard deviation. Normality was tested using the Shapiro&#;Wilk test. The unpaired t-test or Mann&#;Whitney U test was used to calculate P values, with Bonferroni correction (P&#;<&#;.05/3&#;=&#;0.017). This was performed at baseline, single-dose test, and 12 weeks. Data were analyzed using SAS 9.4 (SAS Institute, Inc., Cary, NC, USA).
Discussion
This study evaluated the effects of l-theanine on cognitive function using the Cognitrax test performed on a PC. We investigated whether the regular intake of theanine for 12 weeks could improve attentional function and which cognitive functions a single dose of theanine would affect.
A cup of green tea contains about 25&#;mg of theanine.25 Kuriyama et al. reported that people who drink green tea have less cognitive dysfunction.9 In the previous report, the amount of theanine that led to an improvement in attentional function was 50.3&#;mg. In this study, the dose of theanine was set at 100.6&#;mg for the purpose of clearly showing the effect of theanine alone. A single dose of l-theanine reduced reaction time in the attention task and increased correct answers and decreased the number of omission errors in the working memory task. This suggests that l-theanine may improve working memory and executive function based on the improvement in attention.
It is interesting that caffeine,26 which acts as a stimulant for neural activity, and l-theanine,27 which acts as a depressant, are both contained in green tea. Several studies have reported synergistic effects of caffeine and l-theanine on cognition and mood,28 as well as on tasks related to attentional function.18 Our results suggest that l-theanine by itself improves working memory. It remains possible that the improvement in attention, as described previously,18 may have contributed to this effect. In this study, after 12 weeks of regular ingestion, theanine had no effect on the processes related to attentional function as previously reported, even though our subjects had ages and MMSE scores similar to those of subjects in previous studies. The difference in this effect may have been due to the combined effect of caffeine and theanine or catechin and theanine, but details of such interactions are unknown, and further investigation is required.
Studies that explored brain activity have previously reported that l-theanine intake increases α-wave activity.29,30 A study by Gomez-Ramirez et al.31 found that subjects who ingested 250&#;mg of l-theanine had increased α-wave activity for the attention task to be performed. Furthermore, a study that used a visuospatial task also showed that the intake of 250&#;mg of l-theanine contributed to sustained attention.32 Although increased α-wave activity does not simply indicate wakefulness in the brain, l-theanine may affect selective or sustained attentional function. In this study, a significant decrease in reaction time was observed for ST (Part 1), which indicates sustained attention and provides further support for the effects of l-theanine on attentional function. It will therefore be necessary to use neurophysiological techniques to study how the regular intake of theanine affects nervous system activity.
According to a study by Baddeley,33 working memory is composed of three factors: a phonological loop for language information processing, a visuospatial sketch pad for visuospatial information processing, an episodic buffer, and a central executive system that integrates the other three parts. The central executive system is considered to be related to attention control. The effects observed in the two-back task (FPCPT, Part 4) are the results of l-theanine contributing to the improvement of working memory through distribution of attention resources and movement of focus of attention, that is, efficient shifting. Based on this observation, it is also necessary to examine brain activity during task execution using functional magnetic resonance imaging.
Because attention and working memory are closely related,34 it is difficult to consider them separately. It is therefore necessary to examine, in more detail, attentional function and working memory, which were found to be improved by l-theanine in this study.
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The limitations of this study involve subject age and cognitive function status. This study was conducted in middle-aged and older subjects who were aware of a decline in their cognitive function. Previous studies tested elderly people, including those who had mild cognitive impairment35 or vascular dementia,36 to verify whether green tea powder could improve cognitive function. In the future, a comparative study on the preventive or restorative effects of l-theanine in younger adults, the aged, and patients with mild cognitive impairment must also be considered. We also could not explain why regular administration of l-theanine was necessary, as is accepted for epidemiological studies. Future studies are therefore required to investigate the differential effects of single dose and daily intake of l-theanine on brain structure and cognitive function.
The following sections discuss the existing evidence for the possible benefits of L-theanine.
1. Better mental focus and cognition
Many people drink black or green tea while at work, believing that it boosts their mental focus. A study focusing on the effects of L-theanine on cognitive function in older adults appears to support this.
Researchers in this study looked into whether the regular intake of theanine in the form of green tea for 12 weeks could improve subjects&#; attention and cognition.
They concluded the study with positive initial findings, stating that attentional function and working memory did appear to improve with L-theanine consumption.
However, they also stated that more research is necessary to determine how L-theanine might affect a person&#;s attention and focus.
There is a need for more high-quality research to clarify the effects of this compound on people&#;s mental functions.
2. Improved sleep
Several studies have suggested that L-theanine could help people relax before bedtime, get to sleep more easily, and sleep more deeply.
These benefits may result from the specific effects that the amino acid has on brain chemicals that play a role in sleep.
A study found that people reported having greater sleep satisfaction after taking 450&#;900 mg of L-theanine daily for 8 weeks. The study participants had generalized anxiety disorder and were taking antidepressants.
The authors noted that there were no reported improvements in anxiety or insomnia severity.
3. Relaxation
People often drink a cup of tea or another hot beverage to help them relax. Research suggests that the L-theanine in green or black tea may contribute to this feeling of relaxation by reducing a person&#;s resting heart rate.
4. Weight loss
As part of a calorie-controlled diet, replacing a snack with green tea or another low-calorie hot beverage could aid weight loss.
The L-theanine in green tea can create a savory taste, also known as umami flavor. Research suggests that umami flavors may increase feelings of fullness, which often helps with weight loss.
5. Boosting the immune system
L-theanine may support the body in fighting off illness. Several studies have suggested that taking L-theanine could boost a person&#;s immune system, making them less likely to get common colds or the flu.
Its potential anti-inflammatory effects could also help fight illness.
7. Reducing blood pressure
Research has linked high blood pressure with a higher risk of several health problems, including heart attack and stroke.
L-theanine may help reduce stress, and a reduction in stress and increased relaxation can lower the heart rate. In turn, this may help lower blood pressure.
8. Supporting certain cancer drugs
Some research on animals suggests that L-theanine may help to increase kidney function and protect the kidneys from damage during the use of a chemotherapy drug called doxorubicin.
However, scientists need to do more research to understand the specific interactions between these chemicals.
While there is some evidence that L-theanine could benefit people&#;s mental and physical health, more studies are necessary before doctors can be sure of the actual effects of this compound. Scientists have not yet conducted high-quality research in humans.
Many studies to date have had a small sample size, meaning that very few people took part in the research. Data from just a small number of people are less likely to be conclusive than those from larger groups.
Other studies have used animals, such as rats or mice. However, humans are likely to react differently to animals, so these results may not be applicable.
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