What is the recommended dosing of l-theanine for mood? What are the long-term risks or safety concerns? Are there any specific cautions or drug interactions with the use of this supplement?

Comment by InpharmD Researcher

There is no consensus regarding dosing of L-theanine for mood disorders. The majority of available studies utilized doses ranging from 200-400 mg/day, with 200 mg/day being the most common. While there are limited long-term data evaluating the safety of L-theanine, some literature suggests that 200-400 mg daily doses for up to 8 weeks are not associated with prominent safety concerns. However, excessive and prolonged use of green tea (in which L-theanine is naturally found) in combination with additional herbal products has been associated with liver injury. Drug-drug interactions resulting in harmful effects were not evident in the literature, but a combination of L-theanine and caffeine may synergistically affect attention and alertness.

Background

A 2019 systemic review evaluated the effect of pure L-theanine supplementation on stress and anxiety. Study review supported theories that L-theanine passes through the blood-brain barrier to exert its effects. Nine eligible peer-reviewed randomized controlled trials (N= 270) were identified for review. Trials included pre and post-stress and/or anxiety levels using validated psychological assessments. Acute trials used 200 mg/day dosing, and most chronic trials used 400 mg/day, with one using up to 900 mg/day. Supplementation with 200-400 mg/day of L-theanine appears to reduce stress and anxiety in people exposed to acute stressful situations. A study evaluating use of a 400 mg/day dose reported no side effects; however, the study which assessed an L-theanine dose of 900 mg reported some adverse events in both the placebo and L-theanine groups, but with no significant differences between groups. Due to the limited long-term data, extended trials evaluating use of L-theanine may be required to establish its long-term safety effects. As most of the studies were over only one day, there is insufficient evidence to make recommendations for chronic use. [1]

A 2019 narrative review (N= 14 studies) discussed the effects of L-theanine on anxiety disorders and psychological stress. Daily doses evaluated in the studies generally ranged from 200 to 400 mg/day for up to 8 weeks; these doses were considered to be safe, with some studies suggesting anxiolytic and anti-stress effects for acute and chronic conditions. Specific to anxiety and stress outcomes, an open-label study reported success with a 250 mg daily dose of L-theanine for Major Depressive Disorder (MDD; see Table 3 [Hidese 2017]). In healthy individuals, 200 mg of L-theanine has also been reported to show improvement in the tranquil–troubled subscale of the Visual Analogue Mood Scale (VAMS). A more recent double-blind placebo-controlled trial, however, found no improvements in anxiety or insomnia scores when evaluating the use of 450-900 mg daily doses of L-theanine for 8 weeks. No safety concerns or adverse reactions have been reported for 200-400 mg daily doses when used for up to 8 weeks; however, excessive and prolonged use of green tea (in which L-theanine naturally occurs), particularly in combination with additional herbal products, has been associated with toxicity and liver injury. This risk may be amplified with pharmacokinetic interaction with other pharmacological agents, but specific examples were not provided. [2]

A 2014 systematic review and meta-analysis evaluated the acute effects of tea constituents, including L-theanine, administered alone or in combination with caffeine on cognitive function and mood. The dose range of L-theanine used within the 10 studies included in the analysis was 36 mg to 200 mg, with 200 mg being the most commonly used dose. Long-term safety concerns or adverse events were not addressed. [3]

While L-theanine drug-drug interactions resulting in undesired effects are not reported in the literature, the combination of caffeine and L-theanine has been found to create a synergistic effect resulting in improved attention. A combination of 50-100 mg of caffeine and 100-250 mg of L-theanine has been reported to increase subject alertness. When taken together, L-theanine appears to exert a low overall effect on attentional performance, mainly modifying caffeine’s activity. In some circumstances, L-theanine has been found to negate the effects of caffeine. Ultimately, there is no clear consensus regarding the interaction of these two chemicals. [4]

References:

[1] Williams JL, Everett JM, D'Cunha NM, et al. The Effects of Green Tea Amino Acid L-Theanine Consumption on the Ability to Manage Stress and Anxiety Levels: a Systematic Review. Plant Foods Hum Nutr. 2020;75(1):12-23. doi:10.1007/s11130-019-00771-5
[2] Lopes Sakamoto F, Metzker Pereira Ribeiro R, Amador Bueno A, Oliveira Santos H. Psychotropic effects of L-theanine and its clinical properties: From the management of anxiety and stress to a potential use in schizophrenia. Pharmacol Res. 2019;147:104395.
[3] Camfield DA, Stough C, Farrimond J, Scholey AB. Actue effects of tea constituents L-theanine, caffeine, and epigallocatechin gallate on cognitive function and mood: a systematic review and meta-analysis. Nutr Rev. 2014;72(8):507-522.
[4] Schuster J, Mitchell ES. More than just caffeine: psychopharmacology of methylxanthine interactions with plant-derived phytochemicals. Prog Neuropsychopharmacol Biol Psychiatry. 2019;89:263-274. doi:10.1016/j.pnpbp.2018.09.005
Literature Review

A search of the published medical literature revealed 7 studies investigating the researchable question:

What is the recommended dosing of l-theanine for mood? What are the long-term risks or safety concerns? Are there any specific cautions or drug interactions with the use of this supplement?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Tables 1-7 for your response.

 

A Randomized, Triple-Blind, Placebo-Controlled, Crossover Study To Investigate The Efficacy Of A Single Dose Of AlphaWave L-Theanine On Stress In A Healthy Adult Population

Design

Randomized, triple-blind, placebo-controlled, crossover study

N= 16

Objective

To investigate the efficacy and safety of AlphaWave L-Theanine on whole-scalp and frontal alpha power, midline theta power, and salivary cortisol in healthy, moderately stressed adults

Study Groups

AlphaWave L-Theanine to placebo (n= 8)

Placebo to AlphaWave L-Theanine (n= 8)

Inclusion Criteria

Men and women aged 19–60 years, moderate levels of stress as assessed by scores of 14–26 on the Perceived Stress Scale (PSS), regular sleep–wake cycles (defined as a bedtime between 9:00 pm and 12:00 am and between 7 and 9 h of sleep nightly for at least 3 weeks prior to enrollment), abstain from exercise for 24 h prior to study visits

Exclusion Criteria

Self-reported epilepsy, seizures, or clinical diagnosis of anxiety or depression; employment that called for shift work that would disrupt normal circadian rhythm or travel across one or more time zones during the 3 weeks prior to enrollment or during the study; known allergies to the test product; a history of alcohol or drug abuse within 12 months prior to enrollment, reported high alcohol intake defined as > 2 standard drinks/day, use of nicotine or tobacco products within 60 days of enrollment, use of medical cannabis or chronic use of cannabinoid products more than twice a week; or any other condition that in the opinion of the medical director may have adversely affected their ability to complete the study or its measures, or posed a significant risk to the participant

Methods

The trial consisted of two study periods with a 7-day washout in between. Eligible subjects were randomized to receive either 200 mg of AlphaWave L-Theanine (single capsule with 250 mL of room-temperature water) or a placebo (microcrystalline cellulose and hydroxypropyl methylcellulose). A mental arithmetic test (MAT) was administered before and after the dose to induce stress. Participants were then evaluated for efficacy and safety.

Duration

June 15, 2020, to September 25, 2020

Outcome Measures

Electroencephalogram (EEG), salivary cortisol, blood pressure (BP), heart rate (HR), the state-trait anxiety inventory (STAI), and a visual analog scale (VAS) of self-reported stress

Baseline Characteristics

  

AlphaWave L-Theanine to Placebo

(n= 8)

Placebo to AlphaWave L-Theanine

(n= 8)

 p-Value

Age, years

 35.62 ± 12.65 38.75 ± 11.80 0.617

Female

6 (75%) 3 (37.5%) 0.315

Body mass index (BMI)

 24.54 ± 2.82 25.98 ± 2.21 0.276

Systolic BP, mmHg

 111.25 ± 12.54 118.69 ± 9.82 0.208

Diastolic BP, mmHg

 73.38 ± 7.56 79.31 ± 7.11 0.128

HR, bpm

 72.00 ± 12.04 67.12 ± 16.63 0.513

Results

Endpoint

AlphaWave L-Theanine to Placebo

(n=8)

Placebo to AlphaWave L-Theanine

(n=8)

p-Value

Salivary cortisol

-1 hour

1 hour

Change from -1hour to 1 hour

 

5.95 ± 3.87

3.59 ± 4.73

-2.35 ± 2.23

 

5.46 ± 2.86

3.36 ± 2.00

-2.10 ± 1.94

 

0.951

0.409

< 0.001

STAI

State anxiety

-1 hour

-30 minutes

1 hour

Change from -1 hour to -30 minutes

Change from -1 hour to 1 hour

Trait anxiety

-1 hour

-30 minutes

1 hour

Change from -1 hour to -30 minutes

Change from -1 hour to 1 hour

 

 

32.56 ± 11.53

40.22 ± 10.23

32.56 ± 11.49

7.67 ± 7.98

0.00 ± 5.77

 

41.00 ± 11.67

42.44 ± 13.69

44.57 ± 13.89

1.44 ± 4.07

0.57 ± 3.91 

 

 

34.67 ± 13.60

41.67 ± 13.44

32.00 ± 10.62

7.00 ± 7.26

-2.67 ± 7.48

 

43.89 ± 12.70

44.78 ± 14.46

43.75 ±13.33

0.89 ± 3.33

-1.75 ± 2.19

 

 

0.722

0.769

0.892

0.004

1.000

 

0.314

0.707

0.882

0.195

0.890

Stress- VAS

-1 hour

-30 min

1 hour

Change from -1 hour to -30 min

Change from -1 hour to 1 hour

 

16.20 ± 16.54

40.47 ± 21.16

18.80 ± 18.62

24.27 ± 19.20

2.60 ± 12.03

 

18.88 ± 18.59

40.25 ± 20.84

22.50 ± 16.48

21.38 ± 22.17

3.62 ± 12.40

 

0.536

0.964

0.464

< 0.001

0.529

Frontal region alpha power at 3 hours was significantly greater than predose with AlphaWave L-Theanine over the whole recording and during the eyes-open sections (p≤ 0.048) that were not observed when participants took the placebo.

There was a significant increase (p= 0.050) in whole-scalp alpha power during the eyes-open portion of the EEG alpha task in the AlphaWave L-Theanine group compared to the placebo. There were no significant differences in frontal midline theta power.

Postdose, AlphaWave L-Theanine had greater increases in HR from 0 to 6 minutes (p≤ 0.024) and placebo at 9 minutes (p= 0.004). There was also an increase in systolic and diastolic BP at several time points from 3 to 9 minutes.

Adverse Events

With the exception of one patient, all laboratory results out of range were deemed not clinically significant by the medical director.

Study Author Conclusions

This study was conducted during the SARS-CoV-2 pandemic, which has had a rapid and significant effect on both physical and mental health around the world. A single dose of AlphaWave® l-Theanine significantly increased frontal region alpha power compared to placebo in response to an acute stress challenge. These changes indicate relaxation in the brain and suggest a calming response. AlphaWave® l-Theanine was found to be safe and well-tolerated by participants.

InpharmD Researcher Critique

This study had a small sample size and failed to consider the potential adverse events such as an increase in heart rate. None of the participants had a clinical diagnosis of anxiety or depression, rather all attested to have moderate levels of self-reported stress which may vary per individual. The long-term effect of AlphaWave® l-Theanine on moderately stressed healthy adults is unknown.



References:

Evans M, McDonald AC, Xiong L, Crowley DC, Guthrie N. A Randomized, triple-blind, placebo-controlled, crossover study to investigate the efficacy of a single dose of AlphaWave® L-Theanine on stress in a healthy adult population. Neurol Ther. 2021;10(2):1061-1078. doi:10.1007/s40120-021-00284-x

 

Effects of l-theanine on Cognitive Function in Middle-Aged and Older Subjects: A Randomized Placebo-Controlled Study 

Design

Single-center, double-blind, randomized, placebo-controlled, parallel-group trial 

N= 50

Objective

To clarify whether the intake of l-theanine, which has a neuroprotective effect, affects the cognitive processes of attention, working memory, and executive function and to investigate whether the single response was associated with cognitive function after regular ingestion

Study Groups

L-theanine (n= 26)

Placebo (n= 24)

Inclusion Criteria

Aged 50-69 years, healthy based on hematological and biochemical blood tests, self-assessed declined cognitive function, Mini-Mental State Examination-Japanese (MMSE-J) score ≥24

Exclusion Criteria

Food allergies, taking medication, undergoing treatment 

Methods

Patients were randomized to receive l-theanine or a placebo. The l-theanine group received l-theanine (Suntheanine®) capsules which contained ≥98% l-theanine (100.6 mg per capsule). The placebo group received the same No.1 hard porcine gelatin capsule as the l-theanine group. Participants took one capsule per day with breakfast or in the morning if they had not eaten. Polyphenol-containing beverages (green tea, black tea, oolong tea, etc.) could still be consumed. However, any health foods, supplements, or medications that might affect cognitive function were restricted. 

Cognitrax, a cognitive function test, was conducted at baseline, approximately 50 minutes after a single dose, and after 12 weeks. At baseline and after 12 weeks, the MMSE-J, hematologic, and biochemical blood parameters were assessed. 

Duration

August 8, 2018, to December 6, 2018

Intervention period: 12 weeks 

Outcome Measures

Primary: results from the MMSE-J and Cognitrax

Secondary: blood levels biomarkers; 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)

Baseline Characteristics

  

L-theanine (n= 26)

Placebo (n= 24)

Age, years

 57.7 ± 4.8 57.9 ± 6.3

Female

14 (54%) 13 (54%)

Results

Endpoint

L-theanine (n= 26)

Placebo (n= 24)

Attention Tasks (Stroop Test, ST)

Simple Reaction Time (Part 1)

Baseline 

Single Dose 

12 weeks 

Complex Reaction Time Correct (Part 2)

Baseline 

Single Dose  

12 weeks

Stroop Reaction Time Correct (Part 3)

Baseline

Single Dose 

12 weeks 

 

 

378 ± 138

337 ± 84.0* 

328 ± 59.6

 

706 ± 122

667 ± 97.8

650 ± 70.1 

 

802 ± 121

761 ± 120

754 ± 106

 

 

411 ± 145

365 ± 62.0

337 ± 43.8

 

734 ± 124

706 ± 133

 679 ± 80.1

 

841 ± 129

809 ± 98.2

788 ± 91.1

Attention Tasks (Shifting Attention Test, SAT)

Correct Responses 

Baseline

Single Dose

12 weeks

Errors

Baseline 

Single Dose

12 weeks

Correct Reaction Time

Baseline 

Single Dose

12 weeks

 

 

45.0 ± 8.0

48.6 ± 5.0

50.2 ± 5.4

 

4.7 ± 3.6

4.0 ± 2.4

3.3 ± 2.0

 

1,167 ± 157

1,067 ± 132

1,045 ± 134

 

 

41.0 ± 8.3

46.3 ± 6.8

46.8 ± 7.4

 

5.7 ± 5.0

3.9 ± 4.0

3.8 ± 4.0

 

1,266 ± 144

1,151 ± 121

1,144 ± 163

Attention Tasks (Continous Performance Test, CPT)

Correct Responses

Baseline 

Single Dose

12 weeks

Omission Errors

Baseline 

Single Dose

12 weeks

Commission Errors

Baseline 

Single Dose

12 weeks

Choice Reaction Time Correct

Baseline 

Single Dose

12 weeks

 

 

39.6 ± 1.4

39.8 ± 0.5

39.7 ± 1.0

 

0.38 ± 1.4

0.15 ± 0.46

0.31 ± 0.97

 

0.15 ± 0.46

0.15 ± 0.37

0.27 ± 0.45

 

492 ± 80.4

483 ± 72.1

474 ± 47.7

 

 

38.8 ± 2.3

39.5 ± 0.8

39.7 ± 0.6 

 

1.15 ± 2.3

0.46 ± 0.81

0.29 ± 0.62

 

0.54 ± 0.95

0.38 ± 0.75

0.29 ± 0.55

 

511 ± 50.7

500 ± 43.8

493 ± 42.1

Attention Tasks (Four-Part Continuous Performance Test, FPCPT)

Average Correct Response Time (Part 1)

Baseline 

Single Dose

12 weeks

Correct Responses (Part 2)

Baseline 

Single Dose

12 weeks

Average Correct Response Time 

Baseline 

Single Dose

12 weeks

Incorrect Responses

Baseline 

Single Dose

12 weeks

Average Incorrect Responses

Baseline 

Single Dose

12 weeks

Omission Errors 

Baseline 

Single Dose

12 weeks

 

 

 

409 ± 132

359 ± 62

347 ± 53

 

5.8 ± 0.8

6.0 ± 0.2

5.8 ± 1.2

 

476 ± 95

440 ± 75

420 ± 96 

 

0.23 ± 0.86

0.15 ± 0.61

0.04 ± 0.20

 

36.7 ± 134

31.6 ± 117

16.7 ± 85

 

0.19 ± 0.80

0.04 ± 0.20

0.23 ± 1.2

 

 

 

403 ± 91

394 ± 100

359 ± 48

 

5.7 ± 1.1

5.9 ± 0.3

5.7 ± 1.2

 

486 ± 62

461 ± 50

440 ± 105

 

0.38 ± 0.75

0.15 ± 0.37

0.42 ± 1.1

 

144 ± 253

68.3 ± 171

74.3 ± 175

 

0.31 ± 1.1

0.08 ± 0.27

0.29 ± 1.2 

Working memory tasks

FPCPT 

Correct Responses (Part 3)

Baseline 

Single Dose

12 weeks 

Average Correct Response Time

Baseline 

Single Dose

12 weeks 

Incorrect Responses

Baseline 

Single Dose

12 weeks 

Average Incorrect Response Time

Baseline 

Single Dose

12 weeks 

Omission Errors

Baseline 

Single Dose

12 weeks 

Correct Responses (Part 4)

Baseline 

Single Dose

12 weeks 

Change from baseline 

Single-dose

12 weeks 

Average Correct Response Times 

Baseline 

Single Dose

12 weeks 

Incorrect Responses

Baseline 

Single Dose

12 weeks 

Average Incorrect Response Time

Baseline 

Single Dose

12 weeks 

Change from baseline 

Single-dose

12 weeks 

Omission Errors 

Baseline 

Single Dose

12 weeks 

Change from baseline 

Single-dose 

12 weeks

 

 

 

14.8 ± 2.3

15.9 ± 0.3

15.7 ± 0.8

 

594 ± 135

542 ± 101

535 ± 84

 

0.27 ± 1.2

0.00 ± 0.00

0.08 ± 0.27

 

38.0 ± 136

0.0 ± 0.0

127 ± 564

 

1.15 ± 2.3

0.12 ± 0.33

0.27 ± 0.83

 

11.8 ± 3.4

13.4 ± 2.8*

13.3 ± 2.0 

 

1.6 ± 2.5

1.5 ± 3.4

 

704 ± 173

676 ± 162

625 ± 98

 

1.6 ± 1.9

1.4 ± 1.6

1.5 ± 1.4

 

742 ± 511

584 ± 504

653 ± 415

 

−158 ± 590*

−88.8 ± 756

 

4.2 ± 3.4

2.6 ± 2.8* 

2.7 ± 2.0 

 

−1.6 ± 2.5

−1.5 ± 3.4

 

 

 

14.9 ± 2.0

15.2 ± 1.2

15.6 ± 0.6 

 

629 ± 196

577 ± 89

556 ± 85

 

0.15 ± 0.61

0.19 ± 0.40

0.04 ± 0.20

 

66.6 ± 236

172 ± 433

32.5 ± 159

 

1.12 ± 2.0

0.77 ± 1.2

0.42 ± 0.58

 

12.0 ± 2.3

12.1 ± 2.2

12.5 ± 2.6 

 

0.2 ± 2.3

0.8 ± 2.7

 

698 ± 117

691 ± 129

659 ± 111

 

1.6 ± 1.6

1.6 ± 1.2

1.7 ± 1.7

 

581 ± 431

769 ± 448

467 ± 428

 

188 ± 497

−91.0 ± 448

 

4.0 ± 2.3

3.9 ± 2.2

3.5 ± 2.6

 

−0.2 ± 2.3

−0.8 ± 2.7

*P < 0.05/3 = 0.017 versus placebo group

There was no significant difference in MMSE-J scores and blood biomarkers between the theanine and placebo groups.

l-theanine had no effect on performance in the memory tasks, facial expression recognition task, visual information processing tasks, and motor function either immediately or following chronic ingestion. 

Adverse Events

N/A

Study Author Conclusions

A single dose of l-theanine reduced the reaction time to attention tasks (Stroop test, Part 1), and it increased the number of correct answers and decreased the number of omission errors in working memory tasks (4-Part continuous performance test, Part 4). In conclusion, this study indicated that l-theanine may contribute to improving attention, thus enhancing working memory and executive functions

InpharmD Researcher Critique

This was a small study, conducted in Japan at a single center for a short duration of 12 weeks. The patient population in this study included middle-aged and older adults who were already experiencing a decline in cognitive function based on their self-assessment. Participants could also continue to drink green tea, black tea, etc. which could have impacted the results as they contain L-theanine and caffeine. The benefit of only regularly consumed of L-theanine could not be justified.



References:

Baba Y, Inagaki S, Nakagawa S, Kaneko T, et al. Effects of l-Theanine on Cognitive Function in Middle-Aged and Older Subjects: A Randomized Placebo-Controlled Study. Journal of Medicinal Food. 2020;24(4):333-341

 

Effects of Chronic L-Theanine Administration in Patients with Major Depressive Disorder: An Open-Label Study  
Design

Open-label trial 

N= 20 

Objective

To assess the psychotropic effects of L-theanine in patients with major depressive disorder (MDD) 

Study Groups

Study participants (N= 20)

Inclusion Criteria

Diagnosis of MDD according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)

Exclusion Criteria

 Prior medical histories of central nervous system disease, severe head injury, substance abuse, intellectual disability.

Methods

All patients were given L-theanine 250 mg tablet PO once daily prior to sleep for 8 weeks. Patients were assessed at baseline, week 4, and week 8. Patients were allowed to take antidepressants that would not alter the L-theanine dose. Patients were instructed not to alter their consumption of green tea.

Duration

Follow-up: 8 weeks

Outcome Measures

Change in the 21-item version of the Hamilton Depression Rating Scale (HAMD-21), State-Trait Anxiety Inventory (STAI), Pittsburgh Sleep Quality Index (PSQI), Stroop test, and Brief Assessment of Cognition in Schizophrenia (BACS)

Baseline Characteristics

  

Study participants (N= 20)

      

Age, years (standard deviation [SD])

 42.6 ± 12.1       

Male

 4 (20%)      

Body mass index, kg/m2

 23.5 ± 4.8      

Onset of illness, years (SD)

 30.9 ± 14.4      

Single/recurrent episode

 9/11 (45%/55%)       

Imipramine-equivalent dose, mg/day

 101.7 ± 131.8      

Smoking, n (%)

 2 (10%)      

Results

Endpoint

Baseline

4 weeks 

8 weeks 

p-value

HAMD-21

 12.5 ± 80 8.5 ± 6.3 8.8 ± 7.8  p= 0.007

Core

Sleep 

Activity

Psychic anxiety

Somatic anxiety

Delusion

6.9 ± 3.4

1.0 ± 1.2

1.7 ± 1.3

1.7 ± 1.1

2.5 ± 2.1 

1.9 ± 1.6

4.5 ± 3.4

0.7 ± 1.1 

0.8 ± 1.1

1.0 ± 0.8

1.8 ± 1.4

1.2 ± 1.5

5.1 ± 4.4 

0.6 ± 0.8

1.3 ± 1.5

1.1 ± 0.9

1.7 ± 1.7

1.0 ± 1.3 

p= 0.018

p= 0.070

p= 0.12

p= 0.012

p= 0.023

p= 0.024 

STATI

Anxiety-state

Anxiety-trait

 

52.9 ± 11.5

58.2 ± 13.0

 

51.5 ± 11.2

54.3 ± 11.8

 

49.5 ± 11.6

53.6 ± 12.8

 

p= 0.058

p= 0.012
PSQI  9.6 ± 3.7 8.8 ± 3.2

9.1 ± 2.6

 p= 0.16

Stroop test

Response latency (ms)

Error rate (%)

 

1216 ± 324

2.4 ± 2.3 

 

1130 ± 286

1.5 ± 1.5

 

1080 ± 307 

1.2 ± 1.4

 

p= 0.001

p= 0.036

BACS

Verbal memory 

Working memory

Motor speed

Category fluency

Letter fluency

Attention

Executive function

 

48.1 ± 9.7

22.0 ± 3.2

79.0 ± 15.3 

22.9 ± 6.6

27.8 ± 8.7

64.0 ± 13.5

17.5 ± 2.4

 

48.7 ± 10.5

21.6 ± 3.1 

83.2 ± 14.6

24.9 ± 7.6

28.4 ± 8.7

63.2 ± 12.4

17.2 ± 2.6

 

53.2 ± 8.0

21.5 ± 3.3

81.8 ± 17.4 

24.6 ± 6.1

29.8 ± 10.1

66.1 ± 14.6 

19.0 ± 1.7

 

p= 0.005

p= 0.61

p= 0.29

p= 0.24

p= 0.15

p= 0.12

p= 0.016

Adverse Events

Decrease in high-density lipoprotein (HDL) cholesterol (p=0.011). Increase in L-theanine blood concentration after administration (p=0.005). No significant alteration in liver function, renal function, and glucose metabolism was reported. 

Study Author Conclusions

Our study suggests that chronic (8-week) L-theanine administration is safe and has multiple beneficial effects on depressive symptoms, anxiety, sleep disturbance and cognitive impairments in patients with MDD. However, since this is an open-label study, placebo-controlled studies are required to consolidate the effects.

InpharmD Researcher Critique

The open-label design introduces patient-perceived bias regarding the effectiveness of the medication. Even though a reduction in depressive symptoms was observed after the administration of L-theanine, the mean HAMD score of 12.5 at baseline indicated that the patient had a mild form of MDD which may have been due to the effect of the antidepressant which was administered in adjunct with L-theanine. A larger, more quality controlled trials is needed to confirm the findings of the study.



References:

Hidese S, Ota M, Wakabayashi C, et al. Effects of chronic l-theanine administration in patients with major depressive disorder: an open-label study. Acta Neuropsychiatr 2017;29(2):72-9.

 

Effects of L-Theanine Administration on Stress-Related Symptoms and Cognitive Functions in Healthy Adults: A Randomized Controlled Trial

Design

Randomized, placebo-controlled, crossover, and double-blind trial

N= 30

Objective

To examine effects of four weeks L-theanine daily oral administration on stress-related symptoms and cognitive functions in healthy adults

Study Groups

L-theanine (n= 30)

Placebo (n= 30)

Inclusion Criteria

Healthy adults who did not have any psychiatric disorders but were suffering from some non-clinical symptoms (e.g., emotion, sleep, and cognition)

Exclusion Criteria

Individuals who had been treated for any psychiatric disorder, pregnant women, or severe physical illnesses

Methods

L-theanine (200 mg/day) or placebo tablets were self-administered orally before sleep each night for four-weeks. Compliance was checked verbally. After a two-week wash-out period participants received the other tablets for a further four weeks.

Clinical assessments of depression, anxiety, sleep quality were performed at baseline and weeks 4, 6, and 10. The Japanese version of the Self-rating Depression Scale (SDS), the State-Trait Anxiety Inventory (STAI), and the Pittsburgh Sleep Quality Index (PSQI) were used to evaluate depression, anxiety, and sleep quality, respectively. 

Cognitive functions and laboratory values were also extensively reported, however, this table will primarily focus on mood related outcomes. 

Duration

Data collected between June 2017 to August 2018

Intervention: 10 weeks

Outcome Measures

Changes in SDS, STAI, PSQI at 4 weeks

Baseline Characteristics

  

All (N= 30)

 

  

Age, years

 48.3 ± 11.9     

Female

21 (70%)    

Body mass index, kg/m2

 22.5 ± 3.9    

Alcohol habit

 20 (66.7%)    

Smoking habit

 8 (26.7%)    

Results

Endpoint

L-theanine

Placebo

p-Value

Self-rating Depression Scale

 −2.53 ± 5.38 −0.07 ± 6.60 0.084 

State-Trait Anxiety Inventory-state

 −2.47 ± 9.26 −0.67 ± 8.75 0.82

State-Trait Anxiety Inventory-trait

 −3.37 ± 8.13 0.77 ± 7.52 0.13

Pittsburgh Sleep Quality Index

 −1.37 ± 2.81 −0.03 ± 2.08 0.073
  L-theanine Pretreatment L-theanine Posttreatment p-Value
Self-rating Depression Scale

45.8 ± 7.38

 43.2 ± 7.47 0.019
State-Trait Anxiety Inventory-state

48.6 ± 9.32

 46.1 ± 9.51 0.20
State-Trait Anxiety Inventory-trait

51.9 ± 9.66

 48.5 ± 10.4 0.006
Pittsburgh Sleep Quality Index*

9.67 ± 2.71

 8.3 ± 2.45 0.013

*When compared to placebo, significant improvement was reported with L-theanine for sleep latency, sleep disturbances, and use of sleeping medication subscales of Pittsburgh Sleep Quality Index.

Adverse Events

 No significant adverse events. 

Study Author Conclusions

Stress-related symptom (i.e., depression, anxiety-trait, and sleep) scores decreased and cognitive function (i.e., verbal fluency and executive function) scores improved after four weeks of L-theanine administration. The reduction in sleep quality problems (disturbances in sleep latency, sleep disturbance, and use of sleep medication) was greater in the L-theanine administration compared to the placebo administration, while verbal fluency, especially letter fluency, was improved in the L-theanine administration among individuals who showed relatively low performance at pretreatment. Moreover, L-theanine administration was safe and well complied with. Therefore, L-theanine may be a suitable nutraceutical ingredient for improving mental conditions in a healthy population.

InpharmD Researcher Critique

While the study reported significant differences pre- and post-treatment with L-theanine for stress related symptoms, when compared to placebo no significant difference was noted except for specific PSQI subscale scores. This study included a limited sample size and was conducted in a real-world setting where biases and confounding factors were not controlled for. Results should be interpreted with caution. 



References:

Hidese S, Ogawa S, Ota M, et al. Effects of L-Theanine Administration on Stress-Related Symptoms and Cognitive Functions in Healthy Adults: A Randomized Controlled Trial. Nutrients. 2019;11(10):2362. Published 2019 Oct 3. doi:10.3390/nu11102362

 

Anti-Stress, Behavioural And Magnetoencephalography Effects Of An L-Theanine-Based Nutrient Drink: A Randomised, Double-Blind, Placebo-Controlled, Crossover Trial 

Design

Randomized, double-blind, placebo-controlled, crossover study

N= 34

Objective

To evaluate the anti-stress, cognitive, and neurophysiological effects of an L-theanine-based nutrient drink

Study Groups

All patients (N= 34)

Inclusion Criteria

Healthy adults, aged 18-40, non-smokers, free of significant concurrent illness, including diabetes mellitus, bleeding disorders, heart conditions, and psychiatric diagnosis

Exclusion Criteria

Health conditions with the potential to affect food metabolism (food allergies, kidney or liver disease), history of head injury, epilepsy, or stroke

Methods

A minimum 48-hour washout period was required between the test days in which subjects would either consume an L-theanine-based drink or a placebo. Participants consumed approximately 430 mL of the L-theanine-based nutrient drink containing 200 mg L-theanine, 25 mg L-alpha glycerylphosphorylcholine (Alpha GPC) 25 mg, 1 mg phosphatidylserine, and 10 mg micronized chamomile. Both active and vehicle control treatments contained identical sweeteners, preservatives, gum acacia, and malic acid. A multi-tasking framework was used as the stressor and an assessment of cognitive performance, completed three times at each assessment visit. Participants were required to abstain from alcohol 24 hours prior to the testing visit and caffeine 12 hours before testing. 

Duration

Intervention: 20 minutes each for 3 assessments each testing day

Outcome Measures

Subjective stress response to a multi-tasking framework (MTF), salivary cortisol, mood, and fatigue (using State-Trait Anxiety Index [STAI-S]), relaxant effects (using "tranquil-troubled")

Baseline Characteristics

  

All (N=34)

 

  

Age, years

 26.53 ± 5.04    

Female

19 (56%)    

Body mass index, kg/m2

 22.66 ± 2.86     
Trait anxiety (STAI-T) 37.56 ±7.44    
Years of education 17.25 ± 2.85    

Results

Endpoint

Placebo

L-Theanine-based nutrient drink

p-value

Stress response to MTF (n= 26)

1 hour

3 hour

 

1.58 ± 21.54

-6.08 ± 21.70 

 

-13.73 ± 18.49

-6.38 ± 23.48

 

0.003

>0.05

Mood response to MTF (STAI-S)

Fatigue (n= 25)

1 hour

3 hour

Alertness (n= 26)

1 hour

3 hour

Contentedness (n= 26)

1 hour

3 hour

Calmness (n= 26)

1 hour

3 hour

Anxiety (STAI-S) (n= 26)

1 hour

3 hour

 

 

-3.32 ± 23.63

-4.80 ± 23.99

 

-0.72 ± 14.19

5.28 ± 11.77

 

-0.56 ± 7.90

1.99 ± 9.29

 

-0.31 ± 18.39

0.25 ± 13.61

 

1.50 ± 7.12

0.12 ± 5.88

 

 

-5.96 ± 22.48

-7.44 ± 23.62

 

3.86 ± 15.44

5.69 ± 11.30

 

1.41 ± 7.81

0.62 ± 7.89

 

3.87 ± 21.36

0.04 ± 14.64

 

-1.81 ± 6.20

-1.00 ± 6.36

 

 

0.663 

 

 

0.375

 

 

0.885

 

 

0.624

 

 

0.201

Tranquil-troubled

1 hour

3 hour

 

4.23 ± 13.61

2.54 ± 11.83 

 

0.69 ± 9.69

1.50 ± 15.19

 

> 0.05

 

Results of Wilcoxon signed ranks tests showed no significant differences in cortisol change between active treatment compared to placebo 1-hour post-dose (p > 0.05) but a significantly lower cortisol response 3 hours post-dose for the active treatment visit (p= 0.047) 

There were no significant differences between treatments of cognitive performance on the MTF at either post-dose time point.

Adverse Events

Not disclosed

Study Author Conclusions

The findings of the present study further support the anti-stress effects of l-theanine. Following administration of the active treatment, a nutrient beverage containing 200 mg of l-theanine, in addition to smaller doses of PS, alpha GPC and chamomile, subjective stress response to a cognitive stressor was found to be significantly reduced one hour post-dose, and cortisol response was significantly reduced three hours post-dose, using a double-blind, placebo-controlled, balanced crossover design. No differences in cognitive performance were observed.

InpharmD Researcher Critique

The L-theanine-based nutrient drink included ingredients that could have altered the results. Additionally, the data collection timing revolved around mealtime, which potentially impacted results. The placebo also contained less than < 1 mg L-theanine and may have not truly been a placebo. This study did not evaluate any safety outcomes and limits any conclusions regarding potential safety concerns with L-theanine administration.



References:

White DJ, de Klerk S, Woods W, Gondalia S, Noonan C, Scholey AB. Anti-Stress, Behavioural and Magnetoencephalography Effects of an L-Theanine-Based Nutrient Drink: A Randomised, Double-Blind, Placebo-Controlled, Crossover Trial. Nutrients. 2016;8(1):53. Published 2016 Jan 19. doi:10.3390/nu8010053

 

A Double-Blind, Placebo-Controlled Study Evaluating The Effects of Caffeine And L-Theanine Both Alone And In Combination On Cerebral Blood Flow, Cognition And Mood

Design

Placebo-controlled, double-blind, counterbalanced, crossover study

N= 24

Objective

 To examine the effects of caffeine and L-theanine on CBF and extend previous cognitive and mood findings by using lower doses than previous studies of a similar methodology, which more closely reflect the ratios present in tea

Study Groups

Habitual consumers of caffeine (n=12)

Non-habitual consumers of caffeine (n=12)

Inclusion Criteria

Healthy, non-smoking adult volunteers, not currently taking any dietary supplements or medication (including the contraceptive pill), not color-blind, no history of head trauma, learning difficulties, ADHD, neurological, vascular, or psychiatric illness

Exclusion Criteria

 Not specified

Methods

Participants were given 75 mg caffeine, 50 mg L-theanine, 75 mg caffeine plus 50 mg L-theanine, and placebo in counterbalanced order for four separate visits, each at least 48 hours apart. Habitual consumers were categorized as participants who drank tea and consumed more than 150 mg caffeine per day, and non-habitual consumers were those who consumed less than 60 mg caffeine per day and no more than 2 cups of tea/coffee per week.

At baseline and 30 minutes after the dose, a visual analogue scale (VAS) was used to assess cognition and mood, and cerebral blood flow (CBF) was measured using near-infrared spectroscopy (NIRS). Caffeine levels in the saliva and peripheral hemodynamics were both measured. The participants arrived at the lab each morning after a 12-hour fast for each visit. Participants received mood measures and cognitive tasks at baseline and after treatment, and NIRS was monitored before, during, and after treatment and cognitive exercises. 

Duration

 Four sessions with 48-hr washout within 7 days

Outcome Measures

CBF, cognition, mood, blood pressure, and heart rate

Baseline Characteristics

  

Habitual Consumers

(n=12)

Non-habitual Consumers

(n=12)

  

Age, years

 23.3 ± 3.65 20.4 ± 1.88   
Male

5

 5  

Self-report caffeine consumption

Caffeine, mg/day

Tea, cups/day

 

252.2 ± 74.3

3.50 ± 1.46

 

16.7 ± 15.6

0.45 ± 0.62

  
Mean salivary caffeine levels, mcg/mL  

0.34

  

Results

Endpoint

Habitual Consumers

(n=12)

Non-habitual consumers

(n=12)

Treatment 

Effect

VAS, ratings for mood (mm) 

Alert 

Placebo

Pre-dose

Post-dose

L-theanine

Pre-dose

Post-dose

Caffeine

Pre-dose

Post-dose

Combination

Pre-dose

Post-dose

Overall mood

Placebo

Pre-dose

Post-dose

L-theanine

Pre-dose

Post-dose

Caffeine

Pre-dose

Post-dose

Combination

Pre-dose

Post-dose

 

 

 

57.17 ± 5.63

51.83 ± 3.04

 

51.50 ± 4.09

47.92 ± 6.24

 

55.83 ± 4.65

58.42 ± 4.73

 

59.25 ± 3.12

56.92 ± 4.95 

 

 

67.33 ± 4.43

59.33 ± 3.70

 

58.50 ± 4.04

58.33 ± 4.20

 

61.50 ± 3.98

62.00 ± 3.91

 

66.33 ± 4.02

61.17 ± 4.13

 

 

 

50.17 ± 6.07

51.50 ± 6.00

 

58.42 ± 6.34

54.75 ± 6.75

 

49.17 ± 6.98

57.92 ± 6.80

 

54.75 ± 6.30

57.75 ± 5.73

 

 

59.83 ± 4.03

55.92 ± 5.14

 

66.08 ± 4.08

63.67 ± 4.44

 

59.25 ± 4.34

64.83 ± 4.92

 

66.50 ± 3.97

68.42 ± 4.02

 

 

F=3.09

p=0.048*

 

 

 

 

 

 

 

 

 

  

 

   

F=3.13

p=0.046*

Caffeine decreased oxygenated hemoglobin (oxy-Hb), increased deoxy-Hb, improved attention, and raised overall mood ratings. Caffeine-induced increases in deoxy-Hb were more evident in non-consumers. When caffeine was coupled with L-theanine, there was some indication of elevated deoxy-Hb, but this impact was diminished, and the effects of caffeine on oxy-Hb, cognition, and mood were eliminated.

Analysis of blood pressure levels revealed a significant main effect of treatment for systolic [F(3, 66) = 5.50, p< 0.01] and diastolic [F(3, 66) = 3.37, p< 0.05] blood pressure. There were no significant effects of treatment on heart rate.

*Significant difference between groups

Adverse Events

 N/A

Study Author Conclusions

Combining L-theanine with caffeine at levels and ratios equivalent to one to two cups of tea eliminated the vasoconstrictive effect and behavioral effects of caffeine. This supports previous findings of an interaction between these substances, despite a lack of effects of L-theanine in isolation. However, at the levels tested here, this did not lead to a positive impact on behavior.

InpharmD Researcher Critique

Because no safety outcomes were evaluated in this trial, any conclusions about potential safety risks with L-theanine administration are limited. Given the evidence for varied dose effects of the substances tested in terms of behavior and hemodynamics, future studies should also look into the impact of lesser doses, such as one cup of tea. The long-term effects of L-theanine cannot be determined because the trial only lasted four sessions.



References:

Dodd FL, Kennedy DO, Riby LM, Haskell-Ramsay CF. A double-blind, placebo-controlled study evaluating the effects of caffeine and L-theanine both alone and in combination on cerebral blood flow, cognition and mood. Psychopharmacology (Berl). 2015;232(14):2563-2576. doi:10.1007/s00213-015-3895-0

 

Time for tea: mood, blood pressure, and cognitive performance effects of caffeine and theanine administered alone and together

Design

Randomized, double-blind, placebo-controlled study

N= 48

Objective

To study the subjective, behavioral, and blood pressure effects of theanine and caffeine administered alone and together, in doses relevant to the daily tea consumption of regular tea drinkers

Study Groups

Control group (n= 12)

Caffeine group (n= 12)

Theanine group (n= 12)

Caffeine and theanine group (n= 12)

Inclusion Criteria

Healthy, normal weight, young adults, light-to-moderate caffeine consumers, non-smokers or smoked less than five cigarettes a day, and had normal or corrected to normal vision 

Exclusion Criteria

Not stated

Methods

The study employed a between-subjects design. Eligible patients randomly received either 250-mg caffeine, 200-mg theanine, both or neither of these. Each participant attended one test session with either two or three participants being tested during each session. They completed ratings of mood, including anxiety, and alertness, and had their blood pressure measured before and starting 40 min after drug administration. Anxiety was also assessed using a visual probe task. The participants were tested in the same room with the experimenter present and each participant was accommodated in a separate private booth to complete the questionnaires and computer tasks. 

Duration

N/A

Outcome Measures

Mood, alertness, and physical symptoms questionnaire (MAPS), State-Trait Anxiety Inventory (STAI), Depression, Anxiety and Stress Scales (DASS), blood pressure and heart rate, visual probe task, facial expression discrimination task, and habitual caffeine intake and consumption on the day of the study

Baseline Characteristics

  

 

Participants (N= 48) 

Age, years

 20.5 ± 2.0 

Habitual daily caffeine consumption, mg/d

Caffeine from tea

116 ± 81 

56 ± 65

Caffeine consumption during the morning of the study before testing, mg

 11 ± 21 

The four treatment groups were similar in respect of all these characteristics and in gender distribution (p> 0.1).

Results

Measure

Caffeine (n= 12)

Theanine (n= 12)

Caffeine x theanine (n= 12)

MAPS and STAI State anxiety

Headache 

Heart pounding

 

Jittery

 

Light-headed

Hands trembling

 

Sacred

Feeling hot

 

Relaxed 

Clearheaded

 

Happy

Alert

 

STAI state anxiey

 (df = 1, 39)

F < 1

F= 3.62

p= 0.064

F= 4.46

p= 0.041

F < 1

F= 2.36

p > 1

F < 1

F= 2.29

p > 0.1

F < 1

F < 1

 

F < 1

F= 4.93

p= 0.032

F < 1

(df = 1, 39) 

F < 1

F= 1.66

p > 0.1

F < 1

 

F < 1

F < 1

 

F < 1

F < 1

 

F < 1

F= 1.39

p > 0.1

F < 1

F < 1

 

F < 1

(df = 1, 39) 

F < 1

F < 1

 

F < 1

 

F < 1

F < 1

 

F < 1

F < 1

 

F < 1

F < 1

 

F < 1

F= 1.63

p > 0.1

F < 1

Blood Pressure and heart rate

Systolic BP

 

Diastolic BP

 

Heart rate

 

(df = 1, 39)

F= 5.98

p= 0.019

F= 16.45

p < 0.001

F < 1

 

(df = 1, 39)

F =1.61

p > 0.1

F= 2.02

p > 0.1

F < 1

 

(df = 1, 39)

F= 6.19

p= 0.017

F= 7.89

p= 0.008

F= 1.47

p > 0.1

Visual probe task

Social threat

Bias score

Reaction time

 

Physical threat

Bias score

Reaction time

 

(df = 1, 40)

 

F < 1 

F < 1

 

 

F < 1

F < 1

 

(df = 1, 40)

 

F < 1

F= 4.24

p= 0.046

 

F < 1

F= 2.84

p= 0.100

(df = 1, 40)

 

F < 1

F < 1

 

 

F < 1

F < 1

 

Caffeine increased jitteriness and alertness and had a similar, although statistically non-significant, effect on ‘heart pounding’.

Both systolic and diastolic blood pressure were significantly higher after caffeine alone than after caffeine plus theanine, theanine alone, and placebo (p< 0.05).

Adverse Events

N/A

Study Author Conclusions

Theanine is a physiologically and behaviourally active compound. While it is unclear how its effects might explain perceived differences between tea and coffee, evidence suggests that it may be useful for reducing raised blood pressure.

InpharmD Researcher Critique

This study did not restrict caffeine consumption or theanine intake before testing. The outcome measures were subjective to the patients and the results could have been impacted by confounding variables, such as the timing of the test or the amount of sleep the participant had the previous night.



References:

Rogers PJ, Smith JE, Heatherley SV, Pleydell-Pearce CW. Time for tea: mood, blood pressure and cognitive performance effects of caffeine and theanine administered alone and together. Psychopharmacology (Berl). 2008;195(4):569-577. doi:10.1007/s00213-007-0938-1