Journal Article | Integrative Med

November 29, 2020

Hidese S, Ota M, Wakabayashi C, Noda T, Ozawa H, Okubo T, Kunugi H.


Major depressive disorder or MDD is a common and serious medical illness that negatively affects how you feel, the way you think, and how you act. The DSM-5 criteria for diagnosing these cases include:five (or more) of the symptoms that have been identified, have been present during the same 2-week period, and represent a change from previous functioning. At least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.1


Usually, MDD presents with depressed mood, anxiety, sleep disturbance, various somatic symptoms, and cognitive impairments.5,9 Although many antidepressants acting on synaptic monoamine levels have been used as the first-line drug treatment for MDD, they are not effective in a substantial proportion of patients.3 This justifies the development of new treatment strategies in terms of efficacy and tolerability for patients suffering from MDD.10


Several natural compounds (e.g. St. John’s wort, omega-3 fatty acids, and S-adenosyl-L-methionine) have been reported to be effective for MDD, whereas having fewer side effects and relatively low placeboresponse rates than antidepressants.2, 8


For centuries, people all over the world have testified to the relaxing and invigorating qualities of tea. The traditional calming effects of the plant Camellia sinensis , which is produced from its leaves, have been used to a role beyond quenching thirst. Tea is taken as an aid for meditation, to help soothe the nerves or simply to unwind. But although the mental-health benefits of Camellia sinensis are common knowledge among tea drinkers, scientists are only now beginning to examine how tea exerts its effects on mood and cognition.


L-theanine (L-γ-glutamylethylamide) is a amino acid analogue of the proteinogenic amino acids L-glutamate and L-glutamine and is found primarily in particular plant and fungal species, which is uniquely contained in green tea (Camellia sinensis).13 In in vivo experiments, stress-induced suppression of recognition memory was rescued by L-theanine administration, which recovered the attenuation of in vitro hippocampal CA1 long-term potentiation (LTP) after stress exposure.11


Recognition memory was also enhanced in the L-theanine-administered mice, showing increased population spike amplitude in the induction of in vivo hippocampal dentate gyrus LTP.12 It has been shown that L-theanine has various psychotropic effects 7 In healthy humans, L-theanine was effective in reducing state anxiety scores, as well as in decreasing sympathetic nerve responses following acute stress task 6



Although L-theanine has been shown to have various psychotropic effects, there has been no clinical study performed to show whether this compound affects symptoms and cognitive functions in patients with MDD.


The aim of this study was to examine the psychotropic effects of L-theanine in patients with MDD in an open-label clinical trial.



Subjects were 20 patients with MDD (four males; mean age: 41.0±14.1 years, 16 females; 42.9±12.0 years). L-theanine (250 mg/day) was added to the current medication for MDD of each participant for 8 weeks. Symptoms and cognitive functions were assessed at baseline, 4, and 8 weeks after L-theanine administration by 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).


Possible effects of L-theanine in an open-label clinical trial were examined and it was noted that psychiatric symptoms and cognitive functions of patients with MDD were improved after L-theanine administration. HAMD-21 scores, an objective index of depression, were reduced in unremitted patients at baseline.


Among the HAMD-21 subscales, core, psychic anxiety, somatic anxiety, and delusion scores were reduced. The scores in STAI and PSQI metrics were also reduced. Response latency and error rate decreased in the Stroop test and verbal memory and executive function increased in the BACS. Furthermore, there were no dropout subjects and no serious adverse events in either UKU side effect rating scale or laboratory data.


Depressive symptoms were significantly reduced after L-theanine administration, which suggests that it has antidepressant effects. Considering the structural commonality of L-theanine to L-glutamate, the primary site of action is likely to be the glutamatergic pathway which is a therapeutic target for depression


Furthermore, there was a noted tendency for reduction in anxiety-state scores and a significant reduction in anxiety-trait scores after L-theanine administration as well as a significant improvement of sleep disturbance and enhanced cognitive functions in patients with MDD.



Reduced depressive symptoms, anxiety, sleep disturbance, and enhanced cognitive functions were found in patients with MDD after chronic (8-week) L-theanine (250 mg/day) administration. There is also a high tolerability of L-theanine. These results suggest that L-theanine could be a useful natural compound in the treatment of MDD.4


A limitation noted in this study include the placebo effect thus placebo-controlled clinical trials are required to confirm the therapeutic effect of L-theanine as an adjunct therapy in the treatment of MDD.4 Moreover, the majority of the subjects were affected by relatively mild forms of MDD and the sample size of the study was relatively small, thus it is recommended to further increase the sample size and add more specific criteria to eliminate bias to improve the study results.4


  • American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5), Fifth edition. 2013.
  • Freeman MP, Mischoulon D, Tedeschini E Et Al. Complementary And Alternative Medicine For Major Depressive Disorder: A Meta-Analysis Of Patient Characteristics, Placebo-Response Rates, And Treatment Outcomes Relative To Standard Antidepressants. J Clin Psychiatry 2010;71:682–688.
  • Hamonm & Blier P. Monoamine Neurocircuitry In Depression And Strategies For New Treatments. Progress In Neuro- Psychopharmacology And Biological Psychiatry 2013;45:54–63.
  • Hidese S, Ota M, Wakabayashi C, Noda T, Ozawa H, Okubo T, Kunugi H., Effects of chronic L-theanine administration in patients with major depressive disorder: an open-label study. Acta Neuropsychiatrica 2016, DOI: 10.1017/neu.2016.33. June 9, 2016
  • Kennedy SH. Core Symptoms Of Major Depressive Disorder: Relevance To Diagnosis And Treatment. Dialogues Clin Neurosci 2008;10:271–277.
  • Kimura K, Ozeki M, Juneja LR, Ohira H. L-Theanine Reduces Psychological And Physiological Stress Responses. Biol Psychol 2007;74:39–45.
  • Lardner AL. Neurobiological Effects Of The Green Tea Constituent Theanine And Its Potential Role In The Treatment Of Psychiatric And Neurodegenerative Disorders. Nutr Neurosci 2014;17:145–155.
  • Nahas R, Sheikh O. Complementary And Alternative Medicine For The Treatment Of Major Depressive Disorder. Can Fam Physician 2011;57:659–663.
  • Rock PL, Roiser JP, Riedel WJ, Blackwell AD. Cognitive Impairment In Depression: A Systematic Review And Metaanalysis. Psychol Med 2014;44:2029–2040.
  • Rush AJ, Trivedi MH, Wisniewski SR Et Al. Acute And Longer-Term Outcomes In Depressed Outpatients Requiring One Or Several Treatment Steps: A Star*D Report. Am J Psychiatry 2006;163:1905–1917.
  • Tamano H, Fukura K, Suzuki M, Sakamoto K, Yokogoshi H, Takeda A. Preventive Effect Of Theanine Intake On Stressinduced Impairments Of Hippocamapal Long-Term Potentiation And Recognition Memory. Brain Res Bull 2013;95:1–6.
  • Tamano H, Fukura K, Suzuki M, Sakamoto K, Yokogoshi H, Takeda A. Advantageous Effect Of Theanine Intake On Cognition. Nutr Neurosci 2014;17:279–283.
  • Yokogoshi H, Kobayashi M, Mochizuki M, Terashima T. Effect Of Theanine, R-Glutamylethylamide, On Brain Monoamines And Striatal Dopamine Release In Conscious Rats. Neurochem Res 1998;23:667–673. 

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