Good for neuroprotection, stress, and sleep …

Theanine Turns Depression Around
And so much more (see sidebar)

By Will Block

A

Figure 1 Stressful forced swim and tail suspension tests.
LEM1609Fig1_274.jpg

n amino acid found almost exclusively in green and white teas (Camellia sinensis), L-theanine (hereafter theanine) has recently been confirmed to be effective for patients with major depressive disorders (MDDs).1

Prior studies with theanine have shown anti-depressive benefits in mice. In one study,2 mice were pretreated with theanine at doses of 1, 4, and 20 mg/kg or placebo for 10 days, and then subjected to stressful forced swim and tail suspension tests (see Fig. 1). The mice dosed with theanine had significantly reduced immobility time (they were quicker to recover) in response to these highly stressful tests compared to the animals subjected to the tests that received no theanine.

Quoting the authors, “Taken together, these results indicate that [theanine] possessed an antidepressant-like effect in mice, which may be mediated by the central monoaminergic neurotransmitter system. [Emphasis added.]” Monoamine neurotransmitters are neurotransmitters and neuromodulators containing one amino group that is connected to an aromatic ring by a two-carbon chain (-CH2-CH2-). All monoamines are derived from aromatic amino acids like phenylalanine, tyrosine, tryptophan, and the thyroid hormones by the action of aromatic amino acid decarboxylase enzymes. These include:

• L-DOPA to dopamine—a neurotransmitter

• 5-HTP to serotonin (5-HT)—a neurotransmitter

• L-histidine to histamine—a neurotransmitter

• phenylalanine to phenethylamine —trace amine neuromodulator

• L-tyrosine to tyramine—trace amine neuromodulator

• tryptophan to tryptamine—trace amine neuromodulator

The enzyme uses pyridoxal phosphate, the active form of vitamin B6, as a cofactor.

The Many Benefits of Theanine

Increases Neurogenesis

In another study,1 cognitive function and the related mechanism were examined in theanine-administered young rats. Newborn rats were fed theanine through dams, which were fed water containing 0.3% theanine, and then fed water containing 0.3% theanine after weaning. The theanine level in the brain was below the detectable limit 6 weeks after the start of theanine administration. Theanine administration did not influence locomotor activity in the open-field test.

However, rearing behavior was significantly increased in theanine-administered rats, suggesting that exploratory activity is increased by theanine intake. Furthermore, object recognition memory was enhanced in theanine-administered rats. The increase in exploratory activity in the open-field test seems to be associated with the enhanced object recognition memory after theanine administration.

On the other hand, long-term potentiation (LTP) induction at the perforant path-granule cell synapse (the mechanism that creates and maintains memory in the brain) was not changed by theanine administration. To check hippocampal neurogenesis, BrdU was injected into rats 3 weeks after the start of theanine administration, and brain-derived neurotropic factor (BDNF) level was significantly increased at this time. Theanine intake significantly increased the number of BrdU-, Ki67-, and DCX-labeled cells in the granule cell layer 6 weeks after the start of theanine administration. This study indicates that 0.3% theanine administration facilitates neurogenesis in the developing hippocampus followed by enhanced recognition memory. Theanine intake may be of benefit to the postnatal development of hippocampal function.

Reference

1. Takeda A1, Sakamoto K, Tamano H, Fukura K, Inui N, Suh SW, Won SJ, Yokogoshi H. Facilitated neurogenesis in the developing hippocampus after intake of theanine, an amino acid in tea leaves, and object recognition memory. Cell Mol Neurobiol. 2011 Oct;31(7):1079-88. doi: 10.1007/s10571-011-9707-0. Epub 2011 May 22.


Exploratory activity is increased
by theanine intake.


Treats Alzheimer’s

Mitochondrial dysfunction has been implicated in the pathogenesis of Alzheimer’s disease (AD).2 However, it is unclear how amyloid-beta (Aβ) can impair mitochondria in the early stage of AD pathology. Using a double-transgenic AD mouse model, researchers found that abnormal mitochondrial morphology and damaged mitochondrial structure in hippocampal neurons appear in the early stage of AD-like disease development. They also found consistent mitochondrial abnormalities in the human cell line known as SH-SY5Y, which express amyloid precursor protein Swedish mutation (APPsw) and have been used as a cell model of early-onset AD.


Object recognition memory was
enhanced in rats given theanine.


Significant changes of mitofusin GTPases —mitofusins are GTPases (hydrolase enzymes) embedded in the outer membrane of the mitochondria— both in the double-transgenic AD mouse brains and SH-SY5Y cells. Moreover, the results show that Aβ accumulation in neurons of the double-transgenic mice can affect the neurogenesis prior to plaque formation.


Brain-derived neurotropic factor
level was significantly increased.


These findings suggest that mitochondrial impairment is a very early event in AD pathogenesis, and abnormal expression of mitofusin GTPases caused by excessive intracellular Aβ is the possible molecular mechanism.


Theanine facilitates
neurogenesis in the developing
hippocampus resulting in
enhanced recognition memory.


Interestingly, theanine has significant effects on regulating mitochondrial fusion proteins in APPsw cells. Overall, the results not only suggest a new early mechanism of AD pathogenesis, but also propose a preventive candidate—L-theanine—for the treatment of AD.

Reference

2. Wu Z1, Zhu Y, Cao X, Sun S, Zhao B.Mitochondrial toxic effects of Aβ through mitofusins in the early pathogenesis of Alzheimer’s disease. Mol Neurobiol. 2014 Dec;50(3):986-96. doi: 10.1007/s12035-014-8675-z. Epub 2014 Apr 8.


Aβ accumulation in neurons of
the double-transgenic mice can
affect the neurogenesis prior to
plaque formation.


Increases BDNF

Theanine has received growing attention in recent years due to its reported effects on the central nervous system.3 It readily crosses the blood-brain barrier, where it exerts a variety of neurophysiological and pharmacological effects.


Overall, the results not only suggest
a new early mechanism of AD
pathogenesis, but also propose a
preventive candidate—theanine—
for the treatment of AD.


Among theanine’s more documented effects has been its apparent anxiolytic and calming effect due to its up-regulation of inhibitory neurotransmitters and possible modulation of serotonin and dopamine in selected brain areas. Theanine has also recently been shown to increase levels of brain-derived neurotrophic factor [BDNF]. BDNF acts on certain neurons of the central nervous system and the peripheral nervous system, helping to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses.

An increasing number of studies demonstrate neuroprotective effects following cerebral infarct and injury.


Among theanine’s more documented
effects has been its apparent
anxiolytic and calming effect
due to its up-regulation of
inhibitory neurotransmitters.


Theanine also elicits improvements in cognitive function including learning and memory, in human and animal studies, possibly via a decrease in NMDA-dependent CA1 long-term potentiation (LTP) and increase in NMDA-independent CA1-LTP. As well, theanine administration elicits selective changes in alpha brain wave activity with concomitant increases in selective attention during the execution of mental tasks.

 


Theanine also elicits improvements
in cognitive function including
learning and memory.


Developing studies also demonstrate a promising role for theanine in augmentation therapy for schizophrenia, while animal models of depression report positive improvements following theanine administration. A handful of studies are beginning to examine a putative role in attention deficit hyperactivity disorder, and theoretical extrapolations to a therapeutic role for theanine in other psychiatric disorders such as anxiety, panic disorder, obsessive-compulsive disorder (OCD), and bipolar disorder are discussed.

Reference

3. 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 Jul;17(4):145-55. doi: 10.1179/1476830513Y.0000000079. Epub 2013 Nov 26.

 


Theanine elicits selective changes in
alpha brain wave activity with
concomitant increases in selective
attention during mental tasks.


Better Sleep through Anxiolysis

Sleep deprivation is associated with an elevated risk of various diseases and leads to a poor quality of life and negative socioeconomic consequences. Sleep inducers such as drugs and even herbal medicines may often lead to dependence and other side effects. Theanine has anxiolytic effects via the induction of α brain waves without addictive and other side effects associated with conventional sleep inducers. Anxiolysis is required for the initiation of high-quality sleep.

 


Because theanine does not induce
daytime drowsiness, it may be useful
at any time of the day.


In a new review,4 Sleep studies based on actigraphy—a non-invasive method of monitoring human rest/activity cycles—showed that taking 200 mg of theanine before bed supported improved sleep quality by anxiolysis, not by sedation. These studies encompassed the obstructive sleep apnea sleep inventory questionnaire, wakeup after sleep onset and autonomic nervous system assessment, sympathetic and parasympathetic nerve activities, and a pediatric sleep questionnaire (PSQ).

 


Theanine is not a sedative but
promotes good quality of sleep
through anxiolysis. This review
indicates that theanine is a safe
natural sleep aid.


Because theanine does not induce daytime drowsiness, it may be useful at any time of the day. Sleep deprivation-associated morbidity is an increasing public health concern posing a substantial socioeconomic burden. Chronic sleep disorders may seriously affect quality of life and may be etiological factors in a number of chronic diseases such as depression, obesity, diabetes, and cardiovascular diseases. Most sleep inducers are sedatives, and are often associated with addiction and other side effects. Theanine promotes relaxation without drowsiness. Unlike conventional sleep inducers, theanine is not a sedative but promotes good quality of sleep through anxiolysis. This review indicates that theanine is a safe natural sleep aid.

Reference

4. Rao TP, Ozeki M, Juneja LR. In Search of a Safe Natural Sleep Aid. J Am Coll Nutr. 015;34(5):436-47. doi: 10.1080/07315724.2014.926153. Epub 2015 Mar 11. Review. PubMed PMID: 25759004.

MDDs are a serious mental illness presenting with depressed mood, anxiety, sleep disturbance, various somatic symptoms, and cognitive impairments. Although many antidepressants acting on synaptic monoamine levels have been used as first-line drug treatment for MDD, they are not effective in a substantial proportion of patients.3 Thus the theanine study is important.


Theanine possessed an
antidepressant-like effect in mice.


Theanine Combined with Antidepressant Medication

In the clinical trial with humans, 20 patients with MDD (four males; mean age: 41.0 ± 14.1 years, 16 females; 42.9 ± 12.0 years) were given 250 mg of theanine each day in addition to the current medication of each participant for 8 weeks. Twelve patients (60%) were treated with antidepressant medication at baseline. This medication was unchanged during the intervention period.

Symptoms and cognitive functions were assessed at baseline, 4, and 8 weeks after theanine administration by the 21-item version of the Hamilton Depression Rating Scale, State-Trait Anxiety Inventory (STAI), Pittsburgh Sleep Quality Index (PSQI), Stroop test, and Brief Assessment of Cognition in Schizophrenia (BACS). The Hamilton Depression Rating Scale score was improved after theanine administration.

This reduction was observed in unremitted patients at baseline. Anxiety-trait scores decreased after theanine was given in the STAI test. PSQI scores also decreased after theanine administration in the unremitted patients at baseline.

Regarding cognitive functions, response latency and error rate decreased in the Stroop test, and verbal memory and executive function were enhanced in the BACS test after theanine administration.

This study suggests that chronic (8-week) theanine administration has multiple beneficial effects on depressive symptoms, anxiety, sleep disturbance and cognitive impairments in patients with MDD.

References

  1. 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 Neuropsychiatr. 2016 Jul 11:1-8.
  2. Yin C, Gou L, Liu Y, Yin X, Zhang L, Jia G, Zhuang X. Antidepressant-like effects of L-theanine in the forced swim and tail suspension tests in mice. Phytother Res. 2011 Nov;25(11):1636-9.
  3. Hamon M, Blier P. Monoamine neurocircuitry in depression and strategies for new treatments. Prog Neuropsychopharmacol Biol Psychiatry. 2013 Aug 1;45:54-63.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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