SleepScape™ ingredient 5 of 5

Theanine
Neuroprotective, Stress Reducing, Sleep Quality Improver

By Durk Pearson & Sandy Shaw

T he final ingredient in our SleepScape™ is theanine (gamma-glutamylethylamide), an amino acid found in white and green tea. It can pass the blood-brain barrier and, in fact, has been shown to have neuroprotective effects in the brain that include protection against the injury induced by transient forebrain neuronal ischemia,1,2 oxidative stress in the brain,3 reduced brain cell death due to stroke in mice3A and reduced stress induced by a mental arithmetic task in human volunteers.6 (Most people find mental arithmetic very stressful!) We expect that, since theanine protects against transient forebrain neuronal ischemia, it would also provide protection from the reduced brain oxygenation caused by sleep apnea.

Theanine was isolated from green tea as a flavor constituent by Sakato in 1949. A 1998 paper (unfortunately in Japanese)3B was said to show that oral intake of L-theanine caused a feeling of relaxation in human volunteers; the study was cited in a 2000 paper.4 The latter paper4 reported on a study that showed that theanine can modulate the stimulating effects of caffeine, thus acting as a relaxant, in 9 week old Wistar rats.

In the rat-caffeine study,4 the rats had electrodes implanted in the cortex, hippocampus, and amygdala of their brains in order to follow changes in EEG as a result of treatment. After caffeine administration (0.970 mg/kg b.w., similar to what a person would get from a cup of tea or coffee), the researchers observed “a remarkably fast wave in the cortex and amygdala, and a rhythmical wave in the hippocampus … in the stimulant condition after caffeine administration compared with at rest.” Slow waves were also observed in the cortex and amygdala. The EEG changes indicated that 5 μmol/kg (0.970 mg/kg) b.w. (body weight) is the minimum dose of caffeine as a stimulant.

Ten minutes after i.v. administration of the caffeine, the rats were treated by i.v. with various doses (0, 5, 10, 25, and 50 μmol/kg (0.871, 1.742, 4.355, and 8.710 mg/kg) b.w. of theanine. Results showed that a suppressive effect of theanine on caffeine stimulation emerged at higher than 10 μmol/kg, (1.742 mg/kg) b.w. of theanine. At very low doses (2 μmol/kg (0.348 mg/kg) b.w.), however, theanine exerted a stimulatory effect.

This rat EEG study is consistent with the reports of theanine inducing feelings of relaxation and improved sleep quality5 and reduced physiological stress responses during a stressful task situation6 in human subjects that has appeared in recent research. Although theanine has been linked to improved sleep quality, it has also been reported to produce no drowsiness in humans.6B

Theanine Partially Counteracts Caffeine-induced Sleep Disturbance in Rats

In another recent (published this year) study of the effects of caffeine on sleep in rats,7 researchers found that 22.5 mg/kg and 37.5 mg/kg of theanine (but not 75 mg/kg or 150 mg/kg) significantly reversed the caffeine-induced decrease in SWS (slow wave sleep) but didn’t significantly affect the caffeine-induced increase in wakefulness or the decrease in REM sleep. This study used a much higher dose of caffeine than the Kakuda et al study4 discussed above (7.5 mg/kg intraperitoneally v. 0.97 mg/kg i.v.). Though none of the doses of theanine in this study reduced the time it took (latency) to sleep for an hour, the lowest dose of theanine produced a trend toward reduced latency that did not reach statistical significance, but came close (p=0.054).

A 2006 human study6 of the effects of theanine on stress involved 12 healthy volunteers (male undergraduate students, age range 20–25 years, mean = 21.50, S.D. (standard deviation), 1.38 years). The subjects performed a stressful mental arithmetic task and were assessed for changes in heart rate, heart rate variability, and salivary immunoglobulin A (s-IgA) as indicators of physiological stress. The researchers also determined the frequency domain of heart rate variability, which has a high frequency band (HF) and a low frequency one (LF). The HF band is said to be related to respiratory sinus arrhythmia and “is exclusively attributable to parasympathetic [cholinergic] influence reflecting vagal activity while the latter [LF] mirrors the baroreceptor feedback loop that controls blood pressure and appears to reflect both sympathetic and parasympathetic activity.”6 The LF/14F ratio was thought to reflect the sympathovagal balance. Our observation of the significant decrease in the HF component and a remarkably increased LF/HF ratio during the task indicated that the sympathetic nervous system was prominently activated by this [mental arithmetic] task.”6 In addition to these physiological changes, the subjects experienced acute feelings of stress and anxiety. With this background, the researchers felt this was a good experimental basis for evaluating the effects of theanine in a stressful situation.

The experimental subjects received 200 mg of theanine dissolved in 100 ml of water as treatment. To detect a possible time lag between when the theanine was administered and when it took effect, the authors gave the theanine to the subjects at two time points. The subjects performed the mental arithmetic for 20 minutes.

In previous studies, the researchers reported6 that they had found the mental arithmetic task to induce “remarkable” stress feeling and sympathetic (adrenergic) nervous activation reflected by elevated heart rate and s-IgA, an immunoglobulin, demonstrating a stress effect on the immune system,

The results were similar to expectations, although contrary to what the authors had thought, they didn’t find any significant differences between the theanine administered at the two time points. The post-hoc analysis indicated that the LF/HF ratio was significantly higher under the placebo condition than under theanine treatment, indicating that the participants had more activation of the sympathetic nervous system during the stress of the mental arithmetic under the placebo condition than when they had received theanine. The researchers stated in their discussion: “[t]he main findings in this study were that the acute stress responses elicited by the mental arithmetic task were reduced by the oral administration of L -theanine. Moreover, this effect of L -theanine was consistently observed not only in the subjective perception of stress but also in physiological stress responses such as HR [heart rate] and s-IgA. ... after termination of the experimental sessions, no participants could identify whether they drank water or water containing L -theanine.” And, of course, the study was done double blind.

Because the researchers did not actually measure blood pressure, vascular resistance, noradrenaline, and adrenaline, they admit that they could only speculate about the changes in sympathetic nervous system activity on the basis of the HR, HRV, and s-IgA data. They suggest further studies of neural mechanisms and with a larger number of participants. They conclude by noting that despite the limitations of their study, the results suggest that L-theanine “was effective for reducing the stress responses elicited by the mental arithmetic task.”

Induction of Long Term Potentiation by Theanine in Young Rats

Researchers tested the effects of theanine treatment on long-term potentiation (LTP) induction at hippocampal CA1 synapses as well as the effects on acute stress in young rats receiving either water or water containing 0.3% theanine.8 Long term potentiation is a process that is an important part of learning.

EFFECT OF THEANINE ON STRESS HORMONES: Serum corticosterone level was markedly decreased six weeks after the start of theanine administration.

LONG TERM POTENTIATION: The researchers used electrical stimulation administered via implanted electrode to detect CA1 LTP in both theanine-treated rats and control rats. As they explained,8 “CA1 LTP consists of NMDA receptor-dependent and NMDA receptor-independent components.” “NMDA receptor-dependent and NMDA receptor-independent LTP mediate different aspects of acquisition and retention of spatial memory.” The influence of theanine on CA1 LTP under conditions of stress (tail suspension for 30 seconds) was examined. An hour after tail suspension, hippocampal slices were prepared for the experiment. The results showed that in the untreated (no theanine) control rats subject to tail suspension, CA1 LTP induced by a 100 Hz tetanus and by a 200 Hz tetanus was attenuated. But neither level of stimulation-induced CA1 LTP was attenuated in the theanine-administered rats. Hence. theanine intake modifies the mechanism of CA, LTP induction.”8

Effect of Theanine on Grain Monoamines and Striatal Dopamine Release in Rats

Another paper9 reports that theanine administered intragastrically at various doses resulted in significant increases in serotonin and/or dopamine concentrations in the brain, especially in the striatum, hypothalamus, and hippocampus. Direct administration of theanine via microinjection into the brain striatum resulted in dose-dependent increases in dopamine release. This dopamine release was significantly inhibited by pretreatment with an NMDA glutamate receptor antagonist. Another paper9B declared. [p]reclinical studies suggest that L-theanine increases a number of neurotransmitters including serotonin, dopamine and GABA, levels and has micromolar affinities for AMPA, kainate, and NMDA receptors,”

Theanine Increases Neurogenesis in Young Rats

Another paper10 reports facilitated neurogenesis in the developing hippocampus of young rats after the administration of 0.3% theanine in their drinking water. “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.”10

Anti-Depressant-Like Effects of L-Theanine in the Forced Swim and Tail Suspension Tests in Mice

Another paper reports on anti-depressant-like effects in mice subject to the stressful forced swim and tail suspension tests. The mice pretreated with (or without) L-theanine at doses of 1, 4, and 20 mg/kg for 10 days were subject to the forced swim and tail suspension tests. The mice dosed with L-theanine had significantly reduced immobility time in response to these highly stressful tests as compared to the animals subject to the tests and receiving no theanine. “Taken together, these results indicate that L-theanine possessed an antidepressant-like effect in mice, which may be mediated by the central monoaminergic neurotransmitter system.”11

L-Theanine Improves Sleep Quality in Boys with Attention Deficit Hyperactivity Disorder

Does your workload sometimes pile up to where you feel as though you can hardly keep track of what you just did, let alone what you’re supposed to do next? If so, you have probably felt much like boys (or girls, though there are far fewer of them) who have ADHD (attention deficit hyperactivity disorder). This sense of overload can have a negative impact on your ability to sleep as well as to do productive work. A recent paper12 reported that L-theanine was safe and effective in improving sleep quality in 98 boys 8–12 years of age formally diagnosed with attention-deficit/hyperactivity disorder (ADHD).

The boys were treated with two chewable tablets (each containing 100 mg of L-theanine) twice daily (total 400 mg daily) or an identical tasting placebo. Those who received L-theanine experienced significantly higher sleep percentage and sleep efficiency scores, as indicated by the actigraph watches each subject wore—the watches are an activity-based sleep monitor that uses an accelerometer to detect wakefulness and patterns of sleep. Theanine did not, however, decrease the time it took subjects to fall asleep (latency) or sleep duration.

STRESS, STRESS, STRESS RELIEVED BY THEANINE

Most of your problems are probably due to how you respond to them—the stress that you experience—and that is something that you can do something about entirely independently of correcting the problems themselves. The hippocampus, a major center controlling cognitive processes, is enriched with glucocorticoid receptors and thus plays an important role in stress responses. Increasing stress can have negative effects on hippocampal-derived cognitive behavior and synaptic plasticity such as LTP (long term potentiation) involvement in memory.

Some new studies have indicated significant protection by L-theanine against stress. Examples include a paper13 reporting a protective effect by L-theanine in post-weaning mice subject to acute stress (such as being dunked in water), where the animals were treated with drinking water containing 0.3% L-theanine for 3 weeks before being stressed. Results showed decreased, levels of serum corticosterone (a stress hormone) in rats receiving L-theanine after water immersion stress. In addition, the treated rats did not have attenuation of LTP in their hippocampi unlike the control rats. The treated rats didn’t have a decreased object memory recognition following stress, as the control rats did.

Another example was a paper14 in which male mice were subject to psychosocial stress by being housed in a confrontational situation with other male mice. The ingestion of theanine (>5 μg/ml) prior to being put into the confrontational housing situation significantly suppressed the adrenal hypertrophy (increased size of the adrenal gland induced by stress).

And, a final example was a paper15 reporting on the protective effect of L-theanine against cognitive impairments and oxidative stress induced in mice put into a chronic restraint tube for 8 hours a day for 21 days. We would call being confined to a tube where you can barely move, even though the tube was well ventilated, and you were deprived of food and water a very severe stress. Yet, treatment with 4 mg/kg of L-theanine caused a statistically significant decrease in mistakes made in a test following the period of confinement stress; 2 mg/kg and up to 4 mg/kg of L-theanine only caused a tendency toward decreased mistakes that did not reach significance.

Finally, the L-theanine significantly inhibited the decrease in noradrenaline and dopamine levels induced by the chronic restraint stress in the hippocampus and cortex of the mice. These sorts of protective effects would be expected to produce a “normalizing” effect on the feelings and cognition of humans subject to severe stresses.

While we can’t say that being cooped up in a tube would be anything but unpleasant, you might come out of it with a much more positive mood by supplementing with L-theanine!

References

1. Kakuda. Neuroprotective effects of the green tea components theanine and catechins. Biol Pharm Bull. 25(12):1513-8 (2002).
2. Egashira et al. Involvement of GABAA receptors in the neuroprotective effect of theanine on focal cerebral ischemia in mice. J Pharmacol Sci. 105:211-4 (2007).
3. Nishida et al. Altered levels of oxidation and phospholipase C isozyme expression in the brains of theanine-administered rats. Biol Pharm Bull. 31(5):857-60 (2008).
3A. Egashira et al. Neuroprotective effect of gamma-glutamylethylamide (theanine) on cerebral infarction in mice. Neurosci Lett. 363;58-61 (2004).
3B. Kobayashi et al. Effects of L-theanine on the release of alpha-brain waves in human volunteers. Nihon Nogeikakgaku Kaishi (in Japanese) 72:153-7 (1998) [we haven’t read this].
4. Kakuda et al. Inhibiting effects of theanine on caffeine stimulation evaluated by EG in the rat. Biosci Biotechnol Biochem. 64(2):287-93 (2000).
5. Ozeki, Juneja, and Shirakawa. The effects of theanine on sleep with physiological evaluation using actigraph. Proceedings of the 50th Meeting of Japan Society of Physiological Anthropology, Chiba (Oct, 25-26, 2003).
6. Kimura et al. L-theanine reduces psychological and physiological stress responses. Biol Psychol. 74(1):39-45 (2006).
6B. Itoh et al. Effects of L-theanine on the release of alpha-brain waves in human volunteers. Nippon Nogeikacaku Kaishi [in Japanese, so we have not read this] 72:153-7 (1996).
7. Jang et al. L-theanine partially counteracts caffeine- induced sleep disturbances in rats. Pharmacol Biochem Behav. 101:217-21 (2012).
8. Takeda et al. Unique induction of CA1 LTP components after intake of theanine, an amino acid in tea leaves and its effect on stress response. Cell Mol Neurobiol. 32:41-48 (2012).
9. Yokogoshi et al. Effect of theanine, r-Glutamylethylamide, on brain monoamines and striatal dopamine release in conscious rats. Neurochem Res. 23(5):667-73 (1998).
9B. Nathan et al. The neuropharmacology of L-theanine (N-ethyl L-glutamine): a possible neuroprotective and cognitive enhancing agent. J Herb Pharmacother. 6(2):21-30 (2006).
10. Takeda et al. Facilitated neurogenesis in the developing hippocampus after intake of theanine, an amino acid in tea leaves, and object recognition memory. Cell Mol Neuromol. 31(7);1079-88 (2011).
11. Yin et al. Antidepressant-like effects of L-theanine in the forced swim and tail suspension tests in mice. Phytother Res. 25:1636-39 (2011).
12. Lyon et al. The effects of L-theanine (Suntheanine®) on objective sleep quality in boys with attention deficit hyperactivity disorder (ADHD): a randomized, double-blind placebo-controlled clinical trial. Altern Med Rev. 16(4):348-54 (2011).
13. Tamano et al. Preventive effect of theanine intake on stress-induced impairments of hippocampal long-term potentiation and recognition memory. Brain Res Bull. 95:1-6 (2013).
14. Unno et al. Ingestion of theanine, an amino acid in tea, suppresses psycho­social stress in mice. Exp Physiol. 98(1);290-303 (2013).
15. Tian et al. Protective effects of L-theanine on chTonic restraint stress-induced cognitive impairments in mice. Brain Res. 1503:24-32 (2012).


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