Does Theanine actually agonize GABA receptors / increase GABA? +Serotonin

cs3000

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I've seen some people concerned with GABA rebound effects from l-theanine due to effects on increasing GABA. Theanine is commonly mentioned as a gaba agonist.

1. Does it actually have significant effects on GABA that would lead to rebound?

2. Would a daily gram amounts be safe for potential serotonin lowering effects?

Looking around i haven't seen much substantial on GABA effects. actually on Theanine Research Breakdown one rat study says it REDUCED gaba, and another said in increased.

But the study that showed an increase only lasted for 30 minutes after taking - then it DECREASED gaba a bit for the remainder of time tested so it didnt last long if this was the mechanism you'd think you'd only get 30 minutes of upside which people dont


imgur .com/5SYooXb

reddit .com/r/ Nootropics/comments/4mcbd1/comment/d3uqdey

think it was about 1.2g / kg maybe ~12g human dose

Also typical doses would be underdosed if going for the serotonin reducing effect. https://www.tandfonline.com/doi/pdf/10.1271/bbb.62.816 brain serotonin went down after 100mg / 100g so 1g/kg. going by this would maybe ~10g human dose for this - i wonder if gram amounts are safe?

this one suggests GABA A receptor activity though Involvement of GABAA Receptors in the Neuroprotective Effect of Theanine on Focal Cerebral Ischemia in Mice

significant GABA agonism / downregulation (especially at typical doses) does not align with schizophrenia studies where 8 weeks of 400mg supplementation showed reduced anxiety (you would expect tolerance/rebound by this time if it was going to right)


I wonder about gram amounts where you see a 30 minute spike which comes back down below baseline. & i guess there are other mechanisms that could see downside / rebound effect annoyingly things are more complicated than 1 angle - so probably not a good idea megadosing grams

edit: this one haidut posted [Effects of theanine on monoamine neurotransmitters and related genes in cerebral ischemia-reperfusion injury rats]. | Semantic Scholar

also showed serotonin lowering with dopamine increasing effect highest at ~1g for human and worked by 15 days [90 mg/kg (6/37)*90 * 70kg = 1000mg , also good effects on less e.g 30mg/kg 333mg]
3/37 for mouse 6/37 for rat

Theanine Stops And Reverses The Stress Reaction (cortisol, Noradrenalin, Dopamine) but 1.5g also reduced baseline cortisol a lot which may not be good for people with daytime sleepiness. maybe lower doses attenuate cortisol response to stress without affecting baseline cortisol too much?
 
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toolhead

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I've seen some people concerned with GABA rebound effects from l-theanine due to effects on increasing GABA. Theanine is commonly mentioned as a gaba agonist.

1. Does it actually have significant effects on GABA that would lead to rebound?

2. Would a daily gram amounts be safe for potential serotonin lowering effects?

Looking around i haven't seen much substantial on GABA effects. actually on Theanine Research Breakdown one rat study says it REDUCED gaba, and another said in increased.

But the study that showed an increase only lasted for 30 minutes after taking - then it DECREASED gaba a bit for the remainder of time tested so it didnt last long if this was the mechanism you'd think you'd only get 30 minutes of upside which people dont


imgur .com/5SYooXb

reddit .com/r/ Nootropics/comments/4mcbd1/comment/d3uqdey

think it was about 1.2g / kg maybe ~12g human dose

Also typical doses would be underdosed if going for the serotonin reducing effect. https://www.tandfonline.com/doi/pdf/10.1271/bbb.62.816 brain serotonin went down after 100mg / 100g so 1g/kg. going by this would maybe ~10g human dose for this - i wonder if gram amounts are safe?

this one suggests GABA A receptor activity though Involvement of GABAA Receptors in the Neuroprotective Effect of Theanine on Focal Cerebral Ischemia in Mice

significant GABA agonism / downregulation (especially at typical doses) does not align with schizophrenia studies where 8 weeks of 400mg supplementation showed reduced anxiety (you would expect tolerance/rebound by this time if it was going to right)


I wonder about gram amounts where you see a 30 minute spike which comes back down below baseline. & i guess there are other mechanisms that could see downside / rebound effect annoyingly things are more complicated than 1 angle - so probably not a good idea megadosing grams

edit: this one haidut posted [Effects of theanine on monoamine neurotransmitters and related genes in cerebral ischemia-reperfusion injury rats]. | Semantic Scholar

also showed serotonin lowering with dopamine increasing effect highest at ~1g for human and worked by 15 days [90 mg/kg (6/37)*90 * 70kg = 1000mg , also good effects on less e.g 30mg/kg 333mg]
3/37 for mouse 6/37 for rat

Theanine Stops And Reverses The Stress Reaction (cortisol, Noradrenalin, Dopamine) but 1.5g also reduced baseline cortisol a lot which may not be good for people with daytime sleepiness. maybe lower doses attenuate cortisol response to stress without affecting baseline cortisol too much?
It’s been many years since I played with theanine but I remember the conventional wisdom was that it had a paradoxical dose-response curve. Low doses were sedating but high doses were stimulating, as I recall.
 

Elie

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From Examine.com

4Neurology​

4.1Kinetics and Mechanisms​

Theanine has been found to cross the blood brain barier, as systemic injections[44] and oral intake[6] can increase brain concentrations of the compound which appears to be mediated via the leucine-preferring transport system[45] (the neutral amino acid transport[46]).

Following oral intake L-theanine reaches the brain within an hour and is elevated up to 5 hours, which it then proceeds to get eliminated ultimately having no concentrations left at 24 hours post oral intake (4,000mg/kg).[6] The concentrations reaching the brain at this oral dose are around 2µM/g[6] and serum concentrations in this study peaked at above 12.5µM/mL within an hour, and were reduced to similar concentrations as the brain at 16 hours.[6]

Specific brain organs that have been shown to have increases in theanine concentration following oral intake include the hippocampus.[47]

Orally administered L-Theanine supplementation is able to cross the blood brain barier
L-Theanine supplementation in the standard dosages (50-250mg) has been repeatedly noted to increase α-waves in otherwise healthy persons. This may only occur in persons with somewhat higher baseline anxiety[48][49] or under periods of stress (positive[39] and negative[50] results), but has been noted to occur during closed eye rest[30] as well as during visuospatial tasks[41] around 30-45 minutes after ingestion.[30][29] It appears that only the α-1 wave (8-10Hz) is affected, with no influence on α-2 wave (11-13Hz).[29]

α-waves (8-12Hz) are known to be associated with a state of relaxation[51] which has been noted to occur alongside α-wave promotion with L-theanine.[7] Beyond relaxation, increased α-waves are associated with selective attention mechanisms[52][53] and arousal/mental alertness.[54] These altered wave functions are said the be evidence that theanine has 'relaxing and attention promoting' properties.

One study has reported increased theta wave function, but with a combination supplement of both theanine (60mg) and green tea extract (360mg) taken thrice daily over 16 weeks.[18]

Theanine supplementation appears to cause an increase in alpha-1 wave production within 30-45 minutes following oral ingestion of standard supplemental doses. This increase in alpha-1 production is highly associated with the most common benefits of Theanine supplementation (relaxation and attention)

4.2Catecholamines​

Dopamine and noradrenaline do not appear to be significantly influenced with oral intake of theanine in rats (2% of drinking water, sufficient to increas plasma theanine to 7763.3+/-3875.4nmol/g) over 3 weeks.[26]

Direct injections of theanine into the striarum also cause dose-dependent increases in dopamine secretion for 40 minutes before returning to baseline.[45]

10µM/kg injections of theanine have been noted to reduce noradrenaline by 16% and 9% at 30 and 75 minutes, respectively; this was abolished with coadministration of caffeine.[55]

4.3Serotonin​

Oral intake of theanine which increases plasma theanine to 7763.3+/-3875.4nmol/g (2% of rat drinking water) has failed to significantly influence serotonin concentrations.[26]

10µM/kg injections have failed to significantly influence serotonin levels per se, but have been able to attenuate a caffeine-induced increase in serotonin.[55]

L-Theanine at an oral dose of 2,000-8,000mg/kg in rats (human estimated dose of 320-1280mg/kg) cause a dose dependent increase in brain tryptophan and reduction of serotonin, reaching 20.5% and 15.5% at the highest dose.[56]

Technically has anti-serotonergic mechanisms, but this occurs at a very high dose and likely isn't relevant for standard oral supplementation

4.4GABAergic mechanisms​

Injections of theanine (30µM/kg only; 15µM/kg being ineffective and all doses higher than 30µM/kg being ineffective) have been found to increase cerebral concentrations of GABA by 19.8% following.[44]

Conversely, 4% L-theanine in the drinking water of rats has been noted to reduce extracellular GABA in the frontal cortex.

4.5Glutaminergic mechanisms​

L-Theanine has been found to have affinity for all three glutamate receptor subsets with IC50 and Ki values (respectively) of 24.6+/-0.9µM/19.2+/-0.7µM (AMPA), 41.5+/-7.6µM/29.3+/-5.4µM (Kainate), and 347+/-47µM/329+/-44µM (NMDA); these were 80-30,000 fold less potent than the endogenous ligand L-glutamate.[57]

Theanine has been found to accumulate in glutaminergic neurons (via two mechanisms with KM values of 42.3μM and 1.88mM) with at least one being the glutamine transporter, as the two amino acids compete for uptake (glutamine inhibits with an IC50 of 329.2+/-59.5μM while the opposite inhibition is weaker, at greater than 1,000μM).[58] It has been noted that incubation with 1-10mM theanine was able to also suppress extracellular glutamate concentrations.[58]

Theanine is an antagonist of the NMDA receptors (albeit with fairly weak efficacy) and can inhibit synaptic release of glutamate via blocking the transporter competitively. Theanine may also reduce glutamate levels, but this is also a fairly weak mechanism requiring a high concentration of theanine
As an increase in calcium release[57] and dopamine stimulation[45] with high concentrations of Theanine (800µM) seem to be blocked with the NMDA antagonist D-2-amino-5-phosphonopentanoate, it appears that theanine may signal through NMDA receptors at high concentrations.

Oddly, some mechanisms of theanine are blocked by NMDA antagonists. This suggests that higher concentrations of theanine may have their properties dependent on NMDA signalling

4.6Sedation​

Some studies that measure α-wave production also note that participants self-report a more relaxed state.[30]

Theanine (5-10mM/kg injections) were able to increase hexobarbital induced sleep time by 11-21%, but not in a dose dependent manner.[44]

ADHD tends to be associated with symptoms related with hyperactivity, such as restless leg syndrome or disturbed sleep;[59][60] in persons with ADHD (8-12 year old boys) given 200mg L-theanine twice daily for 6 weeks, sleep quality appears to be improved by reducing sleep activity (10%) and increasing sleep efficiency.[36]

In studies assessing sleep latency (time taken to fall asleep) and sleep duration (time elapsed between going to bed and waking in the morning), these parameters appear unaffected.[36] Additionally, supplemental doses of theanine to promote relaxation do not appear to have sedative side-effects.[30]

4.7Schizophrenia​

In persons with diagnosed schizophrenia or schizoaffective disorder given 400mg L-theanine in addition to standard antipsychotics, 8 weeks of supplementation was able to significantly reduce positive and general psychopathology symptoms and anxiety.[61]

4.8Neuroimmunology​

Oral consumption of 2-4mg/kg L-Theanine daily to mice for 5 weeks via the drinking water was able to attenuate the toxic effects on memory of Abeta(1-42) injection, and appeared to work via suppressing proinflammatory responses via ERK/p38 and NF-kB.[62]

4.9Memory​

One study using a supplement called LGNC-07 (360mg of green tea extract and 60mg theanine; thrice daily dosing for 16 weeks) in persons with mild cognitive impairment based on MMSE scores, supplementation was associated with improved delayed recognition and immediate recall scores with no effect on verbal and visuospatial memory (Rey-Kim test).[18]

4.10Seizures​

Theanine has been noted to have anticonvulsive properties at 2.5-10mM/kg injections against caffeine, although it was not effective against other agents such as picrotoxin or strychnine.[44] Elsewhere, oral intake of 4% theanine in the water of rats was noted to be protective against pilocarpine but augmented seizures from pentylenetetrazol; the authors suggested usage in treating limbic seizures but not generalized seizures[63] and hypothesized that the mechanism was related to reducing GABA concentrations in the frontal cortex.[63] A potentiation of seizures induced by pentylenetetrazol, a GABAA antagonist,[64] have been noted elsewhere with both green and black tea containing theanine.[65]

May have anti-seizure properties, but due to also being implicated in augmenting seizures (depending on the research drug used) and no current human studies its usage for controlling seizures is limited

4.11Anxiety​

A comparative study between L-theanine (200mg and alprazolam control; 1mg) on anticipatory anxiety has noted that while theanine promoted relaxation, both theanine and alprazolam failed to significantly reduce anxiety symptoms in the model of anticipatory anxiety.[50] Some other studies that measure state anxiety fail to find a difference between theanine and placebo at this dose.[49]

In studies assessing relaxation[49][48] or attention/reaction time,[49] it appears that only persons with high baseline anxiety note benefits associated with relaxation whereas those who are not anxious fail to outperform placebo.

4.12Attention and ADHD​

In persons with mild cognitive impairment, a combination supplement of green tea extract (360mg) and theanine (60mg) over 16 weeks was able to improve selective attention as assessed by a Stroop test.[18]

An improvement in attention has been noted in otherwise healthy persons with high baseline anxiety, with no apparent effect on those with lower anxiety scores at baseline.[49]

4.13Stress​

Rats fed 0.3% of their drinking water as L-theanine appear to have less circulating corticosterone at rest[66][47] and after stress testing[67][47] to approximately half of control, and in hippocampal CA1 cells theanine appears to cause a shift away from NMDA-dependent long term potentiation (LTP) towards NMDA-indepedent potentiation[66] while protecting from stress-induced memory impairment at this oral dose.[47][67]

It is known that increases in corticosterone[68][69] and stress itself[70] are able to suppress LTP and memory processing in the hippocampus and the reduction of corticosterone is thought to underlie the memory preserving effects of theanine.[47][67]

Oral intake of L-theanine in rats at feasible dosages is able to reduce circulating biomarkers of stress with or without an actual stressor being present, and can reduce the adverse effects of stress such as memory impairment
Supplementation of 200mg Theanine prior to an arithmatic stress test has been noted to reduce perceived stress following the task and to attenuate the risk in salivary IgA concentrations (biomarker of stress) by approximately half at the conclusion of the task.[39]

Reductions of percieved stress have been reported in human subjects given oral theanine at the standard dosages
 

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