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L-Theanine for ADHD


L-Theanine for ADHD

Theanine (L-theanine, 5-N-ethyl-L-glutamine, delta-glutamylethylamide; gamma-glutamylethylamide) is an amino acid found in green tea.1
Theanine passes the blood-brain barrier.2

1. Neuropsiological effect of theanine

L-theanine acts neurophysiologically as:

  • Glutamate reuptake inhibitor3
    • Theanine acts strongly on the glutamine transporter and inhibits glutamine reuptake, which in turn suppressed the conversion of glutamine to glutamate by glutaminase.2
  • competitive low-affinity glutamate receptor antagonist in the hippocampus3
    • very weakly antagonistic to glutamate AMPA and glutamate kainate receptors.2
  • binds to GABA-A receptors3
  • increased gene expression with large effect size4
    • in the hippocampus
      • EGR1 (Early growth response protein 1; also ZNF268 = Zinc finger protein 268 or NGFI-A = Nerve growth factor-induced protein A)
      • MAO-A (monoamine oxidase A; degrades serotonin, dopamine, and norepinephrine)
      • ANXA9 (Annexin A9)
      • S100a10 (Calcium-binding protein A10; P11)
      • GABRB2 (GABA-A receptor beta-2 subunit)
      • CHRM2 (muscarinic acetylcholine receptor M2)
    • in the amygdala
      • GABRA4 (GABA-A receptor alpha-4 subunit)
      • SLC5A7 (high-affinity choline transporter; solute carrier family 5 member 7)
      • DRD2 (D2 dopamine receptor gene)
      • DRD1a (D1a dopamine receptor gene)
      • GLRA2 (glycine receptor alpha 2)
      • CHRNA6 (nicotinic receptor / choline receptor alpha 6)
      • HTR3A (serotonin 3A receptor)
      • CHRNB4 (nicotinic receptor / choline receptor beta 4)
      • GABRD (GABA-A receptor subunit delta)
      • PRIMA1 (Proline Rich Membrane Anchor 1)
      • CHRNA3 (nicotinic receptor / choline receptor alpha 3)

L-theanine is safe in daily doses of 200 to 400 mg for up to 8 weeks, he said.5

2. Behavioral effect of theanine

Theanine has a sedative and relaxing effect,6 moreover this better than the benzodiazepine alprazolam, but not anxiolytic.7 According to other studies, theanine has anxiolytic and stress-inhibiting effects,5 whereby the anxiolytic effect does not appear to occur through action on the GABA-A receptor.8
Caffeine and gallate catechins, which are abundant in tea, inhibit the relaxing effects of theanine.9

Theanine inhibited the deterioration of cognitive functions in elderly subjects2 and may be parkinsonism preventive due to neuroprotective effects.10

L-theanine administration promoted the release of dopamine and norepinephrine in mouse hippocampus and stimulated protein kinase A (PKA) phosphorylation. The long-term potentiation in the hippocampus improved by L-theanine in an Alzheimer’s disease mouse model could be impaired by a PKA inhibitor. It is likely that L-theanine improves memory and long-term potentiation in the hippocampus of Alzheimer’s disease mice via the dopamine D-1/D-5 receptor PKA pathway. L-theanine may be considered as a candidate for the treatment of Alzheimer’s disease.11

Theanine counteracted a caffeine-induced increase in blood pressure but had no effect on mood.12

3. L-Theanine for ADHD

Apparently, theanine increases dopamine levels in the striatum. Except for improved learning abilities, the behavior of mice receiving theanine for 3 months was unchanged.13

Direct theanine administration into the striatum of mice significantly increased dopamine in a dose-dependent manner. The dopamine increase was attenuated by a previously given calcium-free ring buffer. If the ring buffer also contained the non-NMDA glutamate receptor antagonist MK-801, the significant dopamine increase by L-theanine was maintained. When an NMDA glutamate receptor antagonist was given instead, this significantly inhibited theanine-induced dopamine release in the striatum. Theanine altered the concentrations of norepinephrine, 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5HIAA) only in the striatum but not in other brain regions.
Theanine caused a significant increase in serotonin and dopamine in the brain, especially in striatum, hypothalamus and hippocampus.14

A very small study of 5 boys with ADHD examined the effects of L-theanine (2.5 mg/kg) and caffeine (2.0 mg/kg) (alternative, combined, and versus placebo):15

L-Theanine alone

  • improved overall cognition
  • tend to worsen inhibitory control (increased stop-signal reaction time)

Caffeine alone

  • worsens the inhibitory control

L-theanine and caffeine combined

  • improved overall cognitive performance
  • improved the signal sensitivity to the Go signal (the d-prime in the Go/NoGo task)
  • tended to improve inhibitory control
  • decreased the task-related reactivity of the default mode network associated with mind wandering

A randomized placebo-controlled trial found improved directed attention with L-theanine and even more so with a combination of L-theanine with caffeine.16

400 mg L-theanine (200 mg each in the morning and at noon) improved sleep quality in a randomized, double-blind, placebo-controlled study in boys with ADHD. Actigraph measures showed a significantly higher percentage of sleep and sleep efficiency achieved, along with a nonsignificant trend toward less activity during sleep. Sleep latency and other sleep parameters remained unchanged. No significant adverse events occurred.17

There are no studies on the use of L-theanine in relation to other ADHD symptoms.

  1. Alramadhan, Hanna, Hanna, Goldstein, Avila, Weeks (2012): Dietary and botanical anxiolytics. Med Sci Monit. 2012 Apr;18(4):RA40-8.

  2. Kakuda (2011): Neuroprotective effects of theanine and its preventive effects on cognitive dysfunction. Pharmacol Res. 2011 Aug;64(2):162-8. doi: 10.1016/j.phrs.2011.03.010.

  3. Anas Sohail, Ortiz, Varghese, Fabara, Batth, Sandesara, Sabir, Khurana, Datta, Patel (2021): The Cognitive-Enhancing Outcomes of Caffeine and L-theanine: A Systematic Review. Cureus. 2021 Dec 30;13(12):e20828. doi: 10.7759/cureus.20828. PMID: 35111479; PMCID: PMC8794723. REVIEW

  4. Ceremuga, Martinson, Washington, Revels, Wojcicki, Crawford, Edwards, Kemper, Townsend, Herron, Ceremuga, Padron, Bentley (2014)_- : Effects of L-theanine on posttraumatic stress disorder induced changes in rat brain gene expression. ScientificWorldJournal. 2014;2014:419032. doi: 10.1155/2014/419032. PMID: 25165739; PMCID: PMC4137547.

  5. Lopes Sakamoto, Metzker Pereira Ribeiro, Amador Bueno, Oliveira Santos (2019): 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 Sep;147:104395. doi: 10.1016/j.phrs.2019.104395. PMID: 31412272. REVIEW

  6. Weeks (2009): Formulations of dietary supplements and herbal extracts for relaxation and anxiolytic action: Relarian. Med Sci Monit. 2009 Nov;15(11):RA256-62.

  7. Lu, Gray, Oliver, Liley, Harrison, Bartholomeusz, Phan, Nathan (2004): The acute effects of L-theanine in comparison with alprazolam on anticipatory anxiety in humans. Hum Psychopharmacol. 2004 Oct;19(7):457-65.

  8. Heese, Jenkinson, Love, Milam, Perkins, Adams, McCall, Ceremuga (2009): Anxiolytic effects of L-theanine–a component of green tea–when combined with midazolam, in the male Sprague-Dawley rat. AANA J. 2009 Dec;77(6):445-9.

  9. Unno, Yamada, Iguchi, Ishida, Iwao, Morita, Nakamura (2017): Anti-stress Effect of Green Tea with Lowered Caffeine on Humans: A Pilot Study. Biol Pharm Bull. 2017;40(6):902-909. doi: 10.1248/bpb.b17-00141. PMID: 28566632.

  10. Cho, Kim, Lee, Park, Kim, Chun (2008): Protective effect of the green tea component, L-theanine on environmental toxins-induced neuronal cell death. Neurotoxicology. 2008 Jul;29(4):656-62. doi: 10.1016/j.neuro.2008.03.004.

  11. Zhu, Yang, Xie, Wan (2018): Synaptic modification by L-theanine, a natural constituent in green tea, rescues the impairment of hippocampal long-term potentiation and memory in AD mice. Neuropharmacology. 2018 Aug;138:331-340. doi: 10.1016/j.neuropharm.2018.06.030.

  12. Rogers, Smith, Heatherley, Pleydell-Pearce (2008): Time for tea: mood, blood pressure and cognitive performance effects of caffeine and theanine administered alone and together. Psychopharmacology (Berl). 2008 Jan;195(4):569-77.

  13. Yokogoshi, Terashima (2000): Effect of theanine, r-glutamylethylamide, on brain monoamines, striatal dopamine release and some kinds of behavior in rats. Nutrition. 2000 Sep;16(9):776-7.

  14. Yokogoshi, Kobayashi, Mochizuki, Terashima (1998): Effect of theanine, r-glutamylethylamide, on brain monoamines and striatal dopamine release in conscious rats. Neurochem Res. 1998 May;23(5):667-73.

  15. Kahathuduwa, Wakefield, West, Blume, Dassanayake, Weerasinghe, Mastergeorge (2020): Effects of L-theanine-caffeine combination on sustained attention and inhibitory control among children with ADHD: a proof-of-concept neuroimaging RCT. Sci Rep. 2020 Aug 4;10(1):13072. doi: 10.1038/s41598-020-70037-7. PMID: 32753637; PMCID: PMC7403383.

  16. Kahathuduwa, Dhanasekara, Chin, Davis, Weerasinghe, Dassanayake, Binks (2018): l-Theanine and caffeine improve target-specific attention to visual stimuli by decreasing mind wandering: a human functional magnetic resonance imaging study. Nutr Res. 2018 Jan;49:67-78. doi: 10.1016/j.nutres.2017.11.002. Epub 2017 Nov 16. PMID: 29420994.

  17. Lyon, Kapoor, Juneja (2011): 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. 2011 Dec;16(4):348-54. PMID: 22214254.

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