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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 have parkinsonism-preventive effects 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 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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