Park SK, Jung IC, Lee WK, et al. A combination of green tea extract and l-theanine improves memory and attention in subjects with mild cognitive impairment: a double-blind placebo-controlled study. J Med Food. 2011;14(4):334-343.
Randomized placebo controlled prospective trial. Neuropsychological tests were performed at baseline and at 8 and 16 weeks after treatment.
These tests included the Rey-Kim memory test and the Stroop color-word reading test. Twenty-four subjects were randomly selected for EEG measurements.
Ninety-one participants (25 male) were enrolled in this study. Ages ranged from 40 to 75 years. Forty-six received treatment and 45 received placebo. All complained of poor memory, scored between 21 and 26 on the Mini Mental Scale Examination-K (MMSE-K), and were between second and third stage of the Global Deterioration Scale (GDS).1,2 The MMSE-K is a Korean version of the MMSE and is designed to measure various cognitive functions quickly with scores ranging from 0–30, where a score of 30 is normal. The GDS is a test used to assess clinical symptoms and severity of Alzheimer’s disease. GDS scores range from “no cognitive decline” (GDS 1) to “very severe” (GDS 4–7). Study participants ranged from GDS 2 (normal with subjective memory impairment) to GDS 3 (mild dementia). Caffeine-containing food and beverages were restricted during the study period.
Study Medication and Dosage
Subjects were randomized to either treatment or placebo groups. All took two 430 mg capsules twice a day 30 minutes before eating for 16 weeks. The treatment capsules consisted of 360 mg green tea extract and 60 mg l-theanine, for a daily dose of 1,440 mg green tea extract and 240 mg of l-theanine. The strength of the green tea extract is not specified in the study.
EEG was used to evaluate short-term response to a daily dose of the medication taken all at once. The Rey-Kim memory test was used to assess changes in verbal and visuospatial memory, and the Stroop color-word reading test was used to assess attention.
In the area of verbal and visuospatial memory, those subjects with an initial MMSE-K score of 21 to 23 showed a significant memory quotient (MQ) increase at 16 weeks (P=0.0478). Treatment also improved immediate recall (P≤0.01) after 16 weeks compared to baseline. No improvement was seen in those receiving placebo. Total differences between the treatment and placebo group did not reach significant levels. When attention was measured using the Stroop color-word reading test, the subgroup of participants with a MMSE-K score of 21–23 again showed a significant increase against placebo at 8 weeks (P=0.0306) and 16 weeks (P=0.133). There was no significant effect in the placebo group. Theta brain wave activity began increasing one hour after taking the medication and lasted up to 3 hours in the eye-opened state. EEGs measured while reading showed increased theta waves after 2 and 3 hours. The combination of green tea and l-theanine tested in this study significantly improved cognitive functions by increasing memory and attention in subjects with mild cognitive impairment whose MMSE-K score was between 21 and 23.
There is no reason to question the need for additional nontoxic and low-cost therapies that will slow the development of Alzheimer’s disease. We will leave it to other reviews to summarize both the large financial and emotional costs of this disease.
Green tea, and especially l-theanine, should be added to a growing list of possible therapies for treating early Alzheimer’s disease. Although the improvements measured in this study were modest, these data taken in context with other studies create a convincing argument that L-theanine with green tea polyphenols and caffeine provide clinical benefit.
Kakuda reported in 2002 that green tea had several neuroprotective effects. It protected neurons from the toxic effects caused by glutamic acid exposure. Pre-administration of L-theanine protected hippocampal CA1 pyramidal neurons against transient forebrain ischemia in the gerbil. L-theanine also protected the neurons in the hippocampal CA3 region from injury from kainate exposure. L-theanine also protected low-density lipoproteins (LDL) from the type of oxidative changes that lead to atherosclerosis.3 Egashira confirmed the protection from ischemic damage in 2008.4
A 2006 paper by Nathan et al partly explains these protective effects: “L-theanine increases brain serotonin, dopamine, GABA levels and has micromolar affinities for AMPA, Kainate and NMDA receptors. In addition has been shown to exert neuroprotective effects in animal models possibly.… Overall, L-theanine displays a neuropharmacology suggestive of a possible neuroprotective and cognitive enhancing agent and warrants further investigation in animals and humans.”5
Combining caffeine with green tea epicatechin, epigallocatechin, and epigallocatechingallate induces enzyme activity.
Another possible explanation for green tea’s benefit in Alzheimer’s disease is its effect on the activity of enzymes called neutral endopeptidases. These enzymes degrade amyloid beta-peptide plaques in the brain. Combining caffeine with green tea epicatechin, epigallocatechin, and epigallocatechingallate induces enzyme activity.6
A 2009 study on mice is of particular interest. Pre-treating the mice for 5 weeks by putting L-theanine in their drinking water protected them from brain damage when they were subsequently injected with beta-amyloid protein.7
Of equal interest is a paper published in April 2011. In it, Kakuda describes “an investigation of elderly persons with normal or slight cognitive dysfunction, volunteers who ingested powdered green tea containing a high theanine concentration (equivalent to 47.5 mg/day (-1) of theanine).” They “showed significantly lower decline in cognitive function compared with that of the placebo group.”8
There is another angle to this research. Patients suffering from Alzheimer’s disease, as well as their family members who act as caretakers, may suffer from anxiety.9 Spouses who act as caretakers for people with Alzheimer’s disease are at increased risk of developing the disease themselves—approximately 6 times the expected risk.10 L-theanine may be employed to reduce anxiety.11,12,13 We might consider giving green tea and L-theanine not only to our Alzheimer’s disease patients, but also to the family members caring for them.
Green tea and L-theanine should be added to the list of foods and nutrients we consider using in treating early Alzheimer’s disease.
2. Global Deterioration Scale. Available at: http://www.mirecc.va.gov/visn21/pdf/GDS_Basic_Package.pdf. Accessed June 6, 2011.
3. Kakuda T. Neuroprotective effects of the green tea components theanine and catechins. Biol Pharm Bull. 2002;25(12):1513-1518.
4. Egashira N, Ishigami N, Pu F, et al. Theanine prevents memory impairment induced by repeated cerebral ischemia in rats. Phytother Res. 2008;22(1):65-68.
5. Nathan PJ, Lu K, Gray M, Oliver C. The neuropharmacology of L-theanine (N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent. J Herb Pharmacother. 2006;6(2):21-30.
6. Ayoub S, Melzig MF. Induction of neutral endopeptidase (NEP) activity of SK-N-SH cells by natural compounds from green tea. J Pharm Pharmacol. 2006;58(4):495-501.
7. Kim TI, Lee YK, Park SG, et al. l-Theanine, an amino acid in green tea, attenuates beta-amyloid-induced cognitive dysfunction and neurotoxicity: reduction in oxidative damage and inactivation of ERK/p38 kinase and NF-kappaB pathways. Free Radic Biol Med. 2009;47(11):1601-1610.
8. Kakuda T. Neuroprotective effects of theanine and its preventive effects on cognitive dysfunction. Pharmacol Res. 2011 Apr 6. [Epub ahead of print]
9. Ocaña GG, Robles RG, Vinuesa DS, De Castro FL. [Family repercussions due to Alzheimer disease]. Rev Enferm. 2007;30(3):59-64.
10. Seppa N. Caring for a spouse with dementia leaves caregiver at risk. Science News. 2010;177(13). Available at: http://www.sciencenews.org/view/generic/id/59316/title/Caring_for_a_spouse_with_dementia_takes_a_toll. Accessed June 6, 2011.
11. Lu K, Gray MA, Oliver C, et al. The acute effects of L-theanine in comparison with alprazolam on anticipatory anxiety in humans. Hum Psychopharmacol. 2004;19(7):457-465.
12. Heese T, Jenkinson J, Love C, et al. Anxiolytic effects of L-theanine—a component of green tea—when combined with midazolam, in the male Sprague-Dawley rat. AANA J. 2009;77(6):445-449.
13. Ritsner MS, Miodownik C, Ratner Y, et al. L-theanine relieves positive, activation, and anxiety symptoms in patients with schizophrenia and schizoaffective disorder: an 8-week, randomized, double-blind, placebo-controlled, 2-center study. J Clin Psychiatry. 2011;72(1):34-42.