Effects of L-theanine and Caffeine on Attention and Attention-related Brain Activity of Children With Attention Deficit Hyperactivity Disorder

Study Overview
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Brief Summary
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L-theanine and caffeine are two natural constituents of tea. Both of these compounds are among the U.S. Food and Drug Administration's list of Generally Recognized as Safe (GRAS) substances. Results of several clinical trials the PI and his team has conducted are consistent with results of many others to indicate that oral intake of each of 2.5 mg/kg body weight of L-theanine and 2.0 mg/kg body weight of caffeine is associated with improved attention in adults. Furthermore, there is evidence to suggest that, when taken in combination, L-theanine and caffeine seem to have additive effects in improving attention in adults. However, the specific actions of these substances have not been examined in children and adolescents with attention deficit hyperactivity disorder (ADHD), who are characterized by impaired attention, hyperkinesia and impulsivity. Therefore, the investigators plan to study the functional activity of brains (both at rest and when performing standard tasks designed to measure attention) in children diagnosed with ADHD using functional magnetic resonance imaging, after they consume either 2.5 mg/kg of L-theanine, 2.0 mg/kg of caffeine and their combination as compared to a placebo (water). Based on our previous findings, the investigators expect to observe improvements (speed of responding and accuracy) in standard tests of attention with intake of L-theanine, caffeine and their combination as compared to the placebo. The investigators also expect to observe decreased functional activity in brain regions that typically show increased activity during mind wandering with intake of L-theanine, caffeine and their combination.

Official Title
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Effects of L-theanine and Caffeine on Attention and Attention-related Brain Activity of Male Children and Adolescents With Attention Deficit Hyperactivity Disorder: a proof-of- Concept fMRI Study.

Conditions
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Attention Deficit Hyperactivity Disorder

Intervention / Treatment
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* Dietary Supplement: L-theanine
* Dietary Supplement: Caffeine
* Dietary Supplement: L-theanine-Caffeine Combination
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children and adolescents (age 8-17 years) Male Diagnosed with ADHD by a clinician (e.g. a psychiatrist or a pediatrician) Responded to stimulants (i.e. the symptoms of ADHD have improved in the past with a prescription of stimulants) Exclusion Criteria: Gross impairment of vision or hearing that would prevent the participants from performing neuropsychological tasks Inability to read and follow written instructions WISC-V IQ score of &lt; 80 Physical, neurological or concurrent psychiatric impairments (except ADHD) that could affect cognitive and motor functions Regular intake of medication that could alter visual, auditory, cognitive or motor functions (except stimulants) History of head injury that resulted in loss of consciousness / history of brain surgery Intake of drugs containing caffeine, other phosphodiesterase inhibitors or adenosine receptor blockers within the past 3 months Intake of medications which are known to have pharmacological interactions with caffeine within the past 3 months Current / past diagnosis of tics or other forms of dyskinesia History of development of headache, drowsiness, anxiety, insomnia or nausea following intake of caffeine or caffeine containing beverages Current / past history of smoking and / or alcohol or drug abuse Absolute contraindications to undergo MRI Unwillingness or inability to entirely refrain from use of electronic devices during study visits Unwillingness or inability to refrain from intake of L-theanine and caffeine containing food or beverages within the 24 hours prior to each study visit Unwillingness or inability to follow written, on-screen and verbal instructions given by the study team

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: 2.5 mg/kg body weight of L-theanine, 2.0 mg/kg body weight of caffeine and their combination each dissolved in 100 ml of water (solvent) or the solvent alone (i.e. placebo) will be administered on 4 separate days (at least 5 days apart) in a random counter-balanced order.
Masking: Single


Arms and Interventions

| Intervention/Treatment |
| --- |
|Dietary Supplement: L-theanine|Oral administration of 2.5 mg/kg body weight of L-theanine dissolved in 100 ml of water|
|Dietary Supplement: Caffeine|Oral administration of 2.0 mg/kg body weight of caffeine dissolved in 100 ml of water|
|Dietary Supplement: L-theanine-Caffeine Combination|Oral administration of a combination of 2.5 mg/kg body weight of L-theanine and 2.0 mg/kg body weight of caffeine dissolved in 100 ml of water|
|Other: Placebo|Oral administration of 100 ml of water|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differences of fMRI blood oxygen level dependent (BOLD) responses of the brain in response to Stop Signals of an SSRT recorded following administration of each treatment and the placebo | L-theanine, caffeine, L-theanine-caffeine combination and placebo will be administered on 4 separate days (at least 5 days apart) in a random counter-balanced order. Differences of functional magnetic resonance imaging reactivity of the whole brain, anterior and posterior nodes of the default mode network, bilateral dorsolateral prefrontal cortex and anterior cingulate cortex in response to stop signals of a stop signal reaction time task following administration of each treatment will be compared with the placebo. | 45 minutes after the administration of each treatment / placebo | 
| Differences of fMRI blood oxygen level dependent (BOLD) responses of the brain in a Go-NoGo CPT recorded following administration of each treatment and the placebo | L-theanine, caffeine, L-theanine-caffeine combination and placebo will be administered on 4 separate days (at least 5 days apart) in a random counter-balanced order. Differences of functional magnetic resonance imaging reactivity of the whole brain, anterior and posterior nodes of the default mode network, bilateral dorsolateral prefrontal cortex and anterior cingulate cortex in Go-NoGo continuous performance task following administration of each treatment will be compared with the placebo. | 60 minutes after the administration of each treatment / placebo | 
| Differences of resting state fMRI functional connectivity recorded following administration of each treatment and the placebo | L-theanine, caffeine, L-theanine-caffeine combination and placebo will be administered on 4 separate days (at least 5 days apart) in a random counter-balanced order. Differences of functional magnetic resonance imaging resting state functional connectivity of the anterior and posterior nodes of the default mode network, bilateral dorsolateral prefrontal cortex and anterior cingulate cortex and the remaining regions of the brain following administration of each treatment will be compared with the placebo. | 75 minutes after the administration of each treatment / placebo | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differences of cerebral blood flow measured following administration of each treatment and the placebo | L-theanine, caffeine, L-theanine-caffeine combination and placebo will be administered on 4 separate days (at least 5 days apart) in a random counter-balanced order. Differences of cerebral blood flow estimated using arterial spin labeled echo following administration of each treatment will be compared with the placebo. | 80 minutes following administration of each treatment / placebo | 
| Differences of delay discounting following administration of each treatment and the placebo | L-theanine, caffeine, L-theanine-caffeine combination and placebo will be administered on 4 separate days (at least 5 days apart) in a random counter-balanced order. Differences of delay discounting as measured using a delay discounting task presented on a laptop computer following administration of each treatment will be compared with the placebo. | 140 minutes following administration of each treatment / placebo | 
| Differences of stop signal delay following administration of each treatment and the placebo | L-theanine, caffeine, L-theanine-caffeine combination and placebo will be administered on 4 separate days (at least 5 days apart) in a random counter-balanced order. Differences of stop signal delay of a stop signal reaction time task performed in the magnetic resonance imaging scanner following administration of each treatment will be compared with the placebo. | 45 minutes following administration of each treatment / placebo | 
| Differences of reaction times of correct Go responses in a Go-NoGo CPT following administration of each treatment and the placebo | L-theanine, caffeine, L-theanine-caffeine combination and placebo will be administered on 4 separate days (at least 5 days apart) in a random counter-balanced order. Differences of reaction times of correct Go responses in a Go-NoGo continuous performance task performed in the magnetic resonance imaging scanner following administration of each treatment will be compared with the placebo. | 60 minutes following administration of each treatment / placebo | 
| Differences of commission errors in the Go-NoGo CPT following administration of each treatment and the placebo | L-theanine, caffeine, L-theanine-caffeine combination and placebo will be administered on 4 separate days (at least 5 days apart) in a random counter-balanced order. Differences of commission errors in the Go-NoGo continuous performance task performed in the magnetic resonance imaging scanner following administration of each treatment will be compared with the placebo. | 60 minutes following administration of each treatment / placebo | 
| Differences of performance in Flanker Inhibitory Control and Attention Test following administration of each treatment and the placebo | L-theanine, caffeine, L-theanine-caffeine combination and placebo will be administered on 4 separate days (at least 5 days apart) in a random counter-balanced order. Differences of performance in Flanker Inhibitory Control and Attention Test of the NIH Toolbox Cognition Battery following administration of each treatment will be compared with the placebo. | 100 minutes following administration of each treatment / placebo | 
| Differences of performance in Dimensional Change Card Sort Test following administration of each treatment and the placebo | L-theanine, caffeine, L-theanine-caffeine combination and placebo will be administered on 4 separate days (at least 5 days apart) in a random counter-balanced order. Differences of performance in Dimensional Change Card Sort Test of the NIH Toolbox Cognition Battery following administration of each treatment will be compared with the placebo. | 100 minutes following administration of each treatment / placebo | 
| Differences of performance in Pattern Comparison Processing Speed Test following administration of each treatment and the placebo | L-theanine, caffeine, L-theanine-caffeine combination and placebo will be administered on 4 separate days (at least 5 days apart) in a random counter-balanced order. Differences of performance in Pattern Comparison Processing Speed Test of the NIH Toolbox Cognition Battery following administration of each treatment will be compared with the placebo. | 100 minutes following administration of each treatment / placebo | 
| Differences of post- vs. pre-treatment change of STAI-CH State Scale following administration of each treatment and the placebo | L-theanine, caffeine, L-theanine-caffeine combination and placebo will be administered on 4 separate days (at least 5 days apart) in a random counter-balanced order. Differences of State Trait Anxiety Inventory for Children (State Questionnaire) immediately prior to and following administration of each treatment will be compared with the corresponding post- vs. pre-treatment change of placebo. | Immediately before and 90 minutes after administration of each treatment / placebo |