L-theanine and Paraxanthine for Cognitive Improvement in Adults With ADHD and ASD

Combining L-theanine and Paraxanthine for Transient Improvement of Cognitive Deficits Among Patients With Attention Deficit Hyperactivity Disorder and Autism Spectrum Disorder: A Series of Translational Pilot Neuroimaging Studies

This pilot study will test whether combining L-theanine and paraxanthine improves sustained attention, inhibitory control, and overall cognition in adults with ADHD and ASD. Two parallel randomized, single-blinded, repeated-measures crossover trials will be conducted. Participants will complete neuropsychological testing, fMRI scanning, and self-report measures following administration of the L-theanine-paraxanthine combination compared to placebo.

Improving cognitive functions, including how fast the brain processes information, staying focused, and controlling impulsive actions, has been a topic of interest for centuries. These functions are frequently impaired in developmental or neurological conditions like attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Although medications like amphetamines can help manage cognitive deficits, they often carry significant side effects, risk of addiction, and high costs. Consequently, many individuals and families turn to complementary and alternative treatments. For instance, people with neurodevelopmental conditions, including ADHD, may consume more caffeinated beverages in the hope of boosting cognitive performance. This highlights the need for the exploration of commonly available alternative approaches to determine their efficacy. This study specifically aims to investigate an alternative approach that could serve as a more affordable, integrative, and complementary treatment modality for ADHD and ASD.

Findings of recent controlled cognitive and fMRI studies corroborate the findings of others to indicate that intake of two constituents of tea and coffee, namely L-theanine and caffeine, improves sustained attention in healthy young adult males by decreasing mind wandering. Interestingly, when administered together, L-theanine and caffeine synergistically acted to reduce mind wandering while engaged in a cognitively demanding task. Given the low cost and safety, oral administration of the L-theanine-caffeine combination seems to be a promising strategy to alleviate ADHD-associated impairments of sustained attention. However, regular high consumption of caffeine has adverse effects, such as jitteriness and sleep disturbance due to its metabolites, and the metabolism of caffeine has individual variability.

Paraxanthine is an active metabolite of caffeine that has cognitive benefits without adverse effects and predictable metabolism. However, the effects of the L-theanine-paraxanthine combination on improving cognitive deficits of adults with ADHD and ASD have not been examined. It is expected that combining theanine with paraxanthine instead of caffeine would result in more predictable, consistent, and possibly more marked improvements. There is a critical need to establish the efficacy and mechanisms of action of the L-theanine-paraxanthine combination in order to improve ADHD and ASD-related cognitive deficits. Therefore, the investigators plan to conduct a randomized, single-blinded, repeated-measures crossover trial to answer the following research questions.

Inclusion Criteria:

Adults (18+ years) diagnosed by a physician (per self-report) with ADHD or ASD

* Participants with a dual diagnosis and ASD and ADHD will be recruited but will only be included in the ASD group - their concurrent ADHD diagnosis will be included as an additional variable in exploratory analyses

Exclusion Criteria:

1. Subjects with gross visual or auditory impairments that might limit their ability to perform neuropsychological tasks
2. Inability to read and follow written instructions
3. Physical, neurological, intellectual, or psychiatric impairments (except ADHD or ASD) that could affect cognitive and motor functions
4. Subjects on medications including antidepressants and antipsychotics that may affect performance in the tasks
5. Subjects on medications that are likely to interact with the administered substances, including regular intake of medication that could alter visual, auditory, cognitive, or motor functions (except stimulants)
6. History of head injury resulting in loss of consciousness/history of brain surgery
7. Subjects who have developed adverse effects when caffeine/paraxanthine /L-theanine/corn starch (will be in placebo) containing products were consumed
8. Subjects who are unwilling or unable to refrain from intake of L-theanine/ caffeine/ paraxanthine containing food or beverages within the 24 hours prior to each study visit
9. Intake of drugs containing caffeine, other phosphodiesterase inhibitors, or adenosine receptor blockers within the past 3 months
10. Intake of medications known to have pharmacological interactions with paraxanthine within the past 3 months
11. Current/past diagnosis of tics or other forms of dyskinesia
12. History of headache, drowsiness, anxiety, insomnia, or nausea following intake of caffeine or caffeine-containing beverages
13. Current/past history of smoking and/or alcohol or drug abuse
14. Subjects with absolute contraindications to undergo MRI after being screened by the TTNI safety screening sheet (Appendix)
15. Unwillingness or inability to entirely refrain from the use of electronic devices during study visits
16. Unwillingness or inability to follow written, on-screen, and verbal instructions given by the study team.