Study Summary:
In a 12-week randomized, double-blind, placebo-controlled study, 100 healthy adults (aged 50–85) with age-associated memory impairment received either 500 mg Cognizin® citicoline or placebo.

Findings:
The citicoline group showed significantly greater improvements in both episodic memory (Paired Associate test) and composite memory scores than the placebo. The study suggested citicoline supplementation supports memory function in healthy aging.

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Nakazaki, et al. (2021). "Citicoline and Memory Function in Healthy Older Adults: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial" Journal of Nutrition.

Study Summary:
This randomized, double-blind, placebo-controlled study tested the effects of daily citicoline (250 mg or 500 mg) for 28 days in 60 healthy women aged 40–60. Attention was assessed at baseline and day 28 using the Continuous Performance Test II (CPT-II).

Findings:
The 250 mg group: Significantly fewer omission errors (p=0.04) and commission errors (p=0.03) vs. placebo. 500 mg group: Significantly fewer commission errors (p=0.03) and a trend toward fewer omission errors (p=0.07). Overall: Both doses improved attention, suggesting citicoline enhances cognitive inhibition and attentional performance.

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McGlade E, et al. (2012). "Improved Attentional Performance Following Citicoline Administration in Healthy Adult Women." Food and Nutrition Sciences

Summary:
This randomized study evaluated the effects of 28 days of citicoline supplementation (250 or 500 mg) compared to placebo in 75 healthy adolescent males. Attention, psychomotor function, and impulsivity were assessed with the Ruff 2&7, Finger Tap Test, and CPT-II.

Findings:
Adolescents receiving citicoline showed significantly improved attention (p=0.02) and faster psychomotor speed (p=0.03) than those given placebo. Higher weight-adjusted doses were associated with greater accuracy on attention tasks (p=0.01), improved signal detectability (p=0.03), and reduced impulsivity (p=0.01). Overall, citicoline supplementation improved attentional performance, psychomotor function, and inhibitory control in adolescent males.

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Agoston AM et al. (2019) "The Effect of Citicoline Supplementation on Motor Speed and Attention in Adolescent Males." Journal of Attention Disorders

Study Summary:
This cross-sectional analysis examined the relationship between total choline intake and cognitive function in 2,393 U.S. adults over 60 years old, using NHANES 2011–2014 data. Choline intake (dietary + supplements) was categorized into tertiles, and cognition was measured with the CERAD Word Learning test, Animal Fluency test, and Digit Symbol Substitution test. Low cognitive function (LC) was defined as scoring in the lowest quartile for each test.

Findings:
Elders with moderate choline intake (187.6–399.5 mg/day, T2) had a significantly lower risk of low cognitive function compared to those with low intake (<187.6 mg/day, T1) across all three cognitive tests, with odds ratios indicating roughly a 40–50% reduction in risk. Higher intake (>399.5 mg/day, T3) was not associated with additional benefits. Overall, moderate choline consumption was linked to better cognitive outcomes in older adults.

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Liu L, et al. (2021) "Choline Intake Correlates with Cognitive Performance among Elder Adults in the United States." Behavioral Neurology.

Summary:
This animal study investigated whether choline supplementation could protect against cognitive impairment caused by chronic sleep deprivation in young mice. Mice were fed a diet containing 11.36 g/kg choline bitartrate and evaluated with behavioral testing, hippocampal imaging, histology, and phospholipidomic profiling.

Findings:
Choline supplementation significantly improved spatial learning despite sleep deprivation and preserved hippocampal structure and connectivity. It reduced blood-brain barrier permeability, neuroinflammation, oxidative stress, and microglial activation while protecting synaptic plasticity. Phospholipidomic analysis identified 313 molecules, with increases in total phospholipids (especially phosphatidylcholine) strongly linked to reduced neuroinflammation and improved cognition. Overall, choline protected against sleep deprivation–induced cognitive deficits through hippocampal protection, reduced inflammation and oxidative stress, and modulation of phospholipid metabolism.

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Si-Yu Huang et al. (2025) "Choline alleviates cognitive impairment in sleep-deprived young mice via reducing neuroinflammation and altering phospholipidomic profile." Redox Biology.

Summary:
This placebo-controlled crossover study tested whether choline supplementation improves visuomotor performance in 28 healthy adults. Each participant consumed 2 g of choline bitartrate or placebo in separate sessions, then performed a visuomotor aiming task 70 minutes later.

Findings:
Choline supplementation led to more precise target hits compared to placebo, indicating improved visuomotor coordination. Pupil size decreased significantly after choline intake and was linked to performance measures: larger pupils correlated with less accuracy, more misses, and slower reaction times. Overall, results suggest choline enhances action precision by shifting the balance toward accuracy over speed, likely via cholinergic effects on the nervous system.

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Naber, M. et al. (2015) "Improved human visuomotor performance and pupil constriction after choline supplementation in a placebo-controlled double-blind study." Scientific Reports.

Summary:
This randomized, placebo-controlled, four-way crossover study tested the acute effects of l-theanine (2.5 mg/kg), caffeine (2.0 mg/kg), their combination, and placebo on attention, inhibitory control, and cognition in five boys (ages 8–15) with ADHD. Cognitive tasks (Go/NoGo, Stop-signal) were paired with fMRI, and the NIH Cognition Toolbox was administered post-dose.

Findings:
L-theanine alone improved overall cognition but showed a trend toward impaired inhibitory control. Caffeine impaired inhibitory control. In contrast, the l-theanine–caffeine combination improved overall cognition, enhanced Go/NoGo accuracy, and showed a trend toward better inhibitory control. fMRI results indicated reduced default mode network activity during tasks, suggesting improved attentional engagement. Overall, the l-theanine–caffeine combination supported cognitive performance and attentional control in boys with ADHD.

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Kahathuduwa, C.N. et al. (2020) "Effects of l-theanine–caffeine combination on sustained attention and inhibitory control among children with ADHD: a proof-of-concept neuroimaging" Nature: Scientific Reports.

Summary:
This randomized, placebo-controlled, crossover study compared the effects of caffeine (50 mg), caffeine plus L-theanine (100 mg), and placebo on cognition and mood in 27 healthy adults. Cognitive performance was measured at baseline, 60 minutes, and 90 minutes after dosing across tasks of word recognition, attention switching, rapid visual information processing, and critical flicker fusion, with mood also assessed.

Findings:
Caffeine alone increased subjective alertness at 60 minutes and improved accuracy on the attention-switching task at 90 minutes. The combination of caffeine and L-theanine improved both speed and accuracy on attention switching at 60 minutes and reduced susceptibility to distraction in the memory task at both time points. Overall, results support that the caffeine–L-theanine combination enhances performance on demanding cognitive tasks beyond the effects of caffeine alone.

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Owen GN, et al. (2008) "The combined effects of L-theanine and caffeine on cognitive performance and mood." Nutritional Neuroscience.

Summary:
This double-blind, placebo-controlled, counterbalanced crossover study tested the effects of caffeine (75 mg), L-theanine (50 mg), their combination, and placebo on cerebral blood flow (CBF), cognition, and mood in 24 adults (12 habitual caffeine consumers, 12 non-consumers). CBF was assessed with near-infrared spectroscopy, alongside cognitive and mood measures.

Findings:
Caffeine reduced oxygenated haemoglobin, increased deoxygenated haemoglobin, improved attention task performance, and enhanced mood, with stronger vascular effects in non-consumers. When combined with L-theanine, caffeine’s vascular and behavioural effects were largely abolished, while L-theanine alone showed no independent impact. At tea-equivalent doses, the combination neutralized caffeine’s vasoconstriction but did not produce additional cognitive or mood benefits.

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Dodd FL, et al. (2015) "A double-blind, placebo-controlled study evaluating the effects of caffeine and L-theanine both alone and in combination on cerebral blood flow, cognition and mood." Psychopharmacology.

Summary:
This preclinical study investigated agmatine’s fast-acting antidepressant effects in mice, showing that oral agmatine reversed depressive-like behaviors and markers of neuroinflammation.

Findings:
Agmatine produced rapid improvements in depressive-like symptoms, comparable to ketamine, by modulating NMDA, AMPA, and TrkB receptors. Behavioral improvements were also linked to increased BDNF levels and changes in neuroplasticity signaling (PI3K/Akt/mTOR), positioning agmatine as a potential candidate for rapid-onset antidepressant therapy.

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Valverde AP et al. (2021) "Agmatine as a novel candidate for rapid-onset antidepressant response." World Journal of Psychiatry.

Summary:
This study focused on a mouse model of depression, finding that acute agmatine administration rapidly improved depressive-like behaviors in both male and female mice during the forced swim test.

Findings:
Agmatine sulfate supplementation may support mood by helping restore imbalances in the brain’s agmatine system, producing rapid antidepressant-like effects similar to ketamine, increasing Brain-Derived Neurotrophic Factor levels, and modulating NMDA receptor activity to promote faster improvements in emotional resilience and mental state.

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Meylan, E. et al. (2016) "Involvement of the agmatinergic system in the depressive-like phenotype of the Crtc1 knockout mouse model of depression." Nature: Translational Psychiatry.

Summary:
Animal studies have repeatedly shown agmatine's neuroprotective effects, including modulation of neurotransmitter receptors and reduction of neuroinflammation and oxidative stress.

Findings:
Agmatine sulfate supplementation has been shown to reduce treatment-resistant neuropathic pain by ~46% in small fiber neuropathy, likely through modulation of nitric oxide signaling and related neurovascular pathways,improving nerve function, reducing pain signaling, and supporting more stable neural communication.

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Rosenberg ML et all (2018) "Evidence for Dietary Agmatine Sulfate Effectiveness in Neuropathies Associated with Painful Small Fiber Neuropathy. A Pilot Open-Label Consecutive Case Series Study." Nutrients.