Dose-Response of Paraxanthine on Cognitive Function: A Double Blind, Placebo Controlled, Crossover Trial

Abstract

Paraxanthine (PXN) is a metabolite of caffeine that has recently been reported to enhance cognition at a dose of 200 mg. Objective: To determine the acute and short-term (7-day) effects of varying doses of PXN on cognitive function and side effects. Methods: In a double blind, placebo-controlled, crossover, and counterbalanced manner, 12 healthy male and female volunteers (22.7 ± 4 years, 165 ± 7 cm, 66.5 ± 11 kg, 24.4 ± 3 kg/m2) ingested 200 mg of a placebo (PLA), 50 mg of PXN (ENFINITY™, Ingenious Ingredients, L.P.) + 150 mg PLA, 100 mg PXN + 100 mg PLA, or 200 mg of PXN. With each treatment experiment, participants completed side effect questionnaires and donated a fasting blood sample. Participants then performed a series of tests assessing cognition, executive function, memory, and reaction time. Participants then ingested one capsule of PLA or PXN treatments. Participants then completed side effects and cognitive function tests after 1, 2, 3, 4, 5, and 6 h of treatment ingestion. Participants continued ingesting one dose of the assigned treatment daily for 6-days and returned to the lab on day 7 to donate a fasting blood sample, assess side effects, and perform cognitive function tests. Participants repeated the experiment while ingesting remaining treatments in a counterbalanced manner after at least a 7-day washout period until all treatments were assessed. Results: The Sternberg Task Test (STT) 4-Letter Length Present Reaction Time tended to differ among groups (p = 0.06). Assessment of mean changes from baseline with 95% CI’s revealed several significant differences among treatments in Berg-Wisconsin Card Sorting Correct Responses, Preservative Errors (PEBL), and Preservative Errors (PAR Rules). There was also evidence of significant differences among treatments in the Go/No-Go Task tests in Mean Accuracy as well as several time points of increasing complexity among STT variables. Finally, there was evidence from Psychomotor Vigilance Task Test assessment that response time improved over the series of 20 trials assessed as well as during the 6-h experiment in the PXN treatment. Acute and short-term benefits compared to PLA were seen with each dose studied but more consistent effects appeared to be at 100 mg and 200 mg doses. No significant differences were observed among treatments in clinical chemistry panels or the frequency or severity of reported side effects. Results provide evidence that acute ingestion of 100 mg and 200 mg of PXN may affect some measures of cognition, memory, reasoning, and response time as well as help sustain attention. Additionally, that acute and daily ingestion of PXN for 7 days is not associated with any clinically significant side effects. Conclusions: PXN may serve as an effective nootropic agent at doses as low as 50 mg.

Paraxanthine Supplementation Increases Muscle Mass, Strength, and Endurance in Mice

“…Yoo and investigators [34] reported on the first human data involving paraxanthine supplementation, wherein they concluded that acute oral ingestion of a 200 mg dose of paraxanthine may affect short-term memory, reasoning, and response time to cognitive challenges. The outcomes were later confirmed in a dose-response study, confirming that paraxanthine may serve as an effective nootropic nutrient at acute doses as low as 50 mg [35]. Certainly, it remains plausible that the observed increases in nitric oxide could explain some of the observed changes in treadmill endurance performance, as exhibited by the mice in this study.…”

Effects of Dietary Supplementation of a Microalgae Extract Containing Fucoxanthin Combined with Guarana on Cognitive Function and Gaming Performance

“…Moreover, Kackley and associates [56] reported that ingesting ketogenic salts may attenuate negative aspects of mood associated with diet intervention. Our group has also reported that acute and one-week ingestion of paraxanthine (the compound that caffeine is primarily converted into after ingestion) [33,57], as well as ashwagandha [58], appears to improve short-term memory, reaction times, and/or errors in healthy individuals. These findings are consistent with studies reporting that various nutrients (with and without caffeine) may influence cognitive function.…”

“…These findings are consistent with studies reporting that various nutrients (with and without caffeine) may influence cognitive function. Additionally, combining various nootropic nutrients may provide some additive and/or synergistic benefit [7,9,10,14,27,33,47,54,55,57,59,60].…”

Paraxanthine safety and comparison to caffeine

“…However, it is predominantly found as the major metabolite of caffeine, accounting for approximately 70%–72% of ingested caffeine ( Stavric, 1988 ). Paraxanthine has been shown to have several of the same nootropic benefits as caffeine, including improved cognition, short-term memory, sustained attention in heathy adults ( Xing et al, 2021 ; Yoo et al, 2021 ) and beneficial cognitive effects in animal models of Parkinson’s disease ( Xu et al, 2010 ; Xing et al, 2021 ; Yoo et al, 2021 ). Moreover, the beneficial impacts on physical endurance and sports performance that have been observed with caffeine use ( Guest et al, 2021 ) have also been suggested for paraxanthine ( Jäger et al, 2022 ).…”

“…Paraxanthine is also unique from other methylxanthine stimulants in that it seems to possess anxiolytic activity ( Costentin et al, 2009 ; Okuro et al, 2010 ). Although human toxicity studies on paraxanthine are scarce, the few studies that have been conducted in humans demonstrate a lack of adverse events ( Xing et al, 2021 ; Yoo et al, 2021 ). In fact, an improved safety profile for paraxanthine in comparison to caffeine has been suggested based on evidence from preclinical in vitro and in vivo studies ( Weinstein et al, 1975 ; Renner, 1982 ; Nakatsuka et al, 1983 ; York et al, 1986 ; Stavric, 1988 ; Institute of Medicine (U.S.), 2001 ; Gressner et al, 2009 ; Monteiro et al, 2016 ).…”