Upon ingestion, caffeine (CA) is metabolized primarily to dimethylxanthines. About 70% of CA is metabolised to Paraxanthine (PXN), with smaller percentages of being metabolised to theobromine (TB) and theophylline (TP).
PXN has been found to have lower toxicity and lesser anxiogenic effects than CA and less negative side effects than other caffeine metabolites which can induce nausea, diarrhea, tachycardia, and arrhythmias.
As with CA, PXN is a central nervous stimulant; however, it has higher binding potencies for adenosine A1 and A2a receptors. Consequently, PXN has a stronger locomotor-activating effect than CA, TB, and TP.
PXN has been shown to protect dopaminergic neurons and protect against neurodegeneration and the loss of synaptic function.The authors of the current study say previous studies suggest PXN may be safer and more effective than CA. yet only two previous studies in humans have been performed with PXN ingestion (Lelo, A., et al and Benowitz, N. L., et al), and studies investigating the potential effects on cognition are currently lacking.
The purpose of the current study, funded by the startup company Ingenious Ingredients (USA), was to examine the effects of acute PXN ingestion (200 mg, ENFINITY, made by Ingenious Ingredients) on markers of cognition, executive function, and psychomotor vigilance.
The researchers hypothesised that since about 70% of CA is metabolized to PXN and it possess some sympathomimetic properties, acute PXN ingestion would promote significant improvements in markers of cognition, memory, and vigilance.
This is the first human study investigating the effects of paraxanthine supplementation in humans on cognition.
This study was conducted in the Human Clinical Research Facility at Texas A&M University as a double-blind, placebo-controlled, crossover trial. A total of 13 participants completed the study (10 males and 3 females aged 24 ± 5 years).
Participants were randomly assigned to consume a placebo (PLA) or PXN. Participants completed stimulant sensitivity and side effect questionnaires and then performed the Berg Wisconsin Card Sorting Test (BCST), the Go/No-Go test (GNG), the Sternberg task test (STT), and the psychomotor vigilance task test (PVTT). Participants then ingested one capsule of PLA or PXN treatment. Participants completed side effect and cognitive function tests 1, 2, 3, 4, 5, and 6 h after ingestion of the supplement. After 7 days, participants repeated the experiment while consuming the alternative treatment.
The BCST assessed reaction time and accuracy in measuring thought, reasoning, learning, executive control, attention shifting, and impulsiveness. The results reveal evidence that paraxanthine decreased the number of errors over time with differences noted from the placebo after 6 h of administration. These findings provide some evidence that paraxanthine helps sustain attention over time, thereby improving accuracy.
The GNG test evaluates the ability to sustain attention, control responses to visual stimulation, reaction time, and accuracy. The results reveal that in comparison to a placebo, paraxanthine ingestion decreased the mean response time to Go Tasks after one hour of administration, while the response time increased over time with the placebo treatment. These findings provide additional evidence that paraxanthine ingestion may improve attention, reaction time, and accuracy.
The STT assessed short-term/working memory involving cognitive control processes, reaction time, and accuracy. Analysis of this cognitive challenge revealed that paraxanthine improved the reaction time from baseline more consistently than the placebo treatment, with reaction time improvements seen with shorter (two-letter) and longer (six-letter) challenges. These findings provide some evidence that paraxanthine enhanced the ability to store and retrieve random information of increasing complexity from short-term memory to a greater degree, as well as helping to sustain attention (i.e., maintained reaction times, prevented mental fatigue).
Finally, the PVTT assessed sustained attention reaction times through responses to visual stimuli. The results reveal that the average reaction time was better maintained over time with paraxanthine. The benefit appeared to peak in about 3–5 h. No side effects were reported, suggesting that acute administration of paraxanthine was well tolerated.
The authors conclude: "The present findings support contentions that paraxanthine may influence memory, cognition, and attention and therefore have nootropic properties. The strength of this study is that it evaluated whether the primary metabolite of caffeine affects cognition, memory, or attention.
"This may increase our understanding about how caffeine and its metabolites influence cognitive and executive function. The limitation of this study is that we only assessed the impact of one oral dose (200 mg) of PXN on primary and secondary outcome measures.
"Additional research will need to examine minimal effective and optimal doses and the impact of longer periods of supplementation and compare paraxanthine to caffeine to determine if it can serve as an effective nootropic alternative with less side effects."
Ingenious Ingredients is currently working on regulatory approval of ENFINITY paraxanthine in all major markets, including the EU. The firm is expecting to finalise self-affirmed GRAS in the USA in November 2021.
Shawn Wells, co-founder of Ingenious Ingredients, spoke to NutraIngredients-USA about the new ENFINITY supplement at the recent Supply Side West event. He explained: “Paraxanthine is a down-stream metabolite of caffeine… It’s a very interesting ingredient. People report to being optimized and not being stimulated...
“We’re not competing against any ingredients. This is caffeine-evolved. It’s a $1 trillion market.”
Yoo, C., Xing, D., Gonzalez, D., Jenkins, V., Nottingham, K., Dickerson, B., Leonard, M., Ko, J., Faries, M., Kephart, W., Purpura, M., Jäger, R., Wells, S.D., Sowinski, R., Rasmussen, C.J., and Kreider, R.B.
"Acute Paraxanthine Ingestion Improves Cognition and Short-Term Memory and Helps Sustain Attention in a Double-Blind, Placebo-Controlled, Crossover Trial"