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. 2025 Jan 16;20(1):e0313486.
doi: 10.1371/journal.pone.0313486. eCollection 2025.

1-Methylxanthine enhances memory and neurotransmitter levels

Ralf Jäger  1   2 , Sidney Abou Sawan  3 , Marco Orrú  4 , Grant M Tinlsey  5 , Martin Purpura  1   2 , Shawn D Wells  1 , Kylin Liao  1 , Ashok Godavarthi  6
Affiliations

1-Methylxanthine enhances memory and neurotransmitter levels

Ralf Jäger et al. PLoS One. .

Abstract

1-Methylxanthine (1-MX) is the major metabolite of caffeine and paraxanthine and might contribute to their activity. 1-MX is an adenosine receptor antagonist and increases the release and survivability of neurotransmitters; however, no study has addressed the potential physiological effects of 1-MX ingestion. The aim of this study was to compare the effect of 1-MX on memory and related biomarkers in rats compared to control. Memory (escape latency in the Morris water maze test), neurotransmitters (acetylcholine, dopamine, gamma-amino butyric acid (GABA)), and neurochemicals (BDNF, catalase, glutathione, Amyloid Beta and cyclic GMP) were analyzed from whole brain samples in young (8-weeks-old) and aged (16-months-old) rats following 12 days of supplementation (100 mg/d HED of 1-MX [UPLEVEL®, Ingenious Ingredients L.P., Lewisville, TX, USA]) via oral gavage. 1-MX supplementation reduced escape latency by 39% in young animals and 27% in aged animals compared to controls (both p<0.001). Additionally, 1-MX increased the levels of acetylcholine, dopamine, GABA, and cyclic GMP (all p<0.001). Furthermore, 1-MX supplementation led to reduced amyloid beta and higher catalase, BDNF and glutathione concentrations (p<0.001). Collectively, our findings suggest that 1-MX may have cognitive-enhancing and neuroprotective properties.

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Conflict of interest statement

RJ, MP, SDW and KL are researchers and principals of Ingenious Ingredients, the sponsor of the study, and inventors of a patent application for the use of 1-MX but have been involved in data collection or analysis. RJ, MP and SDW serve on the scientific advisory board and KL is the CEO of NNB Nutrition, the manufacturer of the 1-MX used in this study. AG is employed by Radiant Research Services Pvt. Ltd., and Radiant Research is a CRO who has received funding from Ingenious Ingredients to conduct this study. GMT provides consulting services, including statistical analysis and dietary supplement formulation, through Tinsley Consulting LLC but has no conflicts of interest related to the use of 1-MX. SA is employed by Iovate Health Sciences, a company selling dietary supplements. SA and MO declare no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. 1-MX is produced through 3-demethylation of theophylline and 7-demethylation of paraxanthine.
XO = xanthine oxidase; AFMU = 5-acetyl-amino-6-formylamino-3-methyluracil; AAMU = 5-acetylamino-6-amino-3-methyluracil; NAT2 = N-acetyltransferase 2; CYP1A2 = cytochrome P450 family 1 subfamily A member 2.
Fig 2
Fig 2. Timeline of treatments and tests.
Fig 3
Fig 3. 1-MX significantly improved escape latency independent of age.
Separate bars are displayed for young and old rats in the 1-MX and CON conditions. Bars indicate mean responses in each group, with error bars indicating standard deviations. Points on the graph indicate individual responses. * indicates significant difference between groups within the specified age group (p<0.001). # indicates significant difference between ages (p<0.001).
Fig 4
Fig 4. 1-MX significantly increases levels of neurotransmitters.
For all neurotransmitters, statistically significant effects of group and age were observed (p<0.01 for each), without statistically significant group × age interactions. Different letters within an age group indicate statistically different values between groups. # indicates a significant difference based on age (i.e., the age main effect).
See this image and copyright information in PMC

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