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Updated: Apr 30, 2026

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Paraxanthine: Connecting Caffeine to Nitric Oxide Neurotransmission
Sergi Ferré1, Marco Orrú1, Xavier Guitart1
1Intramural Research Program, Integrative Neurobiology Section, Department of Health and Human Services, National Institute on Drug Abuse , Baltimore, Maryland.
Abstract:
Recent results obtained in our laboratory indicate that paraxanthine, the main metabolite of caffeine in humans, produces a significantly stronger locomotor activation in rats than caffeine. Furthermore, paraxanthine also produced a very significant increase in striatal extracellular concentrations of dopamine. Searching for an additional mechanism other than adenosine antagonism responsible for these psychostimulant-like effects, it was found that paraxanthine, but not caffeine, inhibited cGMP-preferring phosphodiesterases. Furthermore, interrupting nitric oxide neurotransmision (inhibiting nitric oxide synthase) significantly decreased both the locomotor-activating and the dopamine-releasing effects of paraxanthine. These results open up some obvious questions about the role of paraxanthine in the pharmacological effects of caffeine.
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