Adenosine as the metabolic common path of rapid antidepressant action: The coffee paradox.
Brain medicine : from neurons to behavior and better health December 31, 2025 Julio Licinio, Ma-Li Wong 3 citations
Adenosine signaling is the common mechanism underlying rapid-acting antidepressant therapies, including ketamine, electroconvulsive therapy (ECT), and acute intermittent hypoxia. Using genetically encoded sensors and mechanistic experiments, the study shows that all three treatments induce adenosine surges in mood-regulatory circuits via A1 and A2A receptor activation. Ketamine's mechanism primarily involves modulation of mitochondrial metabolism rather than NMDA receptor antagonism, suggesting potential for improved derivatives with better therapeutic indices. These findings provide a framework for evaluating therapeutic benefit in depression and raise questions about caffeine consumption in treatment-resistant depression—whether chronic use protects against or acute use impedes treatment response.