Histamine: An Evolutionary Framework for Immune–Brain Coordination and Psychiatric Risk

Histamine is traditionally studied either as a peripheral mediator of inflammation and allergic responses or as a central neuromodulator of arousal and wakefulness. These domains, however, are rarely integrated within a unified conceptual framework. Here, we propose that histamine constitutes an evolutionarily conserved system for immune–brain coordination, signalling environmental volatility and mobilising physiological and cognitive resources in response to potential threat. Peripherally, rapid histamine release provides an early, non-specific alert to tissue disruption, while centrally, histaminergic projections reorganise brain state by increasing arousal, sensory gain, and learning under uncertainty. This coupling allows organisms to rapidly shift from energy conservation and stable behavioural policies toward vigilance, exploration, and adaptive updating when environmental conditions become unpredictable. We argue that neuropsychiatric vulnerability may emerge when this alarm system is chronically engaged or poorly calibrated, leading to persistent hyperarousal, sleep disruption, maladaptive learning, and fatigue. Framing histamine as an evolutionary alarm signal offers a coherent account of its roles across immune and neural systems and provides a conceptual basis for understanding immune-related psychiatric risk and for developing more targeted histaminergic interventions.