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

1. Introduction

The capacity to detect and respond to environmental challenge is a defining feature of biological systems. In multicellular organisms, this function is distributed across immune, neural, and endocrine systems that evolved not in isolation, but in continuous interaction. Immune signalling shapes motivation, cognition, and behaviour, while brain states regulate immune readiness and energy allocation. Increasing recognition of this bidirectional coupling has transformed our understanding of how inflammation influences mental health, shifting emphasis from discrete disease mechanisms toward dynamic immune–brain coordination [1,2,3].

Within this landscape, histamine occupies a distinctive yet under-theorised position [4]. It is one of the most rapid mediators of peripheral inflammatory responses [5] and one of the most diffusely projecting neuromodulators in the brain [6]. Peripherally, histamine release accompanies tissue injury, infection, and exposure to toxins, producing stereotyped physiological effects that prioritise defence and repair [5]. Centrally, histaminergic neurons modulate wakefulness, attention, sensory processing, and learning, exerting widespread influence over brain state despite their relatively small number [6]. These dual roles have traditionally been studied separately, resulting in parallel literatures that rarely converge.

This separation obscures a more fundamental question: why does the same molecule operate at both immune and neural levels, and what selective pressures shaped this arrangement? From an evolutionary perspective, the co-option of histamine into both systems suggests a shared functional logic rather than coincidental reuse. Histamine’s speed, diffuseness, and lack of specificity make it poorly suited for fine-grained discrimination, but ideal for signalling that prevailing conditions may no longer be safe or predictable [7]. In this sense, histamine appears optimised to function not as a marker of threat identity, but as a signal that existing physiological and behavioural policies require rapid reassessment.

Central histaminergic signalling is particularly well placed to support such reconfiguration [6]. By increasing arousal and sensory gain while modulating learning under uncertainty, histamine promotes rapid updating of internal models when environmental contingencies shift [8]. At the same time, peripheral histamine release mobilises immune and vascular responses that prepare the organism for potential injury or infection. Together, these effects suggest a coordinated system designed to bias the organism toward vigilance, exploration, and short-term survival in volatile contexts [9].

Here, we propose that histamine functions as an evolutionarily conserved alarm system that couples immune activation to brain-state reorganisation in response to environmental volatility [10]. We argue that this framework provides a unifying account of histamine’s peripheral and central actions and offers new insight into how immune processes shape cognition and behaviour. We further suggest that neuropsychiatric vulnerability may arise when this alarm system is chronically engaged or miscalibrated, leading to persistent hyperarousal, sleep disruption, and maladaptive learning. By reframing histamine within an evolutionary immune–brain coordination model, this Perspective aims to clarify its role in mental health and highlight new directions for translational research.

2. Histamine as a Peripheral Alarm Signal

Histamine is among the earliest mediators released during immune activation. Stored preformed in mast cells and basophils, it can be liberated within seconds in response to tissue injury, pathogen-associated signals, toxins, or mechanical stress. This speed distinguishes histamine from cytokines and chemokines that require de novo synthesis and positions it as an initial alarm rather than a downstream effector of immune specificity [11].

The peripheral actions of histamine are stereotyped and highly conserved. Vasodilation, increased vascular permeability, smooth muscle contraction, itch, and pain sensitivity serve to rapidly alter local tissue dynamics while broadcasting the presence of potential danger to the organism [12,13,14,15]. These effects are often described as pathological in modern clinical contexts, yet from an evolutionary standpoint they represent efficient mechanisms for amplifying weak or ambiguous signals of harm. Importantly, histamine does not encode information about the nature of the threat. Instead, it signals that tissue integrity or physiological stability may be compromised, triggering a state of heightened readiness.

This lack of specificity is a defining feature rather than a limitation [16]. In unpredictable environments, rapid detection of deviation from expected conditions is more valuable than accurate classification. Histamine thus functions as a low-threshold detector of volatility, prioritising speed and coverage over precision. By increasing blood flow, facilitating immune cell extravasation, and activating sensory afferents, histamine ensures that local perturbations are rapidly integrated into systemic responses [4].

Peripheral histamine signalling also interfaces directly with the nervous system. Sensory fibres expressing histamine receptors convey itch, pain, and discomfort, generating behavioural urgency and orienting attention toward the affected region. These signals are not simply nociceptive but motivational, biasing behaviour toward withdrawal, grooming, or avoidance [15]. In this way, histamine translates immune activation into action tendencies before higher-order evaluation is possible.

Crucially, peripheral histamine release rarely occurs in isolation. It often accompanies broader immune and neuroendocrine changes, acting as a trigger that lowers thresholds for subsequent responses [15]. Within the framework proposed here, histamine serves as the first component of an integrated alarm system, signalling that prevailing physiological assumptions may no longer hold and preparing both body and brain for rapid adaptation. In the next section, we turn to the central histaminergic system and examine how this peripheral alarm is mirrored by a coordinated reconfiguration of brain state, linking immune activation to arousal, learning, and behavioural flexibility.

3. Central Histamine and Brain-State Reconfiguration

Central histamine is produced by a small population of neurons located in the posterior hypothalamus, whose axons project broadly across cortical and subcortical regions. This anatomical organisation is characteristic of neuromodulatory systems that regulate global brain state rather than transmitting specific information. Despite their limited number, histaminergic neurons exert widespread influence over arousal, attention, sensory processing, and learning [6,8].

Histaminergic activity is tightly coupled to vigilance [17]. Firing rates are highest during wakefulness, decrease during non-rapid eye movement sleep, and are nearly silent during rapid eye movement sleep. Pharmacological blockade of histamine receptors produces sedation, while enhanced histaminergic signalling promotes alertness and resistance to sleep pressure [17]. These effects are often interpreted narrowly as regulation of the sleep–wake cycle. However, such an interpretation underestimates the functional scope of histamine, which extends beyond maintaining wakefulness to reshaping how information is processed during wake.

Central histamine increases neural gain across sensory and associative cortices, amplifying responsiveness to incoming stimuli [18]. This gain modulation enhances signal salience but also increases neural noise, a trade-off that becomes advantageous when environmental contingencies are unstable [19]. In such contexts, reliance on prior expectations may be maladaptive, and increased sensitivity to novel or unexpected input supports rapid updating of internal models [20]. Histamine thus biases cognition toward exploration and learning rather than exploitation of established strategies.

Histamine also interacts closely with other neuromodulatory systems involved in uncertainty and stress, including noradrenaline [21], acetylcholine [22], and corticotropin-releasing hormone [23]. Through these interactions, histamine contributes to a coordinated shift in brain state characterised by heightened arousal, attentional flexibility, and readiness for action. Importantly, this shift is not intrinsically valenced; histamine does not encode threat or reward but alters the conditions under which such information is evaluated.

From an evolutionary perspective, this pattern is consistent with a system designed to signal that the reliability of existing predictions has diminished. Central histamine does not specify what is wrong, but it alters the computational regime of the brain to prioritise rapid detection of change. In doing so, it mirrors the role of peripheral histamine, which signals disruption without defining its cause. Together, these properties suggest that central histamine functions as the neural counterpart of a peripheral immune alarm. By globally reconfiguring brain state, it ensures that immune-derived signals of potential danger are matched by appropriate cognitive and behavioural flexibility. This coordination provides a mechanistic bridge between inflammation, arousal, and learning, setting the stage for understanding how dysregulation of histaminergic signalling may contribute to psychiatric vulnerability. In the next section, we integrate peripheral and central actions of histamine into a unified evolutionary framework centred on environmental volatility and adaptive trade-offs.

4. Histamine, Environmental Volatility, and Adaptive Trade-Offs

Integrating peripheral and central actions, histamine can be understood as a system tuned to detect and respond to environmental volatility rather than to specific threats. Volatility, in this context, refers to situations in which the statistical structure of the environment changes rapidly or becomes unreliable, rendering previously adaptive physiological and behavioural strategies suboptimal. In such conditions, organisms benefit from mechanisms that prioritise rapid detection of change and flexible updating over efficiency and stability [24,25].

Histamine is well suited to this role [26,27]. Its release is rapid, its effects are diffuse, and its signalling lacks fine-grained specificity. These properties allow histamine to act as a global alert that prevailing assumptions may no longer hold [26,27]. Peripherally, this alert mobilises immune and vascular responses that prepare tissues for injury or infection. Centrally, it induces a shift in brain state characterised by increased arousal, enhanced sensory gain, and altered learning dynamics. Together, these changes bias the organism toward vigilance, exploration, and short-term survival.

This shift entails clear trade-offs. States promoted by histaminergic activation are metabolically costly and incompatible with processes optimised for predictable environments, such as sustained sleep, energy conservation, and reliance on habitual behaviour [28]. Increased neural gain enhances sensitivity to novel information but also increases susceptibility to distraction and noise. Similarly, immune readiness improves defence but raises the risk of collateral tissue effects [29]. From an evolutionary standpoint, these costs are acceptable when volatility is transient, but become maladaptive when the alarm state persists [30].

Framing histamine as a volatility signal helps reconcile its apparently paradoxical effects across domains. It explains why histamine promotes wakefulness without conferring positive affect, why it enhances learning under uncertainty while impairing performance in stable conditions, and why its peripheral actions are protective in acute contexts yet pathological when prolonged. Rather than serving a single function, histamine orchestrates a coordinated reallocation of resources in response to changing environmental demands [30].

This framework also highlights why histaminergic systems are vulnerable to dysregulation in modern contexts. Persistent low-grade inflammation, chronic stress, or repeated immune activation can engage the alarm system in the absence of genuine external volatility [30]. Under these conditions, histamine-mediated adaptations become decoupled from their original evolutionary function, leading to sustained hyperarousal and inefficient behavioural strategies. In the next section, we consider how chronic or miscalibrated activation of this alarm system may contribute to neuropsychiatric vulnerability, particularly in conditions characterised by disturbances of arousal, learning, and fatigue.

5. Histamine Dysregulation and Psychiatric Risk

If histamine functions as an adaptive alarm system under conditions of genuine environmental volatility, then psychiatric vulnerability may arise when this system is persistently engaged, insufficiently terminated, or poorly calibrated to actual threat. In such cases, mechanisms that evolved to support short-term survival may begin to undermine long-term cognitive, emotional, and physiological stability [31,32].

Chronic activation of histaminergic signalling is likely to bias the organism toward a sustained state of hyperarousal. Centrally, this may manifest as sleep disruption, heightened sensory sensitivity, attentional instability, and difficulty disengaging from threat-related information. While these features can be adaptive during acute danger, their persistence interferes with restorative processes such as sleep-dependent learning, synaptic homeostasis, and energy regulation. Over time, this imbalance may contribute to fatigue, cognitive inefficiency, and emotional dysregulation [28,32].

At the cognitive level, prolonged histamine-driven gain modulation may distort learning dynamics [28]. Increased sensitivity to novel or unexpected input can impair the consolidation of stable predictive models, leading to excessive updating in response to noise rather than meaningful change. This pattern resembles forms of maladaptive learning observed across several psychiatric conditions, in which individuals remain locked in states of heightened vigilance despite the absence of clear external threat [33]. Rather than reflecting simple anxiety or hyperreactivity, such states may represent a failure to appropriately downregulate an alarm system that was never designed for chronic engagement.

Peripheral immune processes may further amplify this vulnerability. Low-grade inflammation, recurrent infections, or immune dysregulation can repeatedly trigger histamine release, reinforcing central alarm states through both humoral and neural pathways. In this way, immune activity may shape psychiatric risk not only through cytokine-mediated effects on mood and motivation, but also by sustaining neuromodulatory conditions that favour hypervigilance and impaired recovery [34]. Histamine thus provides a plausible mechanistic bridge linking immune activation to disturbances of arousal, cognition, and affect.

This framework aligns with clinical features observed across a range of psychiatric and neuroimmune conditions, including anxiety-related disorders, obsessive–compulsive spectrum disorders, trauma-related syndromes, and post-infectious states. Common to these conditions are alterations in sleep, heightened threat sensitivity, cognitive rigidity, and fatigue, often in the context of ongoing immune or inflammatory activity [35]. Importantly, the present model does not imply that histamine is a primary cause of these disorders, but rather that dysregulated histaminergic signalling may act as a vulnerability factor that shapes symptom expression and persistence.

By reframing psychiatric symptoms as potential consequences of maladaptive alarm signalling, this perspective shifts emphasis away from static disease categories toward dynamic failures of immune–brain coordination. In the following section, we consider the translational implications of this view and its relevance for therapeutic targeting of histaminergic systems.

6. Translational and Therapeutic Implications

Viewing histamine as an evolutionary alarm system has important implications for how immune-related psychiatric symptoms are interpreted and treated [36]. Rather than conceptualising histaminergic activity as intrinsically pathological, this framework emphasises the context in which alarm signalling is engaged and the mechanisms responsible for its resolution. Symptoms such as insomnia, restlessness, sensory hypersensitivity, or cognitive hypervigilance may reflect the persistence of an adaptive response beyond its appropriate temporal window [37].

This perspective may help explain the mixed clinical effects of antihistaminergic interventions in psychiatric and neuroimmune conditions [37]. Non-specific suppression of histamine signalling can reduce arousal and improve sleep, yet may also impair attention, learning, or motivation when used indiscriminately. Such outcomes are consistent with the idea that histamine plays a regulatory role rather than serving as a simple driver of pathology. Therapeutic benefit may therefore depend on selectively retuning alarm thresholds or facilitating termination of histaminergic activation, rather than globally blocking the system.

Receptor-specific approaches may offer greater precision [38,39]. Different histamine receptor subtypes contribute to distinct aspects of immune and neural signalling, and their spatial distribution suggests that targeted modulation could attenuate maladaptive arousal without compromising necessary alertness or immune readiness. Importantly, the timing of intervention is likely to be critical. Interventions that dampen histaminergic activity during periods of unwarranted alarm may restore balance, whereas suppression during genuine environmental challenge could be counterproductive.

The proposed framework also highlights the potential value of histamine-related markers as indicators of immune–brain coupling. Peripheral measures of histamine release or mast cell activation, combined with central indices of arousal or sleep disruption, may help identify individuals in whom alarm systems are persistently engaged [40]. Such stratification could inform personalised treatment strategies and improve the interpretability of heterogeneous psychiatric presentations.

Finally, this perspective has particular relevance for conditions characterised by prolonged immune activation, such as post-infectious syndromes [41]. In these contexts, histaminergic signalling may remain elevated even after the initiating threat has resolved, sustaining symptoms of hyperarousal and fatigue. Understanding histamine as a mediator of immune–brain coordination rather than a disease-specific factor may therefore guide more nuanced approaches to treatment and recovery. In the final section, we summarise the key elements of this framework and outline directions for future research (see also Figure 1 for a summary).

7. Conclusions

Histamine has traditionally been studied in fragmented domains, as a mediator of peripheral inflammation, a regulator of arousal and wakefulness, or a pharmacological target with undesirable side effects. In this Perspective, we propose an integrative framework in which histamine is understood as an evolutionarily conserved alarm system that coordinates immune activation with brain-state reconfiguration in response to environmental volatility.

By signalling disruption without encoding specificity, histamine enables rapid mobilisation of physiological and cognitive resources when prevailing assumptions about the environment may no longer be reliable. Peripherally, this alarm promotes immune readiness and tissue defence; centrally, it reshapes arousal, sensory gain, and learning dynamics to prioritise vigilance and adaptive updating. These functions are beneficial when engagement is transient, but become costly when the alarm state persists or is poorly calibrated.

Within this framework, psychiatric vulnerability emerges not from histamine activity per se, but from failures to appropriately engage and disengage this system. Chronic immune activation, sustained stress, or repeated inflammatory insults may prolong histaminergic signalling, contributing to hyperarousal, sleep disruption, maladaptive learning, and fatigue. Framing these features as consequences of dysregulated immune–brain coordination offers a coherent account of symptom overlap across neuropsychiatric and post-inflammatory conditions.

An evolutionary perspective on histamine shifts emphasis from static disease categories toward dynamic regulatory processes that govern adaptation to uncertainty. This view encourages more nuanced therapeutic strategies aimed at restoring balance within alarm systems rather than suppressing them indiscriminately, and highlights histamine as a key mediator at the interface of immunity, brain function, and mental health.