Brain histaminergic system: An emerging target for the treatment of feeding and eating-related disorders

Feeding is an intrinsic and fundamental behavior regulated by complex neurobiological networks that integrate peripheral metabolic signals with neurotransmitter systems within key brain regions. Histamine, a biogenic amine acting as a neuromodulator in the central nervous system, plays a crucial role in the regulation of food intake and energy homeostasis. Within the hypothalamus, histaminergic neurons influence appetite-related circuits, primarily through H₁R and H₃R. Central administration of histamine suppresses food consumption, an effect largely mediated via H₁R. The blockade of H₁R has been associated with increased appetite and weight gain, as observed with certain antihistaminic and antipsychotic drugs. Conversely, H₃R antagonists, which enhance histaminergic tone by preventing autoinhibition, exhibit anorexigenic properties. Histamine also modulates peripheral mechanisms such as gluconeogenesis and ketone body production. Clinically, pharmacological modulation of histaminergic receptors has gained interest as a potential therapeutic approach for treating obesity and related metabolic disorders. Promising results are emerging from clinical trials evaluating the efficacy of betahistine, a drug with a dual pharmacological profile as a weak H₁R agonist and potent H₃R antagonist, in restoring histaminergic tone and counteracting weight gain and metabolic side effects induced by antipsychotic therapies. Reduced H₁R binding in certain brain areas has been observed in patients with anorexia nervosa. In this review, we surveyed the role of brain histamine in the control of eating behavior and energy expenditure. We also described the implications of histamine release in the gut-brain axis and discussed available clinical data regarding the efficacy of histaminergic compounds in eating-related disorders.