Histamine Intolerance: Why the DAO Enzyme Story Is Incomplete, and the Real Reason Your Low Histamine Diet Stopped Working — The Receptor Layer Determines What Histamine Actually Does

The third element the standard story underweights is the receptor layer. Histamine produces its effects by binding to four distinct receptor subtypes, each with different tissue distributions and different downstream effects. H1 receptors are the classical allergic receptors. They mediate vasodilation, smooth muscle contraction in the airways, increased vascular permeability, itch, and many of the symptoms people associate with allergic reactions. H1 antihistamines (loratadine, cetirizine, fexofenadine, diphenhydramine, hydroxyzine) block these effects. H2 receptors are present in the stomach (where they stimulate acid secretion) and in immune cells. H2 antihistamines (famotidine, ranitidine, cimetidine) block gastric acid effects and modulate immune signaling. H3 receptors are primarily in the central nervous system, where they regulate the release of histamine and other neurotransmitters. They are involved in wakefulness, cognition, and feeding behavior. H4 receptors are present on immune cells and modulate immune cell chemotaxis and activation. They have only recently been characterized, and selective H4 blockers are still in development. The receptor layer matters because the same amount of histamine produces different effects depending on which receptors are most active in which tissues. Receptor density and sensitivity are not fixed. Chronic exposure to histamine can upre