N-methylhistamine (NMH), also known as 1-methylhistamine, is a product of N-methylation of histamine in a reaction catalyzed by the HNMT enzyme.
NMH is considered a biologically inactive metabolite of histamine. NMH is excreted in the urine and can be measured to estimate the amounts of active histamine in the body. While NMH has some biological activity on its own, it is much weaker than histamine. NMH can bind to histamine receptors but has a lower affinity and efficacy than histamine for these receptors, meaning that it binds less strongly and activates them less effectively. Depending on the receptor subtype and the tissue context, NMH may act as a partial agonist or an antagonist for some histamine receptors. NMH may have some modulatory effects on histamine signaling, but it is unlikely to cause significant allergic or inflammatory reactions by itself. NMH may also serve as a feedback mechanism to regulate histamine levels and prevent excessive histamine release. Still, NMT, being a product in a reaction catalyzed by HNMT, may inhibit expression of HNMT in a negative feedback loop.
Urinary NMH can be measured in clinical settings when systemic mastocytosis is suspected. Systemic mastocytosis and anaphylaxis are typically associated with at least a two-fold increase in urinary NMH levels, which are also increased in patients taking monoamine oxidase inhibitors and in patients on histamine-rich diets.