Histamine shapes the neurocomputational dynamics of human learning

Abstract Histamine was the first canonical monoamine identified in the mammalian brain, yet arguably remains the least understood in its mechanistic contributions to human behaviour. Using a first-in-class causal probe (H 3 R inverse agonist pitolisant), we show how elevating histamine shapes offline and online temporal–hippocampal dynamics — sustaining episodic learning-related activity and polarising retrieval computations. Beyond this, histamine adaptively shifts neurocomputational strategy under high working memory load, while stabilising value updates during aversive reinforcement learning. These findings uncover a mechanistically grounded influence of this underexplored system on human neurocomputation, supporting its therapeutic potential in psychiatry.