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Researchers at Oxford's Department of Psychiatry found that raised histamine levels facilitated communication within the brain's memory networks. Most strikingly, raising histamine forged stronger connections between the deep region where histamine cells originate and the brain's memory hub — the hippocampus — driving our ability to form new memories.
Histamine was among the first brain chemicals to be identified nearly a century ago — before dopamine and serotonin — but its role in human behaviour has remained poorly understood. This study is the first to map that role directly in the human brain.
Published in Nature Communications and funded by the National Institute for Health and Care Research (NIHR) Biomedical Research Centre: Oxford Health and the Medical Research Council, the randomised, double-blind, placebo-controlled study involved 58 healthy participants. Half took a tablet containing pitolisant, which helps cells release more histamine, while the other half took a placebo. Participants then completed memory and learning tasks while undergoing MRI scans, including brain scans taken during rest periods between tasks.
Scientists found that those with elevated levels of histamine were able to access memories in a more efficient way. Crucially, histamine made individuals less reactive to negative setbacks, stabilising how they learned in unfamiliar environments. During challenging tasks, increased histamine helped adapt the brain’s strategy: taking slightly more time to deliberate as tasks grew harder, which led to better overall performance.
Lead author Dr Michael Colwell, a postdoctoral researcher at the Department of Psychiatry, said:
“While histamine was the first of the major players found in the brain, before dopamine and serotonin, its function has remained comparatively unknown. This work shows for the first time how histamine shapes the brain processes that underpin human learning and memory. We found it does this by strengthening the brain's memory networks, by sustaining the neural activity that helps newly learned information stick, and by stabilising how we learn from negative experiences. These same processes go wrong in conditions like depression and dementia.”
Histamine is a chemical that is released as part of the immune response to allergens but the team at Oxford say the way it works in the brain is different, helping the brain flexibly adapt to new experiences and changing demands.
Previous animal studies had indicated histamine played a role in memory, but evidence in humans was sparse. Until recently, there was no safe way to selectively raise histamine levels in the human brain to test its role directly. The recent licensing of pitolisant, originally for treating narcolepsy, provided that opportunity for the first time. Co-author Professor Phil Cowen, Professor of Psychopharmacology at the University of Oxford, said:
"Psychiatry has spent decades focusing on dopamine and serotonin. This study suggests that histamine—best known for its role in allergies—is also an important regulator of human memory and cognition. It could be a promising target to help improve cognitive abilities in neuropsychiatric disorders.”
The human body is often economical, using the same chemical for very different purposes in different places. Although widely associated with allergic reactions, histamine in the body doesn't cross into the brain. Modern antihistamines used for hay fever (such as cetirizine, loratadine, and fexofenadine) are designed not to enter the brain and don't affect brain function. Older 'first-generation' antihistamines like diphenhydramine do enter the brain and are known to cause drowsiness and short-term memory effects, which is consistent with the team's findings about histamine's role in supporting alertness and learning.