Antihistamines linked to higher delirium risk in systematic review of observational studies

Antihistamines, among the most widely consumed medications in hospitals and long-term care facilities, may carry a previously underappreciated association with delirium, according to a new systematic review and meta-analysis published in Aging Clinical and Experimental Research. The analysis pooled data from observational studies in adults and found that exposure to H1 or H2 histamine receptor antagonists was associated with an increased risk of all-cause delirium, with a pooled odds ratio of 1.26 and a 95 percent confidence interval of 1.08 to 1.47. Because the evidence base consists entirely of observational studies, the authors emphasize that the findings demonstrate association rather than proven causation and should be interpreted with caution.

Delirium is a prevalent condition, particularly in intensive care units, postoperative settings, and long-term care facilities. H1 and H2 receptor antagonists are widely used in clinical practice, and their sedative and anticholinergic activities have long raised concerns about a possible link to delirium, yet the evidence has remained controversial. The new analysis was designed to quantify the association between antihistamine exposure and delirium across the adult population.

The researchers followed PRISMA guidelines and searched five online databases, including PubMed, Scopus, Embase, CINAHL, and Web of Science, from inception to July 2026. They included 24 observational studies, of which 22 contributed to the meta-analysis. Pooled odds ratios were calculated using random-effects models, and the risk of bias in the included studies was assessed with the Joanna Briggs Institute Critical Appraisal tools. The team also performed subgroup analyses, separating postoperative delirium from non-surgical delirium, to explore whether the association differed across clinical contexts.

The pooled results showed that antihistamine exposure was robustly associated with an increased risk of all-cause delirium. In the subgroup of non-surgical delirium, the association remained significant, with an odds ratio of 1.24 and a 95 percent confidence interval of 1.05 to 1.46, though the heterogeneity between studies was high, with an I-squared value of 89.4 percent. The overall analysis likewise showed substantial heterogeneity, with an I-squared of 85.2 percent, indicating that the included studies varied considerably in their populations, settings, and exposure definitions.

The subgroup analyses by drug class revealed a differentiated pattern. H2 receptor antagonists showed a significant association with both all-cause delirium and non-surgical delirium, while H1 receptor antagonists showed a significant association with non-surgical delirium. Notably, the authors describe the H2 receptor antagonist associations as fragile, meaning that the pooled estimates may be sensitive to the inclusion or exclusion of individual studies, a caution that underscores the limitations inherent in pooling heterogeneous observational data.

The high heterogeneity across studies is a central limitation of the analysis. Observational designs cannot exclude confounding by indication, since patients who receive antihistamines may already be more susceptible to delirium because of their underlying illness, surgical burden, or other medications. Sedative and anticholinergic properties of these drugs provide a plausible biological mechanism, but the meta-analysis cannot establish that antihistamine exposure itself caused the delirium events observed in the included studies.

The authors conclude that H1 receptor antagonists showed a significant association with non-surgical delirium, and that H2 receptor antagonists showed significant associations with both all-cause delirium and non-surgical delirium, alongside an overall antihistamine association with all-cause and non-surgical delirium. They stress that, due to the inherent limitations of observational studies, the findings should be interpreted with caution rather than as definitive evidence of harm.

Subject of Research: The association between antihistamine exposure and delirium risk in adults

Article Title: Antihistamines’ role in Delirium: A systematic review and meta-analysis of observational studies

Article References: Farhadi, K., Rajabi, E., Mohammadi, P., Kakoienejad, M. M., Seraj, A., Noori, A., Pourkhamseh, A. K., Pourfakhr, P., Neishaboury, M., Najafi, A., Moharari, R. S., & Etezadi, F. (2026). Antihistamines’ role in Delirium: A systematic review and meta-analysis of observational studies. Aging Clinical and Experimental Research. https://doi.org/10.1007/s40520-026-03522-0

Image Credits: AI Generated

DOI: 10.1007/s40520-026-03522-0

Keywords: delirium, antihistamines, H1 receptor antagonists, H2 receptor antagonists, systematic review, meta-analysis, observational studies, postoperative delirium, odds ratio, older adults, hospital care, drug safety