The effect of prescription and over-the-counter medications on core temperature in adults during heat stress: a systematic review and meta-analysis.

Background: Heat stress impacts are an escalating global health concern. Public health bodies such as the World Health Organization (WHO) warn that certain medications impair thermoregulation, with limited supporting evidence. Our aim was to investigate whether medications listed by the WHO increase core temperature responses during heat stress. Methods: For this systematic review and meta-analysis, MEDLINE, PubMed, Scopus, CINAHL, Web of Science, and EMBASE were searched up to Jan.30, 2024. Randomised studies exposing humans to exertional and/or passive heat stress that investigated a drug identified by WHO compared to no drug/placebo were eligible. The primary outcome was core temperature (e.g., rectal, oesophageal, aural, tympanic). We assessed risk of bias (Cochrane's Risk of Bias 2) and certainty of evidence (GRADE). The study was pre-registered on PROSPERO (CRD42020170684). Findings: Thirty-five studies were included enrolling 353 individuals (16 women; 4.5%). Twenty-seven unique medications were tested. The average age of participants across studies was <30 years, and only one study included a clinical population. Under heat stress, there was moderate quality evidence that drugs with high anticholinergic properties increased core temperature at air temperatures ≥30°C (+0.42°C; 95% CI 0.04, 0.79°C; p = 0.03) alongside reduced sweating, although evidence is limited to the drug atropine. Similarly, non-selective beta-blockers (+0.11°C; 95% CI 0.02, 0.19°C; p = 0.02), adrenaline (+0.41°C; 95% CI 0.21, 0.61°C) and anti-Parkinson's agents (+0.13°C; 95% CI 0.07, 0.19°C; p = 0.02) elevated core temperature. Antidepressants, diuretics, or drugs with weak anticholinergic effects did not alter core temperature responses. Interpretation: Current evidence supports strong anticholinergics, non-selective beta-blockers, adrenaline, and anti-Parkinson's agents impairing thermoregulation during heat stress. No evidence indicated thermoregulation is impacted by other WHO-listed medications. Evidence is predominantly limited to healthy young men, with short heat stress exposures. Studies over longer durations, in women, older adults and those with chronic diseases are required to better inform the pharmaceutical management of patients during hot weather. Funding: This study was supported by a National Health and Medical Research Council (NHMRC) Investigator Grant (2021/GNT2009507; Holder: O. Jay).