The Effect of Oral Antihistamines on the Sweating Response During Heat Stress in Adults

To the Editor,

The World Allergy Organization confirms the prevalence of allergic rhinitis (AR) has increased worldwide due to climate change—inflicting 1 in 5 people globally [1]. Global warming and elevations in atmospheric carbon dioxide have caused an earlier onset, prolonged duration, increased intensity, and have amplified allergenicity during the pollen season [1].

Public health guidance heeds certain medications during hot weather, informing general practitioners to be aware of the potential side effects and adjust dosage as needed [2]. Of particular concern are drugs with anticholinergic effects, which may blunt the sweating response. These medications, which include antihistamines, continue to be identified as a risk factor for heat‐related illness [3]. A recent systematic review concluded that limited evidence (n = 1) exists to confirm or refute whether antihistamines impair thermoregulation during heat stress [4]. The only evidence examined fexofenadine, which, unlike other antihistamines, does not bind to M3 muscarinic receptors [5] – the primary receptor stimulating sweat secretion from eccrine sweat glands. Determining if other over‐the‐counter antihistamines, an accessible and common treatment for AR, impair sweating is important as pollen season coincides with the hottest period of the year.

Using a randomized double‐blind crossover design, we investigated whether oral antihistamines across generations and different muscarinic affinity [5] impair thermoregulatory sweating in adults during heat stress. Following approval from Health Canada (AH‐PHS‐2023) and Thunder Bay Regional Health Sciences Centre Research Ethics Board (#100241), and ClinicalTrials.gov registration (NCT06217367), healthy adults aged 18–49 years were recruited from Thunder Bay, Ontario, Canada, between January and June 2024, with follow‐up completed July 2024. The study follows CONSORT reporting guidelines.

With ≥ 48 h between trials and the order determined a priori, participants consumed recommended doses of either (i) diphenhydramine (50 mg, first generation, high muscarinic affinity); (ii) loratadine (10 mg, second generation, low muscarinic affinity); (iii) desloratadine (5 mg, third generation, high muscarinic affinity); or (iv) a placebo (sugar) pill before resting for ~2 h at 25°C/50%RH. Following this, participants were instrumented and passively heated by perfusing 50°C water through a tube‐lined garment until mean body temperature (T _b ) increased 1.5°C above baseline. T _b was estimated in real‐time as a weighted average of esophageal (80%) and mean skin temperature (4‐site weighted average, 20%) measured using a thermistor probe and t‐type thermocouple wires, respectively. Primary outcomes measured at baseline and after every 0.25°C rise in T _b include forearm local sweat rate, heart rate, skin blood flow, and brachial blood pressure, while whole‐body sweat rate (in g/h) was calculated as the change in nude body mass divided by heating time. Data S1 provides detailed methods and statistical approach.

Of 26 participants recruited, only 10 were eligible (5 females, 23 ± 2 y, 73.6 ± 10.8 kg, no known/diagnosed allergies) and completed all 4 conditions after providing written and verbal consent. Heating duration was not different between conditions (Table 1). No significant differences were observed for sweating onset, thermosensitivity, and whole‐body sweat rate (Table 1). No main effect of drug was observed for forearm sweat rate, heart rate, skin blood flow, and mean blood pressure (Figure 1). Data S2 contains all individual data.

TABLE 1.

Heating time and sweating responses to passive heat stress and drug specific treatment effects relative to placebo (n = 10).

Outcome	Mean (standard deviation)				DPH–PLA		LOR–PLA		DES–PLA
	PLA	DPH	LOR	DES	Diff (95% CI)	p	Diff (95% CI)	p	Diff (95% CI)	p
Heating time (min)	81.8 (19.4)	80.1 (17.2)	82.7 (10.2)	87.7 (20.6)	−1.7 (−13.9 to 10.5)	0.79	0.9 (−13.3 to 15.1)	0.90	−5.9 (−3.6 to 15.4)	0.25
Sweating onset a (ΔT b , °C)	0.85 (0.28)	0.73 (0.34)	0.81 (0.18)	0.74 (0.21)	−0.12 (−0.29 to 0.07)	0.22	−0.04 (−0.23 to 0.14)	0.65	−0.11 (−0.30 to 0.07)	0.26
Sweating thermosensitivity b (mg/cm2/min/°C)	1.76 (1.05)	1.81 (1.20)	1.65 (0.80)	1.58 (0.92)	0.05 (−0.44 to 0.53)	0.86	−0.12 (−0.55 to 0.32)	0.62	−0.19 (−0.67 to 0.30)	0.47
Whole‐body sweat rate (g/h)	799 (489)	726 (454)	736 (427)	824 (445)	−73 (−172 to 26)	0.18	−63 (−166 to 39)	0.26	25 (−120 to 170)	0.74

Abbreviations: DES, desloratadine; DPH, diphenhydramine; LOR, loratadine; PLA, placebo.

^a Sweating onset was defined as the change in mean body temperature from baseline corresponding to the upward rise in local sweat rate determined by segmented linear regression.

^b Sweating thermosensitivity was defined as the slope of the relationship between per minute averages of forearm local sweat rate following the onset of sweating against mean body temperature extracted from segmented linear regression analysis.

FIGURE 1.

Mean responses (with standard error, n = 10) plotted against the change in body temperature (T_body) during passive heat stress following oral consumption of placebo (PLA), diphenhydramine (DPH), loratadine (LOR), and desloratadine (DES). From top to bottom: Local sweat rate (LSR), heart rate in beats per minute (BPM), skin blood flow (SkBF, expressed as a percentage of maximum skin blood flow observed during the trial specific 44°C localized thermal clamp), and mean arterial pressure (MAP, 1/3 systolic + 2/3 diastolic). The main effects of each antihistamine relative to placebo were assessed using a two‐way repeated measures analysis of variance with the repeated measures of mean body temperature (7 levels) and drug (two levels).

Neither antihistamine dose altered the sweating response to heat stress compared to placebo, suggesting the absence of, or insufficient, binding to M3 muscarinic receptors. These findings extend the recent systematic review [4] and corroborate the absence of sweating impairments during exercise following oral diphenhydramine consumption [6] supporting their safe use within the manufacturers recommended dose prior to heat stress.

Limitations include healthy adults and a small sample size. Future work should evaluate antihistamine use during heat stress in individuals diagnosed with an allergy and/or experiencing allergic reactions, other administration means (e.g., topical), higher doses, and/or vulnerable populations who may have attenuated sweating responses (e.g., elderly, comorbid).

Author Contributions

Nicholas Ravanelli had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Douglas Newhouse and Nicholas Ravanelli. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Douglas Newhouse and Nicholas Ravanelli. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Douglas Newhouse and Nicholas Ravanelli. Obtained funding: Nicholas Ravanelli. Administrative, technical, or material support: Nicholas Ravanelli. Study supervision: All authors.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Data S1.

Data S2.

Data Availability Statement

The data that supports the findings of this study are available in the Supporting Information of this article.