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Research · Medication

Antihistamines

Trials found newer antihistamines relieved hay fever and hives more than placebo, less than nasal steroid sprays for nasal symptoms. They did not consistently help eczema, and cold relief faded after two days. Diphenhydramine helped sleep only modestly. Drowsiness was more common than on placebo, diphenhydramine impaired driving more than alcohol, and strong anticholinergics were linked to dementia.

Add to Bio HackChecked 2026-11-13
Status
Sold over the counter in the US. Levocetirizine is also a prescription drug, with labeled uses for allergic rhinitis and chronic idiopathic urticaria. Diphenhydramine is also sold over the counter as a nighttime sleep aid for occasional sleeplessness. FDA added a warning in 2025 about itching after stopping cetirizine or levocetirizine.
Also called
H1 antihistamines, H1 blockers, allergy pills, cetirizine, Zyrtec, levocetirizine, Xyzal, loratadine, Claritin, Alavert, fexofenadine, Allegra, diphenhydramine, Benadryl, ZzzQuil, second-generation antihistamines, non-drowsy antihistamines
Taken for
hay fever, allergic rhinitis, itchy eyes, hives, eczema itch, common cold, sleep, anaphylaxis, allergic reactions

Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on

Shown to help2

Reported risks7

What people take it for, and what was found

Shown to help2

Moderate

Hay fever and other allergic rhinitis

Shown to lower hay fever symptom scores more than placebo, but nasal steroid sprays relieved nasal symptoms more than oral antihistamines.

Compared with placebo [1][2]; nasal corticosteroid sprays [3]

The numbers and sources
Effect
In a perennial allergic rhinitis trial, levocetirizine 5 mg lowered the 4-symptom total score (0 to 12) by 1.22 points more than placebo (95% CI 0.76 to 1.69), with similar results at 2.5 and 10 mg [1]. A network meta-analysis found six of seven total nasal symptom estimates in seasonal rhinitis favored active treatment over placebo, but rated all comparisons between drugs very low certainty and found no reliable ranking [2]. Against oral antihistamines, nasal steroids gave more relief of total nasal symptoms (SMD -0.42), blockage (SMD -0.63) and sneezing, with no difference for eye symptoms [3].
Population
517 people aged 12 and older in one levocetirizine trial [1]; 34,831 participants in 61 reports [2]; randomized trials comparing nasal steroids with oral antihistamines [3].
Sources
[1], [2], [3]
Caveats
The network meta-analysis found the evidence mostly placebo-anchored and sparse [2]. The nasal steroid comparison dates from 1998 [3].
Moderate

Chronic hives

Shown to clear chronic hives completely more often than placebo, about 2.7 times as often with cetirizine 10 mg, in evidence drawn from few studies.

Compared with placebo [4][1]; other antihistamines [4]

The numbers and sources
Effect
Cetirizine 10 mg once daily led to complete suppression of urticaria more often than placebo (RR 2.72, 95% CI 1.51 to 4.91). Levocetirizine 5 mg beat placebo in the intermediate term but not the short term, and desloratadine results had very wide intervals. More people had complete suppression on cetirizine than on fexofenadine. Withdrawals for adverse events did not differ significantly [4]. In two 4-week label trials, levocetirizine 2.5, 5 and 10 mg lowered itch scores more than placebo, with fewer and smaller wheals [1].
Population
9,759 participants in 73 studies [4]; 423 adults aged 18 to 85 with chronic idiopathic urticaria [1].
Sources
[4], [1]
Caveats
Most comparisons rest on few studies or single-study estimates [4].

Mixed results3

Moderate

Higher doses for hives that do not respond

Mixed results: raising the dose of a non-sedating antihistamine improved itch in chronic hives but did not change response rates or the number of wheals.

Compared with standard doses and placebo [5]

The numbers and sources
Effect
Response rates and wheal counts did not differ between standard and higher doses. Higher doses significantly improved the itch score of the Urticaria Activity Score [5].
Population
15 studies of chronic spontaneous urticaria [5].
Sources
[5]
Caveats
Only five studies were of high quality, and heterogeneity was significant [5].
ModerateVery common

Common cold

Mixed results: antihistamines slightly eased overall cold symptoms on days one and two in adults, 45% against 38% on placebo, with no difference after that.

Compared with placebo [7]

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
On day one or two, 45% had a beneficial effect on overall severity with an antihistamine against 38% on placebo (OR 0.74, 95% CI 0.60 to 0.92). There was no difference at 3 to 4 days or 6 to 10 days. Sedating antihistamines slightly eased runny nose and sneezing on day three, an effect the authors called clinically non-significant [7].
Population
4,342 participants, 212 of them children, in 18 randomized trials of natural and induced colds [7].
Sources
[7]
Caveats
The review pooled sedating and non-sedating antihistamines [7].
Limited

Sleep (diphenhydramine)

Small trials found diphenhydramine gave modest sleep gains in mild insomnia, such as better sleep efficiency or fewer awakenings, with no change on overnight sleep recordings.

Compared with placebo [8][9]

The numbers and sources
Effect
In adults with mild insomnia, diphenhydramine 50 mg raised diary sleep efficiency more than placebo and showed a trend toward longer sleep in the first 14 days, with lower insomnia severity ratings. Polysomnography showed no difference in sleep continuity, and no rebound insomnia followed stopping [8]. In older adults, diphenhydramine 50 mg reduced only the number of awakenings (1.7 against 2.0 a night) compared with placebo [9]. The American Academy of Sleep Medicine suggested clinicians not use diphenhydramine for sleep onset or maintenance insomnia [10].
Population
184 adults, mean age 44, over 14 days [8]; older adults with insomnia, mean age 73.9, in a 14-night crossover trial [9]; guideline review of trials [10].
Sources
[8], [9], [10]
Caveats
Few small trials. Many sleep-aid products combine diphenhydramine with other drugs.

Not shown to help1

Moderate

Eczema itch, added to skin treatment

Not shown to consistently improve eczema when added to skin treatment, though fexofenadine 120 mg slightly reduced itch over one week in adults.

Compared with placebo [6]

The numbers and sources
Effect
In 795 children followed 18 months, cetirizine showed no difference from placebo in eczema symptoms and fewer adverse events (RR 0.68). In adults, fexofenadine 120 mg a day lowered itch on a 0 to 8 scale by 0.25 points (95% CI -0.43 to -0.07) over one week. Another comparison found no difference in itch on a 100-point scale [6].
Population
3,285 participants in 25 studies, 1,941 of them children [6].
Sources
[6]
Caveats
Studies were too varied to pool, and risk of bias was mostly unclear [6].

Claimed, not studied in people1

Untested

Anaphylaxis

Not studied in people. A Cochrane review found no randomized trial of H1 antihistamines for anaphylaxis, a use that rests on how they block histamine.

No study in people. This rests on how it acts in the body.

The numbers and sources
Effect
A Cochrane review searched for randomized and quasi-randomized trials of H1 antihistamines for anaphylaxis with or without shock and found none that met its criteria. The authors stated they could not draw conclusions for practice [11].
Population
No trials located [11].
Sources
[11]
Caveats
Antihistamines block histamine, one of several mediators of anaphylaxis. Without trials, any effect on outcomes such as survival is unknown [11].

Doses studied

The chronic hives review reports cetirizine 10 mg once daily and levocetirizine 5 to 20 mg a day [4]. The levocetirizine label trials used 2.5, 5 and 10 mg once in the evening [1]. The eczema trial used fexofenadine 120 mg a day [6], and the over-the-counter fexofenadine label lists one 180 mg tablet once a day from age 12 [12]. The sleep trials used diphenhydramine 50 mg at bedtime [8][9], the same amount as one dose of an over-the-counter diphenhydramine sleep aid [13]. The driving trial used single doses of fexofenadine 60 mg and diphenhydramine 50 mg [14].

Risks

Reported risks6

ModerateCommon

Drowsiness and fatigue

Shown in label trials to raise drowsiness on levocetirizine, 6% against 2% on placebo, and it was the most common reason for stopping.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
In placebo-controlled trials of 1 to 6 weeks, rates on levocetirizine 5 mg, 2.5 mg and placebo were somnolence 6%, 5% and 2%, fatigue 4%, 1% and 2%, and dry mouth 2%, 3% and 1%. Somnolence rose with dose and led to stopping in 0.5%. In 4 to 6 month trials, 2.3% stopped for somnolence, fatigue or weakness against under 1% on placebo [1].
Population
1,070 people on levocetirizine 5 mg, 421 on 2.5 mg and 912 on placebo, aged 12 and older [1].
Sources
[1]
Caveats
Rates differ between antihistamines, and no rates for cetirizine, loratadine or fexofenadine were sourced here.
LimitedHow often is not known

Impaired driving (diphenhydramine)

One simulator trial found a 50 mg dose of diphenhydramine impaired driving more than alcohol, while fexofenadine driving matched placebo. Feeling drowsy did not predict impairment.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Coherence in following a lead vehicle was worse after diphenhydramine than after alcohol or fexofenadine, and lane keeping was impaired after diphenhydramine and alcohol. Overall driving was poorest after diphenhydramine. Self-rated drowsiness did not predict loss of coherence [14].
Population
40 licensed drivers aged 25 to 44 with seasonal allergic rhinitis, in a 4-period crossover trial [14].
Sources
[14]
Caveats
One simulator study with single doses [14].
LimitedHow often is not known

Severe itching after stopping cetirizine or levocetirizine

FDA states severe itching has been reported within days of stopping cetirizine or levocetirizine after long-term use, in 209 cases worldwide. It called the reaction rare.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
FDA identified 209 cases worldwide reported from April 2017 to July 2023, 197 in the US, in people with no itching before treatment, most after more than 3 months of daily use. Some were serious, including reports of disability. FDA required a new warning on prescription labels and asked for one on over-the-counter labels [15]. The levocetirizine label states symptoms may improve on restarting or tapering the drug [1].
Population
Spontaneous reports to FDA and other databases [15].
Sources
[15], [1]
Caveats
Spontaneous reports cannot give a rate [15].
LimitedHow often is not known

Overdose of diphenhydramine

FDA warns that taking more diphenhydramine than the label directs can cause serious heart problems, seizures, coma or death, after teenagers were harmed in a social media challenge.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
FDA stated that taking more than the label directs can lead to serious heart problems, seizures, coma or death, and that it was aware of teenagers ending up in emergency rooms or dying after a challenge promoted in TikTok videos [16]. The over-the-counter sleep-aid label limits use to one dose in 24 hours and warns against combining it with any other diphenhydramine product [13].
Population
Reports reviewed by FDA [16].
Sources
[16], [13]
Caveats
No denominator.
LimitedHow often is not known

Urinary retention

The levocetirizine label reports urinary retention after marketing, and the diphenhydramine sleep-aid label asks people with prostate enlargement to consult a doctor first. Neither gives a rate.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The levocetirizine label reports urinary retention and names spinal cord lesions and prostate enlargement as predisposing factors [1]. The diphenhydramine sleep-aid label lists difficulty urinating from prostate enlargement, glaucoma and breathing problems such as emphysema as reasons to ask a doctor before use [13].
Population
Postmarketing reports and labeling statements [1][13].
Sources
[1], [13]
Caveats
No rate is given.
LimitedHow often is not known

Interactions with alcohol, sedatives, ritonavir and fruit juice

The labels warn that alcohol and other sedatives add to antihistamine drowsiness, ritonavir raised cetirizine levels by 42%, and fexofenadine's label says not to take it with fruit juice.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The levocetirizine label states alcohol and other central nervous system depressants may further reduce alertness, and that ritonavir raised cetirizine exposure by about 42% [1]. The fexofenadine label says not to take it with fruit juices or at the same time as aluminum or magnesium antacids [12]. The diphenhydramine sleep-aid label asks people taking sedatives or tranquilizers to consult a doctor and to avoid alcohol [13].
Population
Labeling statements and pharmacokinetic studies [1][12][13].
Sources
[1], [12], [13]
Caveats
No rate of harm is given.

Mixed results1

LimitedHow often is not known

Dementia and strong anticholinergic drugs

Mixed results: one cohort linked heavy use of strong anticholinergics, often first-generation antihistamines, to 1.54 times the dementia risk. Another study did not list antihistamines among linked classes.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
In older adults, the most commonly used strong anticholinergics were tricyclic antidepressants, first-generation antihistamines and bladder antimuscarinics. Against non-use, the highest cumulative use (over 1,095 standard daily doses) was associated with dementia (HR 1.54, 95% CI 1.21 to 1.96), with a dose-response trend [17]. A nested case-control study found significant associations for anticholinergic antidepressants, antiparkinson drugs, antipsychotics, bladder antimuscarinics and antiepileptics, and did not list antihistamines among them [18].
Population
3,434 adults aged 65 and older followed a mean 7.3 years [17]; 284,343 case patients and matched controls, mean age 82 [18].
Sources
[17], [18]
Caveats
Observational studies of anticholinergic drugs as a group. Neither abstract gives a separate estimate for diphenhydramine.

Checked, no increase found1

Moderate

Pregnancy

Not linked to major birth defects, miscarriage, prematurity or low birth weight after first-trimester use, in a meta-analysis of 37 studies.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
In cohort studies, major malformations were not more common after first-trimester H1 antihistamine exposure (OR 1.07, 95% CI 0.98 to 1.16), and case-control studies agreed (OR 1.05). Miscarriage (OR 1.00), prematurity (OR 0.96), stillbirth (OR 1.23, 95% CI 0.48 to 3.18) and low birth weight (OR 1.20) did not differ [19]. The levocetirizine label states human data are insufficient to identify a drug-associated risk [1].
Population
37 studies of first-trimester exposure [19].
Sources
[19], [1]
Caveats
The meta-analysis pooled H1 antihistamines as a class. Observational data [19].

Claims tested and not found

  1. That antihistamines treat eczema. Across 25 studies, add-on oral antihistamines did not consistently improve eczema compared with placebo [6].
  2. That antihistamines shorten a cold. After the first two days, cold symptoms did not differ from placebo [7].
  3. That fexofenadine impairs driving. In a simulator trial, driving on fexofenadine 60 mg was similar to placebo [14].

Sources

  1. U.S. Food and Drug Administration. XYZAL (levocetirizine dihydrochloride) tablets and oral solution, prescribing information. 2025. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1673f7ff-0c7c-4403-86cf-c05eb1475222
  2. Maya Viejo JD, Navarro I Ros FM, Trillo-Calvo E, et al. Oral Second-Generation H1-Antihistamine Regimens for Allergic Rhinitis: Systematic Review and Network Meta-Analysis of Effects and Estimability. Journal of Clinical Medicine. 2026. https://doi.org/10.3390/jcm15187169
  3. Weiner JM, Abramson MJ, Puy RM. Intranasal corticosteroids versus oral H1 receptor antagonists in allergic rhinitis: systematic review of randomised controlled trials. BMJ. 1998. https://doi.org/10.1136/bmj.317.7173.1624
  4. Sharma M, Bennett C, Cohen SN, et al. H1-antihistamines for chronic spontaneous urticaria. Cochrane Database of Systematic Reviews. 2014. https://doi.org/10.1002/14651858.CD006137.pub2
  5. Guillén-Aguinaga S, Jáuregui Presa I, Aguinaga-Ontoso E, et al. Updosing nonsedating antihistamines in patients with chronic spontaneous urticaria: a systematic review and meta-analysis. British Journal of Dermatology. 2016. https://doi.org/10.1111/bjd.14768
  6. Matterne U, Böhmer MM, Weisshaar E, et al. Oral H1 antihistamines as 'add-on' therapy to topical treatment for eczema. Cochrane Database of Systematic Reviews. 2019. https://doi.org/10.1002/14651858.CD012167.pub2
  7. De Sutter AI, Saraswat A, van Driel ML. Antihistamines for the common cold. Cochrane Database of Systematic Reviews. 2015. https://doi.org/10.1002/14651858.CD009345.pub2
  8. Morin CM, Koetter U, Bastien C, et al. Valerian-hops combination and diphenhydramine for treating insomnia: a randomized placebo-controlled clinical trial. Sleep. 2005. https://doi.org/10.1093/sleep/28.11.1465
  9. Glass JR, Sproule BA, Herrmann N, et al. Effects of 2-week treatment with temazepam and diphenhydramine in elderly insomniacs: a randomized, placebo-controlled trial. Journal of Clinical Psychopharmacology. 2008. https://doi.org/10.1097/jcp.0b013e31816a9e4f
  10. Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline. Journal of Clinical Sleep Medicine. 2017. https://doi.org/10.5664/jcsm.6470
  11. Sheikh A, ten Broek V, Brown SG, et al. H1-antihistamines for the treatment of anaphylaxis with and without shock. Cochrane Database of Systematic Reviews. 2007. https://doi.org/10.1002/14651858.CD006160.pub2
  12. U.S. Food and Drug Administration. ALLEGRA ALLERGY 24 HOUR (fexofenadine hydrochloride) tablets, drug facts label. 2026. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2de81a41-8488-7e39-e063-6294a90a394b
  13. U.S. Food and Drug Administration. ZZZQUIL NIGHTTIME SLEEP-AID (diphenhydramine hydrochloride) liquid, drug facts label. 2026. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1d608c94-1651-f318-e063-6294a90aa11e
  14. Weiler JM, Bloomfield JR, Woodworth GG, et al. Effects of fexofenadine, diphenhydramine, and alcohol on driving performance. A randomized, placebo-controlled trial in the Iowa driving simulator. Annals of Internal Medicine. 2000. https://doi.org/10.7326/0003-4819-132-5-200003070-00004
  15. U.S. Food and Drug Administration. FDA requires warning about rare but severe itching after stopping long-term use of oral allergy medicines cetirizine or levocetirizine (Zyrtec, Xyzal, and other trade names). Drug Safety Communication. 2025. https://www.fda.gov/drugs/drug-safety-communications/fda-requires-warning-about-rare-severe-itching-after-stopping-long-term-use-oral-allergy-medicines
  16. U.S. Food and Drug Administration. FDA warns about serious problems with high doses of the allergy medicine diphenhydramine (Benadryl). Drug Safety Communication. 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-serious-problems-high-doses-allergy-medicine-diphenhydramine-benadryl
  17. Gray SL, Anderson ML, Dublin S, et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Internal Medicine. 2015. https://doi.org/10.1001/jamainternmed.2014.7663
  18. Coupland CAC, Hill T, Dening T, et al. Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study. JAMA Internal Medicine. 2019. https://doi.org/10.1001/jamainternmed.2019.0677
  19. Etwel F, Faught LH, Rieder MJ, et al. The Risk of Adverse Pregnancy Outcome After First Trimester Exposure to H1 Antihistamines: A Systematic Review and Meta-Analysis. Drug Safety. 2017. https://doi.org/10.1007/s40264-016-0479-9

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