Diphenhydramine (Benadryl) for Nausea
Diphenhydramine is not recommended as a primary antiemetic for nausea and should not be used as a single-agent treatment. 1
Guideline-Based Recommendations
The American Society of Clinical Oncology explicitly removed diphenhydramine from its antiemetic guidelines in 2017, stating that the rationale for its inclusion no longer exists. 1 The drug was historically incorporated into antiemetic regimens primarily to prevent extrapyramidal side effects (akathisia, dystonia) from high-dose metoclopramide, not for its direct antiemetic properties. 1 With modern antiemetic regimens using 5-HT3 receptor antagonists and NK1 receptor antagonists instead of high-dose metoclopramide, diphenhydramine's role has been eliminated from evidence-based antiemetic protocols. 1
Limited Evidence for Antiemetic Efficacy
Research Findings Show Minimal Benefit
A 1991 randomized controlled trial found that diphenhydramine provided no antiemetic benefit when added to metoclopramide for cisplatin-induced nausea, with patients experiencing more sedation and limited activity without protection from nausea or vomiting. 2
In a 2020 patient survey of chronic gastrointestinal nausea treatments, diphenhydramine scored statistically below average in effectiveness (below the mean score of 1.73 out of 5), performing worse than marijuana, ondansetron, and promethazine. 3
Context Where It May Have Adjunctive Role
Small pilot studies suggest diphenhydramine may have some utility when combined with other agents in topical gel formulations (ABH gel with lorazepam and haloperidol) for breakthrough chemotherapy-induced nausea, though this represents combination therapy rather than diphenhydramine alone. 4
One hospice study showed a cocktail of metoclopramide, diphenhydramine, and dexamethasone provided symptom relief in 90% of patients, but the contribution of diphenhydramine specifically cannot be isolated from the other active antiemetics. 5
Significant Safety Concerns
Anticholinergic Adverse Effects
Diphenhydramine causes epigastric discomfort, dry mouth, constipation, urinary retention, blurred vision, and delirium—anticholinergic effects that may paradoxically worsen gastrointestinal symptoms. 6, 7
The American Geriatrics Society warns that diphenhydramine increases delirium risk 1.7-fold in older adults and should be avoided in this population. 6
High-Risk Populations
Use extreme caution or avoid entirely in patients with: glaucoma, benign prostatic hypertrophy, urinary retention, dementia, cognitive impairment, ischemic heart disease, uncontrolled hypertension, and COPD. 6
Paradoxical reactions (increased agitation, rage) can occur unpredictably, particularly in children and adolescents. 6
Preferred Alternatives
For nausea treatment, use evidence-based antiemetics instead:
Ondansetron is recommended as first-line therapy for most emergency department patients with nausea/vomiting due to superior safety profile (no sedation, no akathisia). 8
Promethazine and prochlorperazine are more effective antiemetics than diphenhydramine, though they carry risks of sedation and akathisia respectively. 8, 3
5-HT3 receptor antagonists, NK1 receptor antagonists, dexamethasone, and olanzapine are guideline-recommended for chemotherapy-induced nausea. 1
Clinical Bottom Line
Diphenhydramine's primary legitimate indication is for treating extrapyramidal symptoms (dystonia, akathisia) caused by antidopaminergic medications, not for nausea itself. 6, 9, 8 When akathisia develops from prochlorperazine or metoclopramide use, intravenous diphenhydramine 25-50 mg can treat this adverse effect. 8 However, this represents treatment of a medication side effect, not treatment of the underlying nausea.
If a patient asks for Benadryl for nausea, redirect to appropriate antiemetics (ondansetron, promethazine, or prochlorperazine) that have established efficacy and guideline support. 1, 8, 3