Overview

Diphenhydramine - perhaps known most commonly as its brand name formulation Benadryl - is a first-generation H1 receptor antihistamine that is used extensively for the treatment of seasonal allergies, insect bites and stings, and rashes . However, it also has antiemetic, antitussive, hypnotic, and antiparkinson properties . As histamine receptors exist both peripherally and in the central nervous system, diphenhydramine has been shown to cause sedation due to its competitive antagonism of histamine H1 receptors within the central nervous system . While its use in allergy therapy can sometimes fall out of favor due to its sedative effect, diphenhydramine has been repurposed for use within many non-prescription over-the-counter sleep aids and cough-and-cold medications that have been marketed for "night time" use . Diphenhydramine is also used in combination with 8-chlorotheophylline as the anti-nausea drug Dimenhydrinate where it is utilized primarily for its antagonism of H1 histamine receptors within the vestibular system . Diphenhydramine has also been shown to be implicated in a number of neurotransmitter systems that affect behaviour including dopamine, norepinephrine, serotonin, acetylcholine, and opioid . As a result, diphenhydramine is being investigated for its anxiolytic and anti-depressant properties.

Indication

Diphenhydramine is a first-generation histamine H1 receptor antagonist (H1 antihistamine) that is widely available as a non-prescription, over-the-counter (OTC) medication. As an OTC medication, diphenhydramine is typically formulated as tablets and creams indicated for use in treating sneezing, runny nose, itchy/watery eyes, itching of nose or throat, insomnia, pruritis, urticaria, insect bites/stings, allergic rashes, and nausea . Additionally, when the use of oral diphenhydramine is impractical, there are also prescription-only formulations such as diphenhydramine injection products that are effective in adults and pediatric patients (other than premature infants and neonates) for: i) the amelioration of allergic reactions to blood or plasma, in anaphylaxis as an adjunct to epinephrine and other standard measures after acute allergic reaction symptoms have been controlled, and for other uncomplicated allergic conditions of the immediate type when oral therapy is impossible or contraindicated ; ii) the active treatment of motion sickness ; and iii) use in parkinsonism when oral therapy is impossible or contraindicated, as follows: parkinsonism in the elderly who are unable to tolerate more potent agents; mild cases of parkinsonism in other age groups, and in other cases of parkinsonism in combination with centrally acting anticholinergic agents .

Associated Conditions

Allergic Reaction
Allergic Rhinitis (AR)
Allergic cough
Allergy to Tree Pollen
Anaphylaxis
Angioedema
Common Cold
Conjunctival irritation
Cough
Cough Variant Asthma
Cough caused by Common Cold
Eye allergy
Fever
Insect Bites
Insect Stings
Insomnia
Irritative cough
Itching of the nose
Itching of the throat
Motion Sickness
Nasal Congestion
Oral Mucositis
Pain
Parkinsonian Syndromes
Productive cough
Pruritus
Rash
Rhinorrhoea
Sinus Congestion
Sinus headache
Skin Irritation
Sneezing
Sunburn
Symptoms of Acute Bronchitis Accompanied by Coughing
Upper respiratory tract hypersensitivity reaction, site unspecified
Urticaria
Cold or flu syndrome
Dermatographism
Dry cough
Watery itchy eyes

Research Report

Published: Jul 28, 2025

A Comprehensive Monograph on Diphenhydramine (DB01075): Pharmacology, Clinical Utility, and Safety Profile

Executive Summary

Diphenhydramine is a first-generation ethanolamine-derivative antihistamine that, since its initial approval in 1946 [1], has become one of the most widely available and recognized over-the-counter (OTC) medications worldwide.[2] While primarily known for its role in treating acute allergic reactions, its diverse pharmacological profile lends it to a broad spectrum of uses, including as an antiemetic for motion sickness, an antitussive in cold preparations, and a hypnotic agent for short-term insomnia.[2]

The drug's primary mechanism of action is potent inverse agonism at the histamine H1 receptor. However, its clinical effects and extensive side-effect profile are profoundly influenced by its ability to readily cross the blood-brain barrier and its significant antagonism of muscarinic acetylcholine receptors.[2] This dual central and peripheral activity, combined with actions on other neurotransmitter systems, is responsible for both its therapeutic versatility and its hallmark sedative and anticholinergic adverse effects.

A central theme of this report is the profound dichotomy between Diphenhydramine's ubiquitous OTC availability and the growing body of evidence and clinical guidelines that caution against its use, particularly in vulnerable populations such as the elderly and young children.[3] Its inclusion in the American Geriatrics Society Beers Criteria as a potentially inappropriate medication for older adults underscores a significant risk profile—including cognitive impairment, delirium, and falls—that is often underappreciated by consumers and even some clinicians.[9]

Continue reading the full research report

Clinical Trials

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Title	Posted	Study ID	Phase	Status	Sponsor
Tailoring Treatment for B Cell Non-hodgkin's Lymphoma Based on PET Scan Results Mid Treatment	2006/05/11	NCT00324467	Phase 2	UNKNOWN	British Columbia Cancer Agency
A Study to Evaluate the Efficacy and Safety of Rituximab in Subjects With International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 Class III or IV Lupus Nephritis	2006/01/26	NCT00282347	Phase 3	Completed	Genentech, Inc.
Effect of Benadryl Sedation During ERCP or EUS	2005/10/17	NCT00240123	Phase 1	Withdrawn	University of Rochester
A Phase 1-2 Trial of Cetuximab in Combination With Oxaliplatin, Capecitabine, and Radiation Therapy Followed by Surgery for Locally-advanced Rectal Cancer	2005/09/27	NCT00226941	Phase 1	Terminated	George Albert Fisher
Treatment of Orthostatic Hypotension in Autonomic Failure	2005/09/22	NCT00223691	Phase 1	Completed	Vanderbilt University
Phase 2 Trial of Prophylactic Rituximab Therapy for Prevention of CGVHD	2005/09/16	NCT00186628	Phase 2	Completed	Stanford University
A Study to Evaluate the Safety of Rituximab Retreatment in Subjects With Systemic Lupus Erythematosus	2005/08/30	NCT00137969	Phase 2	Completed	Genentech, Inc.
Post Burn Pruritus Study in Patients Undergoing Wound Healing	2005/08/29	NCT00137202	Not Applicable	Completed	United States Army Institute of Surgical Research
Combination Immunosuppressive Therapy to Prevent Kidney Transplant Rejection in Adults	2004/03/02	NCT00078559	Phase 1	Completed	University of Wisconsin, Madison
Lymphocyte Depletion and Stem Cell Transplantation to Treat Severe Systemic Lupus Erythematosus	2004/02/03	NCT00076752	Phase 2	Completed	National Cancer Institute (NCI)

FDA Drug Approvals

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EMA Drug Approvals

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HSA Drug Approvals

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NMPA Drug Approvals

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PPB Drug Approvals

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TGA Drug Approvals

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Health Canada Drug Approvals

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Approved Product	Company	DIN	Dosage Form	Strength	Market Date
SLEEP AID EXTRA STRENGTH	Apotex Inc	02297728	Capsule - Oral	50 MG	6/5/2017
SLEEP EZE D CAPLET 25MG	whitehall-robins inc.	01933434	Tablet - Oral	25 MG / TAB	12/31/1993
ALLERGY TABLETS EXTRA STRENGTH	tanta pharmaceuticals inc	02230398	Tablet - Oral	50 MG	3/23/1997
SINUTAB PE SINUS AND ALLERGY	mcneil consumer healthcare division of johnson & johnson inc	02274477	Tablet - Oral	12.5 MG	N/A
SINUTAB DAYTIME/NIGHTIME EXTRA STRENGTH CAPLETS (COMBO PACK)	mcneil consumer healthcare division of johnson & johnson inc	02237707	Tablet - Oral	25 MG	N/A
SLEEP EZE D EXTRA STRENGTH CAPLET 50MG	whitehall-robins inc.	01933450	Tablet - Oral	50 MG / TAB	12/31/1993
EXTRA STRENGTH ALLERGY FORMULA LIQUID CAPSULES	vita health products inc	02321270	Capsule - Oral	50 MG	11/5/2009
NIGHTTIME SLEEP-AID	teva canada limited	02404869	Liquid - Oral	50 MG / 30 ML	2/12/2015
NIGHTTIME PAIN RELIEVER	marcan pharmaceuticals inc	02425866	Capsule - Oral	25 MG	N/A
JACK & JILL BEDTIME COUGH & COLD	the buckley's company	02412349	Syrup - Oral	6.25 MG / 5 ML	8/5/2014

CIMA AEMPS Drug Approvals

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Philippines FDA Drug Approvals

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Saudi SFDA Drug Approvals

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Malaysia NPRA Drug Approvals

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UK EMC Drug Information

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