<p>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 <sup class="text-reference-group"><a class="reference-popover-link" data-content="StatPearls [Internet]: Diphenhydramine" href="#reference-L5263">9</a>,<a class="reference-popover-link" data-content="Electronic Medicines Compendium: Histergan (diphenhydramine hydrochloride) Tablets Patient Information" href="#reference-L5266">10</a>,<a class="reference-popover-link" data-content="Electronic Medicines Compendium: Histergan (diphenhydramine hydrochloride) Cream Monograph" href="#reference-L5269">11</a>,<a class="reference-popover-link" data-content="DIPHENHYDRAMINE- diphenhydramine hcl tablet, coated DailyMed FDA Label" href="#reference-F3379">17</a></sup>. However, it also has antiemetic, antitussive, hypnotic, and antiparkinson properties <sup class="text-reference-group"><a class="reference-popover-link" data-content="Electronic Medicines Compendium: Histergan (diphenhydramine hydrochloride) Cream Monograph" href="#reference-L5269">11</a>,<a class="reference-popover-link" data-content="Diphenhydramine Hydrochloride Injection, USP FDA Label" href="#reference-F3352">16</a></sup>. 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 <sup class="text-reference-group"><a class="reference-popover-link" data-content="StatPearls [Internet]: Diphenhydramine" href="#reference-L5263">9</a>,<a class="reference-popover-link" data-content="Electronic Medicines Compendium: Histergan (diphenhydramine hydrochloride) Tablets Patient Information" href="#reference-L5266">10</a>,<a class="reference-popover-link" data-content="Electronic Medicines Compendium: Histergan (diphenhydramine hydrochloride) Cream Monograph" href="#reference-L5269">11</a>,<a class="reference-popover-link" data-content="DIPHENHYDRAMINE- diphenhydramine hcl tablet, coated DailyMed FDA Label" href="#reference-F3379">17</a>,<a class="reference-popover-link" data-content="Flake ZA, Scalley RD, Bailey AG: Practical selection of antiemetics. Am Fam Physician. 2004 Mar 1;69(5):1169-74. (PubMed ID 15023018)" href="#reference-A174541">5</a></sup>. 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 <sup class="text-reference-group"><a class="reference-popover-link" data-content="StatPearls [Internet]: Diphenhydramine" href="#reference-L5263">9</a>,<a class="reference-popover-link" data-content="Electronic Medicines Compendium: Boots Sleepeaze (diphenhydramine hydrochloride) 50mg Tablets Monograph" href="#reference-L5281">12</a>,<a class="reference-popover-link" data-content="Electronic Medicines Compendium: Nytol One-A-Night (diphenhydramine hydrochloride) Monograph" href="#reference-L5287">13</a></sup>. </p><p>Diphenhydramine is also used in combination with <a href="https://go.drugbank.com/drugs/DB14132">8-chlorotheophylline</a> as the anti-nausea drug <a href="https://go.drugbank.com/drugs/DB00985">Dimenhydrinate</a> where it is utilized primarily for its antagonism of H1 histamine receptors within the vestibular system <sup class="text-reference-group"><a class="reference-popover-link" data-content="Jaju BP, Wang SC: Effects of diphenhydramine and dimenhydrinate on vestibular neuronal activity of cat: a search for the locus of their antimotion sickness action. J Pharmacol Exp Ther. 1971 Mar;176(3):718-24. (PubMed ID 4329456)" href="#reference-A1540">4</a></sup>.</p><p>Diphenhydramine has also been shown to be implicated in a number of neurotransmitter systems that affect behaviour including dopamine, norepinephrine, serotonin, acetylcholine, and opioid <sup class="text-reference-group"><a class="reference-popover-link" data-content="Halpert AG, Olmstead MC, Beninger RJ: Mechanisms and abuse liability of the anti-histamine dimenhydrinate. Neurosci Biobehav Rev. 2002 Jan;26(1):61-7. (PubMed ID 11835984)" href="#reference-A1539">3</a></sup>. As a result, diphenhydramine is being investigated for its anxiolytic and anti-depressant properties.</p>