Despite a growing body of science purporting migraine is a complex multifactorial brain network disease, therapeutics have increasingly focused on headache pain and targeting a very narrow set of receptors i.e. 5HT_1B/1D/F or CGRP.  

A literature review was conducted. Additionally, “state of the art” functional receptor activity of DHE was screened against 170 G-protein coupled receptors.

DHE (10 µM) exhibited agonist activity at the following receptors: Adrenoceptor α2B, CXCR7, Dopamine D2, D5, 5HT_{1A/1B/2A/2C/5A}, binding with high affinity to the 5HT_1B, Adrenoreceptor α2B, Dopamine D2receptors. DHE also exhibited antagonist activity at the following receptors: Adrenoceptor a1B, a2A, a2C, CALCR-RAMP2, Dopamine D1, D3, D4, D5 and 5HT_1F. Further work showed DHE did not bind to 5HT₃ and _4E receptors at concentrations up to 300 nM. Comparative receptor binding of migraine specific therapies is presented in tabular format. A model was created to show where in migraine progression each acute migraine specific therapeutic acts to address migraine symptoms.

DHE interacts with several different important receptor subtypes, unlike other migraine therapeutics, and therefore exerts a wider influence over the pathophysiology of the migraine cycle (premonitory thirst, aura, allodynia, hypersensitivity, withdrawal, ictal pain, vasoconstriction, central sensitization, postdrome and interictal period). Moreover, the slow dissociation of DHE from target receptors is thought to sustain its anti-migraine effects, extending duration of benefit, reducing headache recurrence rates and medication overuse headaches. Achieving dose-to-dose consistency and optimal plasma concentrations of DHE has been demonstrated to maximize therapeutic gain while safely addressing acute migraine. Advances in non-injected, non-oral delivery systems for DHE holds promise to achieve these goals.