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The origins of the major classes of current anti-emetics are examined. Serendipity is a recurrent theme in discovery of their anti-emetic properties and repurposing from one indication to another is a continuing trend. Notably, the discoveries have occurred against a background of company mergers and changing anti-emetic requirements. Major drug classes include: (i)  Muscarinic receptor antagonists –originated from historical accounts of plant extracts containing atropine and hyoscine with development stimulated by the need to prevent sea-sickness among soldiers during beach landings; (ii)  Histamine receptor antagonists –searching for replacements for the anti-malaria drug quinine, in short supply because of wartime shipping blockade, facilitated the discovery of histamine (H 1 ) antagonists (e.g., dimenhydrinate), followed by serendipitous discovery of anti-emetic activity against motion sickness in a patient undergoing treatment for urticaria; (iii)  Phenothiazines and dopamine receptor antagonists –investigations of their pharmacology as “sedatives” (e.g., chlorpromazine) implicated dopamine receptors in emesis, leading to development of selective dopamine (D 2 ) receptor antagonists (e.g., domperidone with poor ability to penetrate the blood-brain barrier) as anti-emetics in chemotherapy and surgery; (iv)  Metoclopramide and selective 5-hydroxytryptamine  3   (5-HT  3  ) receptor antagonists– metoclopramide was initially assumed to act only via D 2  receptor antagonism but subsequently its gastric motility stimulant effect (proposed to contribute to the anti-emetic action) was shown to be due to 5-hydroxytryptamine 4  receptor agonism. Pre-clinical studies showed that anti-emetic efficacy against the newly-introduced, highly emetic, chemotherapeutic agent cisplatin was due to antagonism at 5-HT 3  receptors. The latter led to identification of selective 5-HT 3  receptor antagonists (e.g., granisetron), a major breakthrough in treatment of chemotherapy-induced emesis; (v)  Neurokinin  1   receptor antagonists –antagonists of the actions of substance P were developed as analgesics but pre-clinical studies identified broad-spectrum anti-emetic effects; clinical studies showed particular efficacy in the delayed phase of chemotherapy-induced emesis. Finally, the repurposing of different drugs for treatment of nausea and vomiting is examined, particularly during palliative care, and also the challenges in identifying novel anti-emetic drugs, particularly for treatment of nausea as compared to vomiting. We consider the lessons from the past for the future and ask why there has not been a major breakthrough in the last 20 years.

A History of Drug Discovery for Treatment of Nausea and Vomiting and the Implications for Future Research