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This issue of Anesthesia & Analgesia contains reports of three studies that are excellent examples of, in contemporary parlance,“thinking outside the box.” Two of the studies, one by Ismail and Mowafi1 and the other by Gögenur et al., 2 examined the utility of the neurohormone melatonin as an anesthetic adjunct in the perioperative setting, and the third article, by White et al., 3 examined the use of the-amino butyric acid analog pregabalin as a preoperative anxiolytic. All three studies are noteworthy in that they examined whether old (melatonin) or new (pregabalin) pharmacologically active agents can be used in novel ways. In addition, the studies by Gögenur et al. 2 and White et al. 3 are striking in that they are essentially “negative” studies, to wit, the authors were unable to confirm their primary hypotheses that the compounds in question had clinically meaningful effects. In the past, such articles would have been …