Ketamine

Ketamine exists because phencyclidine worked too well. By 1958, Parke-Davis had tested PCP as an anesthetic and found it remarkable—patients felt no pain, maintained blood pressure, kept breathing without a ventilator. But 20% woke from surgery trapped in prolonged psychosis, some for over a week. The drug that could revolutionize battlefield medicine was instead creating battlefields in patients' minds.

Calvin Stevens, a Wayne State University chemist consulting for Parke-Davis in Detroit, set out to find PCP's benefits without its terrors. The adjacent possible was geographic: Wayne State and Parke-Davis shared the same city, allowing Stevens to synthesize compounds in his university lab and send them directly for animal testing. In 1962, he created CI-581—ketamine—deliberately one-tenth as potent as PCP, hoping the reduced strength would shorten the dissociative state.

The first human trial came on August 3, 1964, when Edward Domino and Guenter Corssen injected ketamine into prisoners at a Michigan facility. Patients emerged disconnected from their surroundings but without PCP's lasting psychosis. Domino's wife, watching him struggle to describe the strange, awake-yet-absent state, suggested calling it "dissociative anesthesia." By 1970, the FDA had approved ketamine, and within months it became the most widely used battlefield anesthetic of the Vietnam War—soldiers could be treated without respirators, maintaining blood pressure even while in shock.

For fifty years, ketamine remained a surgical tool and veterinary staple, occasionally diverted as the club drug "Special K." Then researchers noticed something unexpected: patients with treatment-resistant depression improved within hours of ketamine infusions, not the weeks required for conventional antidepressants. Unlike every other psychiatric medication targeting serotonin or dopamine, ketamine worked through glutamate—an entirely different pathway.

In 2019, the FDA approved esketamine nasal spray for treatment-resistant depression. By 2024, over 140,000 patients had been treated, generating $780 million in sales. In January 2025, esketamine became the first standalone medication for treatment-resistant depression, no longer requiring a companion antidepressant. The anesthetic created to replace a drug that caused psychosis now treats the 7 million Americans whose minds resist conventional therapy.