Ketamine has been around since 1962, when it was first synthesized in a laboratory. That makes it over 60 years old. In that time, it has gone from an experimental anesthetic to a battlefield drug, a veterinary staple, a controlled substance, and most recently, a treatment for depression. Few drugs have had such a winding journey.
Synthesis and Early Testing in the 1960s
Ketamine was created in 1962 by chemist Calvin Stevens, working for the pharmaceutical company Parke-Davis. The company was searching for a safer alternative to an older anesthetic called phencyclidine (PCP), which produced effective sedation but caused severe and prolonged hallucinations when patients woke up. Stevens synthesized a series of related compounds, and one of them, labeled CI-581, stood out: it produced excellent anesthesia and wore off quickly. Because it was chemically a ketone combined with an amine, the compound was named ketamine.
Human trials followed throughout the mid-1960s. Researchers found that ketamine put patients into a unique trance-like state, later called “dissociative anesthesia,” where the brain essentially disconnects from sensory input. Patients could breathe on their own, their heart rate and blood pressure remained stable, and they didn’t need a breathing tube. These qualities made it unusually safe compared to other anesthetics available at the time.
FDA Approval and the Vietnam War
The FDA approved ketamine in 1970, and its first major real-world test came almost immediately on the battlefields of Vietnam. The drug’s properties were nearly ideal for combat medicine: it worked fast, didn’t suppress breathing, and could be injected in the field without the monitoring equipment that other anesthetics required. American medics administered it to wounded soldiers as a safe and effective battlefield anesthetic, earning it the nickname “the drug of war.”
This military use established ketamine’s reputation for reliability in difficult, resource-limited settings. It could keep a patient sedated and pain-free without the risk of respiratory failure that made other anesthetics dangerous outside a hospital.
Veterinary Medicine and Global Adoption
Starting in the 1970s, ketamine became a cornerstone of veterinary anesthesia. Its safety profile made it practical for animals of all sizes, from cats and dogs to horses and exotic species. Veterinarians could use it alone or combine it with sedatives for longer procedures. To this day, it remains one of the most commonly used anesthetics in veterinary practice worldwide.
In 1984, the World Health Organization added ketamine to its Model List of Essential Medicines, recognizing it as one of the most important drugs for a basic healthcare system. That designation reflected its value in low-resource settings, particularly in developing countries where advanced anesthesia equipment isn’t always available. It remains on that list today.
Recreational Abuse and DEA Scheduling
By the 1980s and 1990s, ketamine had found its way into club and rave scenes. Users sought out its dissociative and hallucinogenic effects at lower doses, and the drug became known by street names like “Special K.” Rising abuse prompted the U.S. Drug Enforcement Administration to act. On August 12, 1999, the DEA placed ketamine into Schedule III of the Controlled Substances Act, meaning it was recognized as having medical value but also potential for misuse. That classification added new restrictions on how it could be prescribed, stored, and distributed.
The Depression Breakthrough
The most surprising chapter in ketamine’s history began around the year 2000, when researchers at Yale tested it on patients with major depression. The results were striking: patients showed significant improvement in depressive symptoms within 72 hours of a single low-dose infusion. On average, depression scores dropped by 14 points on a standard clinical scale, compared to zero change with a placebo. This was remarkable because traditional antidepressants typically take weeks to produce any noticeable effect.
That small study launched nearly two decades of psychiatric research. Scientists discovered that ketamine works on a completely different brain pathway than conventional antidepressants. Rather than targeting serotonin or norepinephrine, it blocks a receptor involved in learning and neural plasticity, which appears to rapidly strengthen weakened brain connections in people with depression.
The research culminated in March 2019, when the FDA approved a nasal spray called Spravato, based on esketamine (a mirror-image version of the ketamine molecule). It was specifically approved for treatment-resistant depression, marking the first time in decades that an entirely new class of antidepressant reached the market. The approval required patients to use the spray under medical supervision in a certified clinic, reflecting concerns about both side effects and misuse potential.
Ketamine’s Timeline at a Glance
- 1962: Synthesized by Calvin Stevens at Parke-Davis
- 1970: FDA approved; used as a battlefield anesthetic in Vietnam
- 1970s: Adopted widely in veterinary medicine
- 1984: Added to the WHO’s List of Essential Medicines
- 1999: Classified as Schedule III by the DEA
- 2000: First clinical evidence of rapid antidepressant effects
- 2019: FDA approval of esketamine nasal spray for treatment-resistant depression
Few drugs have been reinvented as many times as ketamine. A compound originally designed to replace a dangerous anesthetic has spent six decades moving through operating rooms, war zones, veterinary clinics, dance floors, and psychiatric research labs, with each era revealing a different use for the same molecule.