Ketamine History: Its Origin and Science

From Battlefield Anesthetic to Mental Health Breakthrough

Ketamine has one of the most fascinating stories in modern medicine. What began as a search for a safer surgical anesthetic in the 1960s has evolved into one of the most promising treatments for depression, anxiety, and PTSD available today.

This article traces ketamine's journey — from wartime operating rooms to cutting-edge psychiatry — and explores why scientists are still uncovering new dimensions of this remarkable compound.

The Discovery: A Search for Safety

In the early 1960s, researchers at Parke-Davis laboratories were looking for a gentler alternative to phencyclidine (PCP). While PCP was an effective anesthetic, patients frequently woke up in states of severe agitation, mania, and "emergence delirium."

In 1962, Dr. Calvin Stevens synthesized CI-581 — later named ketamine. It was a revelation. Ketamine provided profound anesthesia and pain relief while maintaining breathing and heart rate. Patients entered a "dissociative" state where the mind felt detached from the body, but without the dangerous emergence reactions of PCP.

Ketamine quickly proved its value in the most demanding environments. It was widely used on the battlefields of the Vietnam War, where its high safety profile — no need for electricity or complex monitoring equipment — made it invaluable for treating wounded soldiers in field hospitals.

The Chemistry Behind the Molecule

Ketamine is a chiral molecule, meaning it exists in two mirror-image forms: S(+)-ketamine and R(-)-ketamine. Think of them like your left and right hands — structurally identical, but not interchangeable. You can learn more about the differences in our article on R-ketamine vs. S-ketamine.

Chemical name: (RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone

Most medical ketamine used historically has been a racemic mixture — a 50/50 blend of both forms. Modern medicine has begun isolating these enantiomers to target specific conditions more precisely, most notably with the FDA approval of esketamine (Spravato) in
2019.

A Surprise From the Soil

For decades, scientists believed ketamine was purely synthetic — a product of laboratory chemistry with no natural equivalent. That assumption was overturned when researchers discovered that Pochonia chlamydosporia, a common soil-dwelling fungus, naturally produces ketamine.

Why would a fungus make ketamine? Scientists believe it serves as a biological weapon or signaling molecule. Testing has shown that fungal-derived ketamine is an effective antiparasitic, with potential to rival albendazole in treating nematode infections.

This discovery suggests ketamine has been part of Earth's chemical vocabulary long before humans synthesized it in a lab.

The Mental Health Revolution

The most significant chapter in ketamine's story is its transition from the operating room to the psychiatrist's office.

Unlike traditional antidepressants that take weeks to work by affecting serotonin, ketamine acts on glutamate — the brain's most abundant chemical messenger. It can provide relief from suicidal ideation and severe depression within hours rather than weeks.

In 2019, the FDA approved Spravato (esketamine nasal spray) specifically for treatment-resistant depression, marking the first new mechanism of action for depression treatment in over 30 years. Research now shows that ketamine helps regrow synapses — neural connections that have withered under chronic stress and trauma. For a deeper dive into these mechanisms, see how ketamine works.

Current Legal Status

Ketamine holds Schedule III status in the United States — a controlled substance with accepted medical use but potential for misuse. It remains on the WHO's List of Essential Medicines for surgery.

Thousands of ketamine clinics have opened globally, providing IV infusions and other formulations for depression, anxiety, and PTSD under medical supervision.

The At-Home Treatment Movement

The COVID-19 pandemic accelerated a significant shift. Emergency waivers of the Ryan Haight Act — which previously required in-person visits before prescribing controlled substances — enabled a new model of telemedicine-based ketamine therapy.

This shift allowed patients to access sublingual compounded ketamine through telehealth platforms, expanding reach to those in rural areas or with limited mobility. While increasing accessibility, it also underscored the importance of proper medical oversight and safety protocols for unsupervised settings.

Looking Forward

Ketamine continues to defy simple categorization. From a 1960s surgical tool to a 21st-century mental health breakthrough — and a naturally occurring fungal byproduct — its story is still being written. As research advances, particularly into R-ketamine's unique properties, the future of this compound may hold even more surprises.