Ketamine History: From Battlefield Anesthetic to Depression Breakthrough

Ketamine is unusual in medicine. Most drugs do one thing well enough to get approved, and then quietly do that thing for decades. Ketamine has had four distinct lives: battlefield anesthetic, pediatric and veterinary workhorse, club drug, and, most recently, one of the most consequential advances in psychiatric treatment in a generation. Each chapter is worth knowing about, because the fact that ketamine is in your medicine cabinet in 2026 is the result of sixty years of accident, observation, and reluctant consensus.

1962: Synthesis at Parke-Davis

Ketamine was synthesized in 1962 by Dr. Calvin Stevens, a consultant working with Parke-Davis Pharmaceuticals at Wayne State University. The goal was not depression. The goal was a better anesthetic.

The reigning anesthetic of the moment was phencyclidine — PCP — which produced reliable anesthesia but with an ugly emergence profile: agitation, hallucinations, sometimes psychosis that lasted hours after surgery. Parke-Davis wanted a short-acting analog with the same receptor action and less of the psychiatric hangover. Stevens synthesized CI-581, a structurally related molecule that was roughly one-tenth as potent as PCP and wore off much faster. CI-581 eventually became ketamine.

Early volunteer trials were run at the University of Michigan and Jackson Prison in 1964 under the direction of Drs. Edward Domino and Guenter Corssen. Volunteers reported a strange altered state during the drug's peak — feeling disconnected from their bodies, floating, outside of time. Domino's wife Toni coined the term that stuck: dissociative anesthesia. It was an accurate description and it has not been improved on since.

Vietnam: The Field Anesthetic That Kept Soldiers Breathing

Ketamine received FDA approval as Ketalar in 1970. By the time it did, the U.S. military had already been using it extensively in Vietnam.

What made ketamine valuable on the battlefield was the safety profile: it preserves respiratory drive and maintains blood pressure at doses that produce surgical anesthesia. Other anesthetics suppress breathing and crash blood pressure. For a medic operating in a field hospital without ventilators, without an anesthesiologist, often without reliable IV access, ketamine was the difference between a wounded soldier who could be stabilized and one who could not. Intramuscular injection worked. Patients kept breathing. Airways stayed open.

Ketamine became a standard component of the combat medic's kit and remains one today. The World Health Organization lists it as an essential medicine, largely because of that same profile: it works in environments that cannot support more complex anesthetic protocols.

The Veterinary and Pediatric Workhorse

After the war, ketamine settled into two quieter but important roles. Pediatric anesthesia, because the respiratory safety that mattered in a battlefield hospital also matters in a child, and large-animal veterinary practice, because it works well across species and dose estimation with animals is forgiving compared to gentler anesthetics. Your neighborhood veterinary clinic has been using ketamine since the 1970s.

Ketamine is a chiral molecule — it exists in two mirror-image forms, S-ketamine and R-ketamine. Most medical ketamine has historically been racemic: a 50/50 blend of both. We go deeper on the distinction at R-ketamine vs. S-ketamine. The short version is that S-ketamine binds NMDA receptors more tightly and produces faster anesthesia and more dissociation, while R-ketamine appears to drive the antidepressant effect through mechanisms that extend beyond NMDA blockade. Both forms were on the shelf the entire time. Nobody was asking the question which one treats depression.

The Club Years

Recreational use of ketamine began in the late 1970s, accelerated through the 1980s, and became a fixture of club and rave culture in the 1990s as "Special K." Sub-anesthetic doses produced the dissociative experience that had bothered the 1964 trial volunteers, rebranded as a desirable effect. The DEA placed ketamine on Schedule III in 1999, where it remains today: legitimate medical use, moderate abuse potential, legal via prescription.

The recreational era is not incidental to the medical story. It generated a lot of data, much of it informal, about what ketamine does to the brain at sub-anesthetic doses — the doses that turned out to matter for depression. That data was sitting there when the psychiatrists finally got interested.

2000: The Yale Trial That Changed Everything

The moment the modern story begins is a 2000 paper out of Yale, authored by John Krystal, Dennis Charney, and colleagues. Seven patients with treatment-resistant depression received a single sub-anesthetic ketamine infusion (0.5 mg/kg over 40 minutes). Depression scores dropped within hours. The effect was still measurable at 72 hours.

This was unprecedented. SSRIs take weeks. Patients in severe depression sometimes do not have weeks. A drug that produced a same-day response in TRD — even if the response was temporary — was a different kind of tool than anything psychiatry had.

The paper was small. The effect was large. Over the following fifteen years, the finding replicated in progressively larger and better-designed trials. The mechanism, initially framed as pure NMDA antagonism, turned out to be more interesting: ketamine triggers a cascade of downstream signaling that increases brain-derived neurotrophic factor (BDNF), activates mTOR pathways, and drives synaptic growth. It opens a window of heightened neuroplasticity that lasts days to weeks — the biological substrate of the lasting antidepressant effect.

2019: FDA Approval for Spravato

In March 2019, the FDA approved esketamine (Spravato) as the first novel antidepressant mechanism approved in over thirty years. Esketamine is the S-enantiomer delivered as a nasal spray, administered in a certified clinical setting with two hours of monitoring afterward. The approval was controversial — the evidence base was smaller than the FDA usually requires, and the drug's REMS restrictions make it expensive and inconvenient — but it marked the formal entry of ketamine into the psychiatric mainstream.

Parallel to esketamine's regulatory path, off-label use of racemic ketamine expanded rapidly. IV infusion clinics opened in most major cities. Compounded oral and sublingual ketamine, prescribed off-label by physicians and delivered through at-home programs like Discreet Ketamine, put the treatment within reach of patients who could not afford or access clinic-based care. The at-home version uses the same molecule at a lower bioavailability (roughly 20-30% sublingual versus 100% IV), with dosing adjusted accordingly.

The Fungal Connection

A surprising 2015 finding from Martin Bishop's lab at the University of Aberystwyth: Pochonia chlamydosporia, a soil-dwelling fungus, naturally produces ketamine. The finding implies ketamine is part of a broader class of naturally occurring NMDA-active compounds that the biosphere has been synthesizing since long before human chemists. It is an odd historical footnote, but it recontextualizes the molecule: ketamine is not purely a product of 20th-century pharmacology.

What Ketamine Is Now

In 2026, ketamine occupies several roles at once. It is still a standard field anesthetic used by combat medics and EMS. It is still a pediatric anesthetic and the veterinary workhorse it became in the 1970s. It is still a controlled substance with recreational use in some populations. And it is a routine psychiatric treatment for severe and treatment-resistant depression, PTSD, anxiety, and chronic pain, delivered in multiple formats: IV infusion in specialty clinics, esketamine nasal spray under the Spravato REMS program, and oral sublingual formulations prescribed through physician-supervised telehealth programs.

The same molecule, from the same original synthesis, doing four different jobs at once. That is unusual in medicine. It is probably why the depression application took so long to get noticed — the drug was already in use for something else everywhere you looked.

The Mechanism, Briefly

Ketamine's antidepressant mechanism is worth understanding because it is genuinely different from every other antidepressant on the market. We have a longer piece on how ketamine works with the full story. The short version:

Ketamine antagonizes NMDA receptors, preferentially those on inhibitory interneurons, which results in a surge of glutamate activity in prefrontal cortex. That glutamate surge triggers BDNF release. BDNF promotes synaptic growth — specifically, regrowth of the cortical synapses that chronic stress and depression have pruned. The net result is a brain that is, for a window of several days, unusually plastic.

This is why ketamine works for patients who have failed five antidepressants: it is not tuning the same serotonin knob harder. It is reaching for a different system entirely.

What's Next

The research pipeline includes pure R-ketamine (in clinical trials as Perception Neuroscience's PCN-101, among others), next-generation NMDA modulators that aim to preserve the antidepressant effect while reducing dissociation, and ketamine-assisted psychotherapy protocols that combine the pharmacology with structured therapy work. Depression treatment for the next decade will look less like medication cycling and more like targeted neuroplasticity interventions. Ketamine is the first tool in that category to reach mainstream medicine. It will not be the last.

Ready to Start?

If you have been through several antidepressants and are wondering whether ketamine might help, the five-minute eligibility check will tell you whether our at-home program is a fit.

Discreet Ketamine provides at-home ketamine therapy supervised by Dr. Ben Soffer, a board-certified physician, to residents of Florida and New Jersey.