Ketamine has one of the most unusual trajectories in modern pharmacology. Developed as a surgical anesthetic, used on battlefields, and later investigated as a psychiatric medicine — its history reflects broader shifts in how science understands the brain, mood, and treatment.
Understanding this history provides context for why ketamine therapy is now considered a legitimate option in psychiatric practice, and why it took decades of research to arrive at that recognition.
Timeline of Key Milestones
Discovery
Ketamine was first synthesized by Parke-Davis chemist Calvin Stevens as part of a search for a safer anesthetic than phencyclidine (PCP). It showed rapid onset, short duration, and a relatively favorable safety profile.
First Human Trials
The first human clinical trials were conducted at the University of Michigan. Researchers noted effective anesthesia with an unusual dissociative quality — patients remained conscious but disconnected from their surroundings.
FDA Approval as Anesthetic
The U.S. Food and Drug Administration approved ketamine (Ketalar) as an anesthetic for human use. It quickly gained widespread adoption in surgery, emergency medicine, and pediatric care due to its cardiovascular safety profile.
Military and Emergency Medicine
Ketamine became widely used in combat medicine and emergency settings — valued for its ability to provide anesthesia without requiring respiratory support equipment. It was used extensively during the Vietnam War and became a staple of field medicine.
Early Psychiatric Interest
Researchers began noticing anecdotal reports of mood improvement in patients who received ketamine for non-psychiatric purposes. This prompted the first systematic investigations into its potential antidepressant properties.
First Landmark Depression Study
Researchers at Yale University published a randomized controlled trial demonstrating that a single sub-anesthetic intravenous dose of ketamine produced significant antidepressant effects within hours in patients with major depression — unlike conventional antidepressants which require weeks.
Expanding Research
Major academic centers including the National Institute of Mental Health, Columbia University, and Mount Sinai began conducting clinical trials. Ketamine's effects on treatment-resistant depression, suicidal ideation, PTSD, and other conditions were studied extensively.
FDA Approval of Esketamine
The FDA approved esketamine (Spravato) nasal spray — a derivative of ketamine — for treatment-resistant depression in adults. This marked the first regulatory approval of a ketamine-based treatment specifically for depression, representing significant institutional recognition of the glutamate pathway.
Ketamine-Assisted Psychotherapy
The field expanded to integrate ketamine within psychotherapeutic frameworks. Researchers began studying whether structured preparation and integration therapy surrounding ketamine sessions could enhance and sustain treatment outcomes.
Ongoing Development
Research continues across optimal dosing, long-term outcomes, patient selection, and combination with psychotherapy. Regulatory frameworks for clinical use are evolving in multiple countries including the United States, Europe, and Israel.
Ketamine as an Anesthetic
For its first three decades, ketamine's primary medical role was anesthesia. Its properties made it particularly valuable in settings where conventional anesthesia was difficult to deliver:
Cardiovascular Safety
Unlike many anesthetics, ketamine tends to maintain blood pressure and heart rate, making it safer in trauma and emergency settings.
No Respiratory Suppression
Patients typically maintain their own breathing, reducing the need for ventilatory support in field conditions.
Pediatric Use
Its favorable safety profile led to widespread use in pediatric procedures where other anesthetics carry greater risk.
The Shift to Psychiatric Research
The observation that ketamine might affect mood was initially anecdotal. Clinicians occasionally noted that patients seemed brighter or less depressed following ketamine anesthesia. These reports, combined with emerging knowledge about glutamate's role in mood regulation, prompted formal investigation.
The 2000 Yale study — the first rigorous randomized controlled trial — provided the scientific foundation that accelerated research across major academic centers. Over the following two decades, hundreds of studies explored ketamine's effects on depression, PTSD, anxiety, suicidal ideation, and related conditions.
Key Research Institutions
FDA Developments
The 2019 approval of esketamine nasal spray (Spravato) for treatment-resistant depression marked a watershed moment. For the first time, a regulatory body had formally recognized a ketamine-based compound as an antidepressant.
This approval required demonstration of efficacy in multiple Phase III clinical trials and confirmed the biological rationale — that glutamate signaling and NMDA receptor modulation represent a valid pathway for antidepressant treatment.
"The approval of esketamine represents the most significant advance in antidepressant pharmacology in decades." — A perspective shared by many researchers in the field following the 2019 FDA decision.
Ketamine in Israel
In Israel, ketamine is an approved and legally available medication. Its use in psychiatric practice operates within a physician-supervised framework. As the evidence base has grown internationally, Israeli psychiatrists have increasingly incorporated ketamine therapy into treatment plans for appropriate patients, particularly those with treatment-resistant depression.
Further Reading
Consultation
If you are interested in learning about KAP, the first step is a free orientation call with Dr. Rosenbach about the service, process, and practical next steps. If you wish to continue, you may receive a secure portal invitation for intake; a clinician reviews that information before any formal evaluation.