A Complete History of Ketamine: From Anesthetic to Antidepressant

This is a complete history of ketamine from anesthetic to antidepressant, tracing every major turning point in the drug's six-decade journey. Ketamine is a dissociative anesthetic that blocks NMDA receptors in the brain. NMDA receptors are a class of brain receptor that regulates synaptic signaling and memory formation, and blocking them produces ketamine's pain relief and its characteristic sense of detachment from one's surroundings. The story runs from ketamine's 1962 creation as a safer alternative to PCP, through its rise as the standard battlefield anesthetic of the Vietnam War, to its place on the World Health Organization's Essential Medicines List, its 1999 scheduling as a controlled substance, and the landmark 2000 Yale study that revealed its rapid antidepressant effect. That discovery reshaped psychiatric research and led directly to the 2019 FDA approval of esketamine (Spravato) and the ketamine clinics and telehealth programs operating today.

The Origins: 1956-1962

Ketamine's history starts with phencyclidine (PCP), a dissociative anesthetic that the pharmaceutical company Parke-Davis synthesized in 1956 for surgical use. PCP produced strong pain relief and detachment from surroundings, but clinical trials showed severe psychotomimetic side effects. Patients experienced agitation, hallucinations, and delirium on emergence from anesthesia that could last for hours or days. By the early 1960s, PCP was unsuitable for routine medical use, though it continued to circulate as a recreational drug.

Parke-Davis asked organic chemist Calvin Lee Stevens to synthesize and test PCP derivatives that might keep the anesthetic benefits while removing the disturbing psychological effects. In 1962, Stevens synthesized a compound designated CI-581, the molecule that became known as ketamine. It was a shorter-acting analog of PCP with a far more manageable side effect profile.

First Human Trials: 1964-1966

Drs. Edward Domino and Guenter Corssen at the University of Michigan conducted the first human trials of ketamine in 1964, administering the drug to volunteer prisoners at Jackson State Prison in Michigan. That practice was common in pharmaceutical research at the time and would not meet today's ethical standards for human subjects research.

The results were notable. Ketamine produced a state that Domino's wife, Toni, suggested calling dissociative anesthesia. Patients were insensible to pain and appeared disconnected from their surroundings, yet kept protective airway reflexes and spontaneous breathing. Emergence delirium still occurred, but was far less severe and shorter lasting than with PCP. Domino and Corssen published their findings in 1966 in the journal Anesthesia & Analgesia, establishing the clinical profile that would guide ketamine's use for decades.

FDA Approval and the Vietnam War: 1970-1975

The FDA approved ketamine for human use in 1970 under the brand name Ketalar, manufactured by Parke-Davis. The timing mattered. The United States was fighting the Vietnam War, and military medicine needed anesthetic agents that were safe in field conditions where monitoring equipment and trained anesthesiologists were often unavailable.

Ketamine became the most widely used battlefield anesthetic of the war. It kept cardiovascular stability, unlike many other anesthetics that lower blood pressure, preserved spontaneous respiration, could be given by intramuscular injection without IV access, and had a wide margin of safety. Medics and surgeons used it in forward positions, helicopter evacuations, and field hospitals. That track record cemented ketamine's reputation in emergency and field medicine, a reputation it still holds today.

Global Adoption and WHO Recognition: 1975-1985

Ketamine spread worldwide through the 1970s and 1980s. Its safety profile made it valuable in low-resource settings that lacked reliable electricity, oxygen supply, or monitoring equipment. In 1985, the World Health Organization added ketamine to its Model List of Essential Medicines, the WHO's list of medicines considered most important for a basic health system.

The designation reflected ketamine's role in global surgery, particularly in parts of Africa, Asia, and Latin America where it was sometimes the only general anesthetic available. The WHO has since defended ketamine's availability against proposals for stricter international scheduling, arguing that tighter restrictions would hurt surgical care in the developing world.

Schedule III Classification and Recreational Concerns: 1981-1999

As ketamine use grew, reports of non-medical use followed. Through the 1980s and 1990s it entered club and rave culture under street names including Special K, Vitamin K, and Kit Kat. In 1999, the U.S. Drug Enforcement Administration placed ketamine on Schedule III of the Controlled Substances Act, a category for drugs with a moderate to low potential for abuse and dependence relative to Schedule I or II substances. The scheduling added controls on manufacturing, distribution, and prescribing, but did not stop physicians from using it clinically.

The Psychiatric Discovery: 2000

The year 2000 marks the most consequential turn in ketamine's history. A research team led by John Krystal and Dennis Charney at Yale University, with Robert Berman as first author, published a small study in Biological Psychiatry. The trial showed that a single sub-anesthetic intravenous dose of ketamine, 0.5 mg/kg administered over 40 minutes, produced rapid antidepressant effects in patients with major depression.

Patients showed meaningful improvement within hours, a timeline that stood in sharp contrast to conventional antidepressants, which typically require weeks of daily dosing to take effect. See our guide on treatment-resistant depression for more on how that timeline changed clinical practice. The study involved only seven subjects, and much of the psychiatric community initially treated it with skepticism.

Confirmation and Expansion: 2006-2010

According to the 2006 NIMH-led trial published in Archives of General Psychiatry, 71% of patients with treatment-resistant depression responded to a single ketamine infusion within 24 hours. Carlos Zarate and colleagues at the National Institute of Mental Health ran this randomized, placebo-controlled, crossover trial to confirm and extend the earlier Yale findings.

Researchers now consider this study the moment that legitimized ketamine as a psychiatric treatment. It showed that the glutamate system, acting through the NMDA receptor, could be a therapeutic target distinct from the monoamine systems that older antidepressants target. Between 2006 and 2010, follow-up studies traced a mechanism involving AMPA receptor activationBDNF release, and mTOR-mediated synaptogenesis, reshaping the neuroscience of depression research.

The Clinic Era: 2012-2018

By 2012, the first ketamine infusion clinics opened in the United States, typically founded by anesthesiologists and psychiatrists who used the legal framework of off-label prescribing to offer the treatment the research supported. The model grew fast. By 2018, hundreds of ketamine infusion centers operated nationwide, with wide variation in protocols, pricing, and clinical oversight. Professional groups, including the American Society of Ketamine Physicians, Psychotherapists, and Practitioners, formed to set standards of care. Our guide to ketamine treatment methods covers how these protocols differ today.

Spravato Approval: 2019-2020

In March 2019, the FDA approved esketamine (Spravato), the S-enantiomer of the ketamine molecule delivered as a nasal spray, for treatment-resistant depression. It was the first FDA approval of a ketamine-derived medication for a psychiatric indication. See our comparison of racemic ketamine versus esketamine for how the two forms differ.

In August 2020, the FDA expanded Spravato's indication to include adults with major depressive disorder who have current suicidal ideation with intent, making it one of the first medications specifically approved for acute suicidality. The approval came with a Risk Evaluation and Mitigation Strategy requiring administration in certified healthcare settings with post-dose monitoring, reflecting concerns about dissociation and misuse.

Telehealth Expansion and At-Home Protocols: 2020-2023

The COVID-19 pandemic drove a rapid expansion of telehealth, including ketamine therapy. The DEA temporarily relaxed the requirement for an in-person evaluation before prescribing controlled substances, which let telehealth companies prescribe oral and sublingual ketamine for at-home use. Several telehealth companies built ketamine therapy models around this flexibility, expanding access while raising questions about safety and appropriate clinical oversight.

Regulatory Tightening and Ongoing Evolution: 2023-Present

Regulatory scrutiny has increased since 2023. The FDA has issued warnings about compounded ketamine products, and the DEA has signaled it will reinstate in-person prescribing requirements for controlled substances issued through telehealth. See our coverage of the DEA's telehealth prescribing rules for the current status of that requirement.

Research keeps moving. R-ketamine, also called arketamine, is the less-studied enantiomer of the ketamine molecule and has shown antidepressant effects in early clinical trials with potentially fewer dissociative side effects than the S-enantiomer used in Spravato. Novel formulations, combination therapies, and biomarker-guided dosing strategies are under active investigation.

Legacy and Future Directions

Ketamine's path from surgical anesthetic to psychiatric treatment is one of the more notable stories in modern medicine. A molecule Calvin Stevens synthesized in a Parke-Davis laboratory in 1962 has reshaped how researchers understand depression, neuroplasticity, and the brain's capacity for rapid recovery. Its legacy is already established: it opened the door to a new class of psychiatric treatments and gave patients options after conventional therapies had failed them.

References

• MedlinePlus (National Library of Medicine): Ketamine Injection, drug information on ketamine's clinical uses and FDA-approved indications.
• FDA: Drug Information, the U.S. Food and Drug Administration's records on ketamine and esketamine approvals.
• MedlinePlus: Esketamine Nasal Spray, drug information on FDA-approved Spravato for treatment-resistant depression.
• World Health Organization: Depression Fact Sheet, information on global depression burden and the Essential Medicines List.
• StatPearls (NCBI Bookshelf): Ketamine, a clinical reference covering ketamine's history, pharmacology, and evolution as a medical treatment.