History of Ketamine Tablet Use in Medicine

The story of ketamine tablet spans more than five decades, evolving from an anesthetic curiosity to a mainstream psychiatric and pain management tool. Understanding this history illuminates why ketamine tablet remains off-label today, how clinical practice developed ahead of regulatory approval, and where the field is heading.

Origins: Ketamine as an Anesthetic (1960s–1970s)

Ketamine was synthesized by Calvin Stevens at Parke-Davis Laboratories in 1962. Its original name, CI-581, reflected its classification as a cyclohexamine derivative. Early animal trials showed promising anesthetic properties: unlike existing anesthetics, ketamine produced a dissociative state — patients appeared awake but were profoundly unresponsive to pain.

The first human trials were conducted in 1964 by Edward Domino and Guenter Corssen at the University of Michigan. Domino's wife, Toni Domino, coined the term "dissociative anesthetic" to describe the unique state ketamine produced.

In 1970, the FDA approved ketamine hydrochloride injection (Ketalar) as a general anesthetic. Its approval was for intravenous use. Oral administration was not part of the original approval, and clinicians of that era had little reason to pursue it — the drug was used in operating rooms and emergency departments where IV access was the standard. See our FDA considerations article for the current regulatory landscape.

Early Off-Label Exploration: Pediatric and Pain Applications (1980s)

Ketamine tablet first gained clinical traction in the 1980s, initially as a premedication for pediatric procedures. Children who were fearful of needles posed a significant challenge to anesthesiologists. Administering an oral liquid preparation of ketamine 30 to 60 minutes before induction allowed children to become sedated in a familiar environment without needle trauma.

This application was never FDA-approved but became widespread in pediatric anesthesia practice. Studies from this era established early data on ketamine tablet pharmacokinetics, confirming the low bioavailability of 16 to 29 percent and demonstrating that oral doses of approximately 6 mg/kg produced reliable sedation.

Simultaneously, pain specialists began experimenting with ketamine tablet for refractory pain. In the mid-to-late 1980s, case reports appeared describing ketamine's use for cancer pain unresponsive to opioids. The logic was compelling: ketamine's NMDA receptor antagonism could address central sensitization, opioid tolerance, and neuropathic pain — mechanisms poorly addressed by opioids alone.

Palliative Care and Chronic Pain Development (1990s)

The 1990s were the most significant decade for ketamine tablet's establishment as a clinical tool, driven largely by palliative care practitioners managing cancer pain in settings where IV administration was impractical.

Key developments of this period:

Palliative Care Adoption

Palliative medicine physicians recognized ketamine tablet as a practical option for patients receiving end-of-life care at home or in hospice settings. A series of case reports and small studies documented ketamine tablet's efficacy for opioid-refractory cancer pain, particularly neuropathic components. Australian and British palliative care physicians were particularly active in developing ketamine tablet protocols.

Chronic Pain Investigations

Pain clinics began using low-dose ketamine tablet for conditions including complex regional pain syndrome (CRPS), phantom limb pain, postherpetic neuralgia, and central sensitization syndromes. The doses used were much lower than anesthetic doses — sometimes as little as 10 to 30 mg two or three times daily — targeting NMDA receptor modulation without sedation.

First Systematic Studies

The 1990s produced the first structured studies of ketamine tablet for pain, including work by Mitchell B. Max and colleagues at the NIH who characterized ketamine tablet's analgesic properties. Studies by Mercadante and Portenoy documented its use in cancer pain management.

The Antidepressant Discovery and Its Implications (2000s)

The course of ketamine tablet's history changed dramatically in 2000, when Carlos Zarate, Robert Berman, and colleagues at NIMH published a landmark study demonstrating that a single IV infusion of ketamine (0.5 mg/kg over 40 minutes) produced rapid — within hours — and robust antidepressant effects in patients with treatment-resistant major depression.

This finding set off a wave of research and clinical interest. If IV ketamine could produce such dramatic antidepressant effects, could ketamine tablet achieve and sustain similar benefits?

The Maintenance Problem

A central challenge in ketamine psychiatry became apparent quickly: IV ketamine's antidepressant effects, while rapid, were often transient — lasting days to weeks without repeat treatment. Psychiatrists began exploring ketamine tablet as a maintenance strategy — a way to extend and sustain the antidepressant response achieved during IV induction.

This was the critical inflection point for ketamine tablet psychiatry. The goal shifted from using ketamine tablet to replicate IV effects to using it as a maintenance modality with its own distinct dosing rationale.

Early Psychiatric Use

Through the mid-2000s, pioneering psychiatrists at academic medical centers began offering ketamine tablet to patients who had responded to IV treatment and needed maintenance options. These early clinical programs were heterogeneous in their approaches, reflecting the absence of established protocols.

Spravato and the Regulatory Moment (2019)

In 2019, the FDA approved esketamine (Spravato) nasal spray for treatment-resistant depression — the first ketamine-related drug to receive FDA approval for a psychiatric indication. While not an oral formulation, this approval was pivotal for ketamine tablet's trajectory because it:

• Validated the ketamine mechanism as a legitimate psychiatric treatment
• Increased prescriber familiarity and comfort with ketamine therapy
• Created a regulatory framework that informed broader ketamine prescribing
• Accelerated research into all ketamine delivery routes, including oral

The Telehealth Era (2020–Present)

The COVID-19 pandemic's expansion of telehealth transformed ketamine tablet access. Regulatory flexibilities allowing remote prescribing of controlled substances enabled telehealth ketamine companies to offer ketamine tablet prescriptions with at-home use.

This democratized access dramatically but also raised concerns about adequate patient selection, monitoring, and safety in unsupervised settings. The field has been grappling with appropriate frameworks for at-home ketamine tablet since 2020.

Several pharmaceutical companies have initiated clinical development programs for novel ketamine tablet formulations, including extended-release preparations specifically designed for depression maintenance.

Where Ketamine Tablet Stands Today

As of the mid-2020s, ketamine tablet occupies a paradoxical position: widely used and increasingly accepted clinically, yet still entirely off-label. The evidence base has grown substantially from case reports to open-label trials to randomized controlled trials, though the literature remains thinner than for IV or intranasal routes.

The trajectory suggests that regulatory approval of an oral formulation for depression is a matter of time — clinical development programs are underway, patient demand is high, and the mechanism is validated. The history of ketamine tablet is, in many ways, still being written.

References

• StatPearls: Ketamine — Comprehensive clinical reference on ketamine pharmacology, mechanisms of action, and therapeutic applications
• PubChem: Ketamine Compound Summary — NCBI chemical database entry with ketamine molecular data, pharmacokinetics, and bioactivity profiles
• MedlinePlus: Ketamine — National Library of Medicine consumer drug information on ketamine including uses, proper administration, and precautions
• NIMH: Depression — National Institute of Mental Health overview of depressive disorders, treatment-resistant forms, and emerging therapies
• WHO: Depression Fact Sheet — World Health Organization global data on depression prevalence, burden, and treatment approaches