From model psychosis to rapid antidepressant: a historical and conceptual review of ketamine’s psychiatric history

Abstract

Ketamine’s development in psychiatry exemplifies the evolution of psychopharmacology over six decades. Originally introduced as a dissociative anesthetic and psychotomimetic probe, ketamine has been repositioned as a rapidly acting antidepressant, particularly for treatment-resistant depression (TRD). This narrative review draws on historical sources, clinical trials, regulatory documents, and conceptual analyses to examine ketamine’s psychiatric trajectory, integrating historiographical and clinical perspectives to contextualize its shifting roles. Ketamine was initially valued in experimental psychopathology for modeling psychosis via N-methyl-D-aspartate receptor antagonism. By the early 2000s, clinical trials demonstrated rapid and robust antidepressant effects, challenging monoaminergic paradigms and stimulating new glutamatergic and neuroplasticity-based models of depression. Its dissociative effects, once interpreted as liabilities, became focal points of debate, though evidence suggests they are not essential for antidepressant efficacy. Intranasal esketamine received U.S. Food and Drug Administration approval in 2019 for TRD, while off-label intravenous racemic ketamine is widely used in practice. Ongoing challenges include safety, equity of access, regulatory oversight, and commercialization pressures. Ketamine’s psychiatric history illustrates the fluidity of therapeutic meaning and the interplay of pharmacology, diagnosis, and culture. Its repositioning highlights new opportunities for rapid-acting treatments while underscoring the ethical and clinical responsibilities of integrating innovative agents into psychiatric care.

Introduction

Ketamine’s development in psychiatry exemplifies broader transformations that have occurred within psychopharmacology over the past six decades. Originally developed in the early 1960s as a safer alternative to phencyclidine (PCP; Figure 1), ketamine was introduced into clinical practice primarily as a dissociative anesthetic for veterinary as well as human use. ¹ Its unique clinical profile, characterized by rapid onset, limited cardiovascular effects, and induction of profound alterations in consciousness, soon attracted the attention of investigators interested in modeling psychopathological states, including psychosis and exploring altered states of awareness.

Figure 1.

Structures of phencyclidine and R,S-ketamine.

By the 1970s and 1980s, ketamine had emerged as a prominent tool in experimental psychopathology. It was used to investigate schizophrenia-like states in part due to its capacity to induce perceptual distortions and cognitive fragmentation. In addition of interest was its primary pharmacodynamic action as a noncompetitive antagonist at N-methyl-D-aspartate (NMDA) glutamatergic receptors—a pharmacological property that would later prove significant in both neurobiological and therapeutic research.^2,3 Initially, ketamine was viewed through a largely pathophysiological lens: it served to mimic psychiatric symptoms for investigative purposes but was not considered clinically useful in treating mental illnesses. Instead, its dissociative effects were interpreted as psychotomimetic and not directly of therapeutic relevance.

This perception began to shift dramatically by the turn of the 21st century. A series of early clinical trials demonstrated that subanesthetic doses of ketamine could induce rapid and sustained antidepressant effects in individuals with treatment-resistant depression.^4,5 These findings were striking not only for their therapeutic potential but also for challenging longstanding assumptions about the delayed onset of antidepressant efficacy—a principle that had underpinned the monoaminergic paradigm of antidepressant pharmacodynamics for decades.

Reconceptualization of ketamine from a psychotomimetic agent to a rapidly acting antidepressant coincided with a major paradigm shift in psychiatry. It prompted a re-evaluation of prevailing theories of mood disorders and the frameworks through which their pharmacological treatments were interpreted. As ketamine advanced into mainstream clinical trials and eventually gained regulatory approval for intranasal esketamine, it catalyzed renewed interest in glutamatergic signaling, synaptic plasticity, and circuit-based models of depression. Simultaneously, its dissociative properties—once seen as liabilities—emerged as focal points in debates about the role of altered states of consciousness in therapeutic response.^6,7

The present report traces ketamine’s conceptual and clinical transformation within psychiatry, from early use as a model of psychosis to its current role as a rapidly acting antidepressant, particularly for otherwise treatment-resistant depression. We explore the multiple redefinitions, scientific frameworks, and cultural narratives that have shaped ketamine’s evolving status. In doing so, we aim not only to document scientific milestones in ketamine research but also to examine the relationship of ketamine’s development to broader philosophical and methodological shifts within psychiatric therapeutics and theory.

Methodological considerations

Analyzing the psychiatric evolution of ketamine requires a methodological framework that combines empirical rigor with historiographical insight. Standard reviews of psychopharmacological treatments often focus on pharmacodynamic mechanisms or clinical outcomes, but such approaches can overlook cultural, epistemological, and institutional forces that influence how a drug is understood and classified. In this section, we outline the interpretive strategy used in this report, which draws from the historiography of medicine, philosophy of science, and clinical psychiatry to contextualize ketamine’s psychiatric journey.

Our approach is primarily narrative and historically grounded. We examine how ketamine’s psychiatric identity has shifted over time—not merely as a result of accumulating empirical evidence, but also through evolving diagnostic frameworks (e.g., from DSM-III to DSM-5-TR),^8,9 changing neurobiological paradigms for mood disorders (from monoaminergic to glutamatergic models), and shifting sociopolitical contexts. This perspective challenges linear models of scientific progress, instead emphasizing that drug histories are shaped by theoretical assumptions, institutional priorities, and interpretive flexibility.

Primary sources for this review include early pharmacological reports (e.g., the work of Edward Domino and Guenter Corssen), ¹ experimental psychopathology studies (e.g., John Krystal’s ketamine-induced psychosis models), ² and clinical trial data demonstrating antidepressant efficacy of ketamine.^4,5 We also considered psychiatric textbooks, regulatory reports, and recent literature on psychedelic-assisted therapies to identify both continuities and ruptures across decades of research. By triangulating primary data with secondary analyses—such as systematic reviews and historical critiques—we aimed to provide a nuanced, multi-layered account of ketamine’s psychiatric significance.

A central concept informing our approach is that of “conceptual plasticity”—the idea that the clinical and symbolic meanings of a drug can change radically over time, depending on prevailing scientific, clinical, and cultural narratives. Ketamine exemplifies this dynamic. Once viewed primarily as a psychotomimetic agent, its dissociative effects were later reinterpreted as either tolerable side effects or even potentially therapeutic mechanisms. ⁷ Such shifts reveal that the perceived value of a drug is not dictated solely by its pharmacodynamics, but also by the interpretive frameworks in which it arises.

We also consider how methodological factors have shaped ketamine’s development. For example, the limited adoption and delayed validation of dissociation-specific rating scales—such as the Clinician-Administered Dissociative States Scale (CADSS)—complicated early efforts to characterize and standardize ketamine’s clinical effects. ⁶ These delays contributed to inconsistencies in terminology and reporting, reinforcing ambiguity regarding the clinical significance of ketamine’s clinical profile.

Overall, our approach highlights the importance of historical context, interdisciplinary analysis, and epistemic critique. Instead of isolating ketamine’s clinical effects from the broader field of psychiatric thought, we consider how diagnostic constructs, scientific trends, and cultural assumptions have collectively shaped its evolving therapeutic understanding.

Origins in experimental psychosis research

Ketamine’s entry into psychiatric research during the late 1960s and early 1970s occurred within the context of experimental psychopathology. This discipline aims to understand mental illness through pharmacologically induced, transient, reproducible states resembling psychiatric symptoms or syndromes. This method has been particularly attractive in the study of schizophrenia, a disorder that had long eluded definitive pathophysiological explanation. Earlier investigations used lysergic acid diethylamide (LSD), mescaline, and phencyclidine (PCP) as psychotomimetic compounds that can simulate some features of psychotic disorders. Ketamine, however, provided a unique combination of pharmacological safety, rapid onset, short duration of action, and profound dissociative effects that made it especially suitable for research modeling features of psychotic disorders.^1,2

Seminal studies led by Edward Domino, Guenter Corssen, and later John Krystal explored ketamine’s ability to induce schizophrenia-like symptoms, including perceptual distortion, depersonalization, cognitive disorganization, and affective blunting.^1,2 These phenomena were commonly described under the broad category of “dissociation,” a term which itself underwent significant shifts in meaning across studies in anesthesiology, neurology, psychiatry, and trauma research. In the context of experimental psychosis, dissociation was often conflated with psychosis, as both involved disruptions in agency, continuity of thought, and the perception of external reality.

Pharmacologically, ketamine’s role as a noncompetitive NMDA receptor antagonist strengthened its candidacy as a novel agent to model psychosis. Ketamine blocks glutamatergic neurotransmission in cortical and limbic circuits of the brain, which are implicated in schizophrenia and provides experimental support for an emerging glutamate hypothesis of schizophrenia. ³ Compared to serotonergic psychedelics, which primarily induced perceptual anomalies, NMDA antagonists such as ketamine and PCP seemed to replicate a broader range of the features of schizophrenia, including disorganization of thought and cognitive deficits.

Human studies during this period typically involved administering subanesthetic, intravenous doses of ketamine to healthy volunteers or patients with psychiatric diagnoses, followed by structured interviews and psychometric assessments. A particularly influential study was reported in 1994 report by Krystal et al., ² which demonstrated that ketamine could reliably elicit a spectrum of schizophrenia-like symptoms in a controlled laboratory setting. These findings encouraged the use of ketamine as a pharmacological model to explore both symptomatology and neurobiological substrates of psychosis, including through emerging neuroimaging and cognitive neuroscience methods.

However, the foundational assumption of this research program—that inducing symptoms analogous to a disorder could illuminate its underlying biology—would later be questioned. Critics argued that pharmacologically induced states might not accurately replicate endogenously arising psychiatric conditions. In this view, the face validity of psychotomimetic models could obscure the etiological complexity of disorders like schizophrenia, rather than elucidate them, and they might not lead to innovative treatments for the disorders being modeled.

Nevertheless, through the 1980s and into the early 1990s, ketamine maintained a stable place in psychiatric research as a tool for simulating psychosis. It was considered particularly valuable for studies investigating the neural correlates of perceptual and cognitive disruption using electroencephalography (EEG), functional neuroimaging, and pharmacological challenge methods. These investigations established significant groundwork for understanding neural circuits involved in dissociation and psychosis-like states—knowledge that would later inform ketamine’s therapeutic repositioning.

In summary, ketamine’s initial role in psychiatry was closely tied to experimental psychopathology and the quest for biological models of mental illness. Originally conceived as a method for reproducing psychotic symptoms in a controlled setting, ketamine’s complex and context-dependent effects would ultimately lead to re-evaluation of its therapeutic potential and the beginning of its conceptual migration from pathology to treatment.

Decline of the psychotomimetic paradigm

Despite its initial prominence in experimental psychiatry, ketamine’s use as a model of psychosis began to decline by the late 1990s and early 2000s. Several converging factors contributed to this decline, including critical reassessments of pharmacological modeling, evolution of psychiatric diagnostics, and growing ethical and reputational concerns. Collectively, these forces led to the erosion of the psychotomimetic paradigm, based on the questionable proposal that ketamine-induced states were legitimate proxies for endogenous psychosis.

A major critique of this paradigm was its reliance on phenomenological resemblance. While ketamine reliably induced symptoms such as hallucinations, thought disorder, anhedonia, and derealization, it was increasingly questioned whether these pharmacologically induced states were equivalent to those observed in schizophrenia. As psychiatry shifted toward a greater emphasis on construct validity—favoring models that mirrored pathophysiological processes and not mere surface features—ketamine’s relevance as a schizophrenia analog was increasingly challenged. Researchers noted that similarity in symptom presentation did not guarantee shared neurobiological substrates, and that psychotomimetic effects alone were insufficient to validate relevance to clinical disorders.

At the same time, psychiatry underwent a methodological and epistemological transformation. With the emergence of molecular genetics, functional neuroimaging, and computational modeling, the field moved beyond symptom-based models toward neurological circuit-level and network-based proposals concerning mental illness. Initiatives such as the Research Domain Criteria^4,5 and large-scale collaborations, including the Psychiatric Genomics Consortium prioritized biomarkers and endophenotypes over acute pharmacological simulations. ⁶ In this context, ketamine’s short-lived induction of psychosis-like states appeared increasingly inadequate for capturing the complexity of chronic psychiatric disorders and is not considered to contribute to ketamine’s antidepressant effects.^10,11

Diagnostic changes also contributed to the shift. Publication of DSM-III and its successors introduced greater nosological precision but also fragmented the concept of psychosis across multiple diagnostic entities—including mood disorders with psychotic features, schizoaffective disorders, and substance-induced psychosis.^8,9 This fragmentation complicated the rationale for using a single agent such as ketamine as a universal model for “psychosis,” weakening the theoretical foundations of psychotomimetic research.

Ethical considerations further accelerated the paradigm’s decline. Controlled studies with healthy volunteers began to reveal that ketamine could produce intense, distressing experiences, including depersonalization, confusion, anxiety, and dysphoria, ⁶ although a recent estimate of the risk of such effects in the use of ketamine to treat depression was approximately 2%.^12,13 Nevertheless, as research ethics came to prioritize participant safety, particularly in studies involving altered states of consciousness, institutional ethical review boards (IRBs) became more cautious in approving trials with psychotomimetic agents. Simultaneously, the rise of patient advocacy and trauma-informed care placed additional scrutiny on experiments that induced even transient forms of subjectively distressing psychopathology.

Adding to these circumstances was ketamine’s increasing association with recreational misuse. Known colloquially as “Special K,” it became a popular club drug, linked to euphoria, dissociation, and hallucinations. Media reports of its abuse, along with concerns about possible addiction, bladder toxicity, and cognitive impairment, led to regulatory restrictions and a decline in ketamine’s scientific credibility. Funding agencies, academic institutions, and ethics committees became increasingly reluctant to support studies involving a drug perceived as risky, as well as abused and stigmatized. ⁶

By the early 2000s, ketamine had largely retreated from psychiatric laboratories. It remained in use as an anesthetic and in some experimental settings but was no longer viewed as a promising model leading to greater understanding of psychosis. Ironically, the very features that contributed to ketamine’s marginalization—its rapid central nervous system effects, dissociative profile, and NMDA antagonism—would soon re-enter the psychiatric imagination, but under a radically different therapeutic framework.

Retrospectively, the decline of the psychotomimetic paradigm can be viewed not as an endpoint but as a pivot. It signaled a transition in psychiatric thought, from symptom modeling to therapeutic potential, from face validity to mechanistic specificity. Ketamine’s dissociative effects, once interpreted as pathological, would soon be reframed as therapeutic phenomena, underscoring the extent to which psychiatric meaning is contextually and conceptually constructed.

Emergence of antidepressant properties of ketamine

The transformation of ketamine from a psychotomimetic research tool into a novel antidepressant marked one of the most unexpected and consequential shifts in contemporary psychiatry. Emerging in the late 1990s, this therapeutic repositioning was driven by both the limitations of existing antidepressant treatments and the evolving understanding of mood disorders at the neurobiological level. Against the backdrop of treatment-resistant depression (TRD)—a condition characterized by high rates of morbidity, functional impairment, and suicide risk in association with unfavorable treatment response—ketamine offered a radically different pharmacological approach that promised rapidity as well as efficacy.

The first published clinical evidence of ketamine’s antidepressant effects came from a randomized, placebo-controlled crossover trial conducted by Berman et al. in 2000. ⁴ In this study, patients with major depressive disorder (MDD) received a single subanesthetic intravenous infusion of racemic R,S-ketamine (0.5 mg/kg). The results were striking: participants exhibited significant reductions in depressive symptoms within hours, with effects persisting for several days. These early findings were particularly notable because they defied conventional expectations of a delay of days or weeks to an antidepressant response.

Building on this foundation, Carlos Zarate and colleagues at the National Institute of Mental Health (NIMH) conducted a larger trial in 2006 focusing specifically on TRD. ⁵ Their findings corroborated and extended the results of Berman et al. ⁴ In addition to rapid antidepressant effects, ketamine also appeared to reduce suicidal ideation within 40 min of administration. This rapid onset of action, especially in acutely suicidal patients, represented a significant therapeutic breakthrough and generated intense interest in ketamine’s underlying mechanisms.

Mechanistic studies soon revealed that ketamine’s antidepressant effects were mediated through pathways distinct from those of traditional antidepressants. As a noncompetitive NMDA receptor antagonist, ketamine modulated glutamatergic neurotransmission rather than monoamine functions. Its inhibition of NMDA receptors led to downstream effects including activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors, engagement of the mammalian target of rapamycin (mTOR) pathway, and upregulation of brain-derived neurotrophic factor (BDNF).^14,15 These neuroplastic changes promoted synaptogenesis, particularly in the prefrontal cortex and hippocampus—regions implicated in mood regulation and cognitive processing. ¹⁵

Clinically, ketamine’s rapid and robust antidepressant effects prompted a reappraisal of long-held beliefs about the neurobiology of depression. The monoamine hypothesis involving proposed deficiencies of catecholamine and serotonin neurotransmitters, while historically influential and relevant to the actions of tricyclic antidepressants (TCAs), monoamine oxidase (MAO) inhibitors and selective inhibitors of serotonin reuptake (SSRIs), could not account for ketamine’s mechanism of action or its rapid effect. Instead, new models of depression emerged, emphasizing synaptic dysfunction, impaired neuroplasticity, and dysregulated neural circuits involving glutamatergic neurotransmission.

Despite growing enthusiasm, ketamine’s entry into clinical psychiatry was not without caution. Concerns were raised regarding its dose-related dissociative effects, potential for abuse, and lack of long-term data on its safety and sustained efficacy. Nevertheless, repeated-dose studies, clinical observations, and meta-analyses demonstrated consistent antidepressant efficacy across diverse populations, including patients with bipolar depression, comorbid anxiety, post-traumatic stress disorder (PTSD) and sustained suicidal risk.^16–18

In 2019, the U.S. Food and Drug Administration (FDA) approved intranasal esketamine (the S-enantiomer of ketamine), marketed as Spravato^®. This development further validated ketamine’s role in psychiatry. Indicated for use alongside oral antidepressants, esketamine demonstrated significant, although variable, clinical benefit in randomized trials, including for TRD. ¹⁹ Its approval marked both a regulatory milestone and a sign of shifting psychiatric paradigms, as agencies and clinicians began to embrace glutamatergic agents and rapid-acting treatments as attractive alternatives to traditional antidepressants. Curiously, there is some evidence that the R-enantiomer of ketamine may be even more effective as an antidepressant, longer-lasting, and better-tolerated as an antidepressant. ¹³

Importantly, ketamine’s antidepressant action also reignited interest in the role of subjective experience in psychiatric therapeutics. For some patients, the acute effects of ketamine—often described as dissociative, dream-like, or even spiritual—were not only tolerable but perceived as meaningful components of healing. These observations raised a provocative question: were these experiential effects incidental or integral to the therapeutic response? Subsequent studies exploring correlations between the intensity of dissociation and antidepressant efficacy began to blur the boundary between adverse effects and therapeutic mechanisms. ⁷

In summary, ketamine’s emergence as an antidepressant has redefined the field’s expectations regarding treatment onset, mechanism of action, and the role of altered consciousness in psychiatric healing, at least for depressive disorders. It has also set the stage for further exploration to find rapidly acting agents and opened the door to integrative models that combine pharmacology with psychological and experiential aspects of treatment.

Conceptual shifts in psychiatric therapeutics

The re-emergence of ketamine as a psychiatric therapeutic agent has catalyzed a broader paradigm shift in how mood disorders are conceptualized, studied, and treated. Historically, the dominant framework for understanding depression centered on the monoamine hypothesis, which posited that deficiencies in serotonin, norepinephrine or dopamine underpinned depressive symptoms and that antidepressants restored their availability and function. This model informed antidepressant development from the late 1950s onward and shaped decades of clinical practice. However, the modest efficacy and delayed onset of monoaminergic agents—particularly in patients with TRD—highlighted significant limitations in this approach.^21,22 Ketamine’s rapid onset and novel mechanism of action have challenged the field to reconsider core assumptions about both pathophysiology and therapeutic targets in mood disorders.

One of the most significant conceptual developments emerging from ketamine research was a renewed focus on neuroplasticity. Unlike traditional antidepressants, which exert their effects gradually, and supposedly through modulation of monoaminergic neurotransmission, ketamine generates rapid synaptogenic and neurotrophic effects, particularly in the cerebral prefrontal cortex and hippocampus—brain regions critical for regulation of mood and cognition. These changes are mediated through effects of ketamine, including altered glutamatergic signaling, AMPA (α-amino-3-hydroxyl-5-isoxazolepropionicacid) glutamate receptor activation, engagement with the mTOR (mammalian or mechanistic target of rapamycin, a kinase) pathway, increased expression of BDNF, and increased downstream activation of the GluN2 NMDA receptor subtype.^23,24 Consequently, new models of depression have emerged that emphasize disruption of neural circuits, impaired neural connectivity, and reduced synaptic strength, moving beyond the notion of simple neurotransmitter deficits.

This conceptual evolution also prompted a re-evaluation of psychiatric classification systems. Ketamine’s pronounced effects in TRD suggested that categorical diagnoses might not adequately capture relevant biological heterogeneity. Instead, dimensional approaches—such as clinical staging models, endophenotype-based subtypes, and biomarker-guided stratification—gained traction. Ketamine’s clinical utility encouraged efforts to identify predictors of treatment response, including neuroimaging markers, inflammatory profiles, and cognitive phenotypes, with the aim of contributing to greater precision in psychiatric diagnosis and treatment.

Another area of conceptual change involved the interpretation of dissociation and the role of subjective experience in psychiatric treatment. Initially, ketamine’s dissociative effects were viewed as adverse events to be minimized or tolerated. However, growing evidence suggested that these experiences—characterized by derealization, depersonalization, altered time perception, and ego dissolution—might contribute to therapeutic benefit. Some studies, though not all, reported correlations between the intensity of dissociative experiences and the magnitude of antidepressant response,^7,25 raising questions about the psychophysiological and psychological mechanisms through which ketamine exerts its effects. However, the emerging consensus is that dissociative effects do not contribute to the antidepressant actions of ketamine and are adverse, dose-dependent risks to be avoided clinically.^10,11

These considerations align with broader developments in psychedelic research, where altered states of consciousness are not just tolerated but actively harnessed for therapeutic gain. Although ketamine is pharmacologically distinct from classic psychedelics such as psilocybin, 3,4-methylenedioxymethamphetamine (MDMA), or lysergic acid diethylamide (LSD), its ability to induce non-ordinary states has positioned it as a bridge between traditional psychopharmacology and psychedelic-assisted therapies. This development has led to the emergence of ketamine-assisted psychotherapy (KAP), which seeks to combine pharmacological intervention with structured psychological support. ²⁶ While empirical validation of KAP remains in its early stages, preliminary findings suggest a potential synergy between ketamine-induced neuroplasticity and psychotherapeutic processes.^27,26

Ketamine’s integration into routine clinical practice revealed tensions between innovation and regulation, access and equity, and science and commercialization. The proliferation of ketamine clinics—often operating without standardized protocols—sparked debates regarding best practices, patient safety, and the ethical delivery of care. Moreover, the high cost and limited availability of FDA-approved esketamine, particularly in comparison to generic intravenous racemic (R,S) ketamine, raised concerns about pharmaceutical monopolies and disparities in treatment access. ¹⁶

Finally, ketamine has prompted a broader reassessment of the goals and methods of psychiatric care. The field is increasingly embracing integrative models that combine pharmacological, psychological, and experiential dimensions of treatment. This shift moves beyond the traditional view of mental illness as a static “chemical imbalance” toward a dynamic understanding of psychiatric disorders as disruptions in neurocognitive systems and subjective meaning-making processes. In this context, agents like ketamine have value not only for their pharmacological effects but also for their potential to catalyze psychological insight, emotional flexibility, and behavioral change.

In summary, ketamine has acted as both a catalyst and a mirror of a conceptual evolution in psychiatry. The unique profile of ketamine—pharmacological, experiential, and clinical—has encouraged the field to revisit foundational assumptions, explore new therapeutic mechanisms, and reimagine the nature of psychiatric healing in the 21st century.

Regulatory, ethical and cultural dimensions

The clinical and conceptual resurgence of ketamine has unfolded within a complex landscape of regulatory, ethical, and cultural tensions. Unlike most psychiatric medicines, which typically follow a trajectory from pharmaceutical development to clinical deployment, ketamine’s revival in psychiatry evolved largely from academic research and off-label experimentation. This inverted pathway introduced unique challenges for clinicians, policymakers, and patients navigating its integration into mainstream care.

Ketamine was originally approved by the FDA in 1970 as a dissociative anesthetic. Its widespread use in emergency medicine and battlefield surgery reflected its rapid onset, lack of adverse cardiovascular effects, and generally favorable safety profile. However, it was not until 2019 that the FDA approved a version of ketamine—esketamine, the S-enantiomer (Spravato^®)—for a psychiatric indication: TRD, administered as a nasal spray under strict supervision. ²⁸ This approval marked a historic milestone but also exposed regulatory and logistical hurdles that have continued to complicate its clinical dissemination. Of note, it remains uncertain whether the S-enantiomer is superior to the R-form.^29,20

Esketamine’s approval was supported by a series of randomized controlled trials (RCTs), many of which demonstrated rapid improvements in depressive symptoms and suicidal thinking (but as yet, not suicidal behavior). ³⁰ However, the regulatory process was not without controversy. Some trials failed to show significant differences between esketamine and control treatments, prompting debates over clinical significance and trial design. Moreover, the requirement that esketamine be administered in certified medical settings—due to risks of dissociation, sedation, and misuse—has limited its accessibility. Uncertainties about long-term use, relatively high costs, insurance restrictions, and logistical burdens associated with these restrictions have disproportionately affected rural populations and underserved groups, highlighting issues of health equity. ³² Pharmacovigilance data further emphasize the need for caution. Analysis of post-marketing surveillance reports, including the FDA Adverse Event Reporting System (FAERS), indicates that esketamine is associated with dissociation, sedation, dizziness, and, less frequently, urinary symptoms or hypertension. A recent study by Jiang et al. ¹³ highlighted that while most adverse events are transient and manageable, vigilance is warranted given the widespread clinical uptake of intranasal esketamine. These observations complement randomized controlled trial evidence and underscore the importance of careful monitoring and standardized protocols in routine practice.

In parallel, the widespread off-label use of intravenous racemic ketamine for depression and related disorders has grown rapidly, often outside of formal regulatory oversight. Ketamine clinics now operate across North America and beyond, offering infusions or intranasal administrations for mood, anxiety, and trauma-related disorders. Such clinics vary considerably in their protocols, standards of care, integration with comprehensive psychiatric care, and long-term follow-up. While many uphold rigorous clinical standards, others operate in a regulatory gray zone, raising concerns about patient safety, treatment consistency, and potential exploitation of vulnerable populations.

The commercialization of ketamine has further complicated its ethical landscape. Janssen Pharmaceuticals, the manufacturer of Spravato^®, has faced criticism for alleged lobbying efforts that limit insurance coverage of generic intravenous ketamine, effectively steering patients toward its proprietary product. This practice has resulted in a two-tiered system in which clinical decisions may be driven as much by insurance dynamics and geographic availability as by evidence. As a result, access to ketamine therapy remains uneven, with affordability and institutional resources determining who benefits from this innovation.

Cultural narratives around ketamine also have shifted dramatically. Once stigmatized as an abused agent aimed at recreational dissociation, ketamine is now rebranded in media and clinical discourse as a cutting-edge psychiatric intervention. Headlines tout its ability to “rewire the brain” and provide “instant relief” from depression, often simplifying complex evidence and inflating expectations. This duality—between the therapeutic and the sensational—poses challenges for informed consent, as patients may approach ketamine treatment with unrealistic hopes or insufficient understanding of potential risks, including dependency, cognitive effects, and urological toxicity with prolonged use. ⁶

The subjective experience of ketamine also plays a central role in its ethical discourse. Its dissociative and time-distorting properties, while sometimes therapeutically beneficial, can be unpredictable and unsettling. Clinicians must prepare patients for a range of responses and provide appropriate psychological support for safe treatment. In this context, the growing field of KAP has emerged, combining pharmacological effects with a structured psychotherapeutic framework.^27,26 Early data suggest that KAP may prolong and deepen ketamine’s antidepressant effects, but the evidence remains preliminary, and standardization of assessment is lacking. Issues related to clinician training, patient preparation, and integration of treatment protocols remain unresolved.

Ketamine’s regulatory journey is also connected to the broader resurgence of psychedelic medicine. Approval of ketamine for psychiatric use coincided with renewed interest in psilocybin, MDMA, and other substances capable of inducing altered states of consciousness. In this context, ketamine serves as a pharmacological bridge between conventional psychopharmacology and the experiential paradigms of psychedelic therapy. This convergence has prompted new discussions about the roles of consciousness, meaning-making, and therapeutic context in psychiatric care.

As previously noted, the regulatory, ethical, and cultural dimensions of ketamine treatment reflect the complexities of integrating a pharmacologically unconventional agent into psychiatric practice. While ketamine offers hope to many patients with refractory mood disorders, its safe and equitable use depends on thoughtful governance, rigorous science, and a continued commitment to ethical care. The field must strike a balance between innovation and responsibility, ensuring that the enthusiasm surrounding ketamine does not outpace the systems necessary to support its long-term, safe, and sustainable integration.

Conclusion

Ketamine’s development in psychiatry represents a compelling case study in the evolving construction of therapeutic meaning. Its journey—from dissociative anesthetic to psychotomimetic probe, from stigmatized street drug to FDA-approved antidepressant—has unfolded over six decades shaped by shifting scientific paradigms, clinical needs, and sociocultural frameworks. Unlike most psychotropic agents that follow a relatively linear development path, ketamine’s psychiatric identity has undergone multiple reinventions, each reflecting dominant conceptual, diagnostic, and methodological priorities of its time.

In the 1970s and 1980s, ketamine was primarily a tool for experimental psychopathology, valued for its ability to induce transient dissociative and perceptual alterations which were utilized to model the phenomenology of psychosis and investigate neurobiological mechanisms underlying schizophrenia and other psychoses, particularly through the lens of NMDA-mediated neurotransmission. During those earlier times, ketamine was firmly established as a mirror of pathology—valuable for simulating mental illness but not for treating it.

That framing began to dissolve in the early 2000s when clinical trials revealed ketamine’s capacity to produce rapid and robust antidepressant effects, including in individuals with treatment-resistant depression and bipolar depression. These findings were not only therapeutically significant but also epistemologically disruptive, as they challenged longstanding assumptions about the time-course, neurochemical underpinnings, and subjective correlates of antidepressant efficacy. Ketamine’s ability to induce rapid symptom relief—often within hours—catalyzed a conceptual shift from monoaminergic to glutamatergic models of pathophysiology and from passive symptom suppression to active neuroplasticity as a target of psychiatric intervention.

Importantly, ketamine’s reclassification from psychotomimetic agent to antidepressant underscores the fluidity of psychiatric knowledge. The same pharmacological compound, operating through the same receptor mechanisms, was seen as pathological in one era and later as therapeutic. This transformation illustrates how diagnostic categories, research methods, and cultural narratives shape not only what is treated but also how treatment is conceptualized and legitimized.

Ketamine’s rise also coincided with renewed interest in altered states of consciousness as therapeutic tools, linking it to a broader renaissance in psychedelic-assisted psychotherapy. Although pharmacologically distinct from serotonergic psychedelics, ketamine’s dissociative effects prompted similar questions regarding the role of experience, context, and psychological integration in healing. Its use has reignited debates about the boundaries between pharmacotherapy and psychotherapy, biological mechanisms and subjective meaning, as well as scientific innovation and ethical responsibility.

Currently, the clinical use of ketamine for depression involves two main approaches. The only formulation with regulatory approval is intranasal esketamine (Spravato^®), authorized by the U.S. FDA and EMA for treatment-resistant depression and administered under strict medical supervision. While effective for some patients, its high cost and limited insurance coverage restrict access in many regions, raising issues of equity. In parallel, off-label intravenous infusions of racemic ketamine (R,S-ketamine) have been widely adopted in specialized clinics, typically at subanesthetic doses, offering a more affordable and accessible option, though without formal regulatory approval. Beyond these, other galenic formulations are in development, including R-ketamine, hydroxynorketamine, and orally bioavailable NMDA modulators, which may provide sustained benefits with improved tolerability. Together, these evolving practices highlight both the promise and the challenges of integrating ketamine into contemporary psychiatric care.

As ketamine becomes increasingly integrated into routine psychiatric therapeutics, it continues to challenge established models of regulation, delivery, and integration. Issues of access, long-term use, safety, efficacy, and commercialization remain critical concerns. At the same time, its success has opened new avenues for research, including the development of related compounds such as R-ketamine, hydroxynorketamine, and other glutamatergic modulators, which may maintain therapeutic effects while minimizing adverse outcomes and potentially providing oral bioavailability.^32,33

Ultimately, ketamine’s psychiatric biography is not only a story of pharmacological repurposing but a mirror of psychiatry’s broader evolution. It highlights the contingency of medical diagnostic categories, interpretive flexibility in psychopharmacology, and the enduring interplay between scientific discovery, clinical practice, and cultural meaning. Understanding ketamine’s transformation helps illuminate how treatments gain (or lose) legitimacy—and how psychiatry, as both a science and a profession, continually redefines its boundaries of healing. ³⁴