1Department of Pharmacology, Matoshri College of Pharmacy, Eklahare, Nashik, Maharashtra, India
2Department of Pharmacology, K. V. N. Naik S. P. Sanstha's, Institute of Pharmaceutical Education & Research, Nashik, Maharashtra, India
Ketamine, originally synthesized in the early 1960s as a safer alternative to phencyclidine (PCP), has since evolved into a multifaceted agent with applications extending far beyond its initial use as a dissociative anesthetic in surgical settings. With a unique pharmacological profile characterized by N-methyl-D-aspartate (NMDA) receptor antagonism, ketamine induces rapid anesthesia, analgesia, and dissociation. However, over the past two decades, it has garnered significant attention for its rapid-acting antidepressant effects, particularly in individuals with treatment-resistant depression (TRD), a condition that fails to respond to conventional antidepressants. Clinical trials and real-world data have demonstrated that low-dose ketamine, administered intravenously or intranasally, can produce profound and sustained improvements in mood within hours, a stark contrast to the delayed onset of traditional antidepressants.The therapeutic promise of ketamine has extended into the realms of post-traumatic stress disorder (PTSD), bipolar depression, anxiety disorders, and suicidal ideation, positioning it as a breakthrough in psychiatric medicine. Nevertheless, ketamine’s benefits are tempered by concerns surrounding its safety, potential for abuse, and long-term neuropsychiatric effects. As a Schedule III controlled substance, ketamine is also misused recreationally, known colloquially as “Special K,” for its hallucinogenic and dissociative properties. Chronic use has been associated with cognitive deficits, urinary tract dysfunction, and addiction, necessitating careful monitoring in both clinical and non-clinical contexts.This review paper provides a comprehensive examination of ketamine’s evolving role in modern medicine by exploring its pharmacodynamics and pharmacokinetics, mechanisms of antidepressant action, and evidence from clinical studies. It also delves into its misuse potential, societal impact, ethical considerations in off-label psychiatric use, and regulatory challenges. By synthesizing data from preclinical and clinical research, the paper seeks to present a balanced perspective on ketamine’s dual identity—as a therapeutic breakthrough and a drug of misuse—highlighting the imperative for responsible clinical integration and ongoing research.
Ketamine (2-(2-chlorophenyl)-2-(methylamino)cyclohexanone) stands as one of the most intriguing and versatile compounds in modern pharmacology. Synthesized in 1962 and approved for medical use in 1970, ketamine was initially introduced as a dissociative anesthetic with a better safety profile than its predecessor, phencyclidine (PCP). Its rapid onset, profound analgesic properties, and minimal respiratory depression made it a valuable anesthetic, especially in battlefield and emergency settings. Unlike many traditional anesthetics, ketamine produces a trance-like state characterized by profound analgesia, sedation, and amnesia, while maintaining airway reflexes and cardiovascular stability. These properties positioned ketamine as a vital tool in surgical and critical care settings, particularly in resource-limited environments. In recent decades, ketamine’s clinical profile has expanded dramatically beyond its traditional anesthetic role. A growing body of research has uncovered its powerful antidepressant effects, especially in individuals suffering from treatment-resistant depression (TRD), where conventional pharmacotherapies often fail. Low-dose intravenous ketamine and, more recently, intranasal esketamine (an enantiomer of ketamine), have shown rapid and robust antidepressant activity, sometimes within hours of administration. These findings have revolutionized the approach to mood disorders and prompted a re-evaluation of the neurobiology of depression itself. The emerging role of ketamine in psychiatry now includes applications for anxiety disorders, bipolar depression, post-traumatic stress disorder (PTSD), and suicidal ideation, with ongoing clinical trials exploring even broader indications. The pharmacological underpinnings of ketamine’s effects are multifaceted. Primarily, ketamine acts as a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptor involved in synaptic plasticity, learning, and memory. This mechanism not only accounts for its anesthetic and dissociative effects but also underlies its rapid antidepressant action, possibly through enhancement of synaptogenesis and neurotrophic signaling pathways, such as brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR). However, ketamine’s pharmacodynamics extend beyond NMDA receptor antagonism, involving interactions with opioid receptors, monoaminergic systems, and inflammatory pathways—highlighting its complex and still not fully understood mechanism of action. Despite these promising therapeutic applications, ketamine’s profile is shadowed by its significant potential for misuse and dependence. Recreational users seek its hallucinogenic and dissociative effects, often referring to experiences such as the “K-hole,” a state of extreme dissociation. Chronic recreational use has been associated with a range of health issues, including cognitive impairment, urinary tract dysfunction (ketamine-induced ulcerative cystitis), hepatic toxicity, and psychological dependence. These risks complicate ketamine’s integration into routine psychiatric practice and raise ethical, regulatory, and societal concerns. As ketamine straddles the line between a revolutionary therapeutic agent and a substance of abuse, its role in medicine remains complex and dynamic. The regulatory landscape continues to evolve in response to its rising medical use and concurrent misuse. In some countries, ketamine clinics have emerged, offering outpatient treatment for depression, anxiety, and chronic pain. At the same time, law enforcement and public health officials grapple with increasing illicit use. This review aims to present a comprehensive and critical analysis of ketamine’s multifaceted identity in modern medicine. It explores the historical development of the drug, its pharmacological mechanisms, clinical applications, and therapeutic efficacy. It also addresses the risks associated with misuse, dependence, and long-term health outcomes. Through an examination of current research, clinical practices, and ongoing debates, this paper provides an in-depth understanding of ketamine’s medical evolution and its implications for the future of psychiatric and anesthetic care.
Rahul Chaudhari*, Mohan Nikam, Krushna Bharwad, Onkar Khatode, Aniruddh Thorat, Pratik Bhabad, Ketamine in Modern Medicine: Antidepressant Breakthrough, Anesthetic Staple, or Substance of Misuse, Int. J. Sci. R. Tech., 2025, 2 (5), 644-657. https://doi.org/10.5281/zenodo.15560054
10.5281/zenodo.15560054
