Scientific Literature – American Society of Ketamine Physicians, Psychotherapists, and Practitioners


Ketamine was introduced into clinical practice in the 1960s and continues to be both clinically useful and scientifically intriguing. With its diverse molecular targets and neurophysiological properties, ketamine’s effects on the central nervous system remain incompletely understood. Researchers have utilized ketamine’s unique characteristics to investigate fundamental mechanisms of anesthetic action. Recent evidence suggests that ketamine-induced anesthesia may disrupt corticocortical information transfer in a frontal-to-parietal (“top-down”) distribution. This proposed mechanism has also been observed with anesthetics in other pharmacological classes. Ketamine remains indispensable in anesthesiology and critical care due to its ability to maintain cardiorespiratory stability while providing effective sedation and analgesia.

Moreover, ketamine is increasingly recognized for its potential in treating refractory depression and Post-Traumatic Stress Disorder (PTSD). This article reviews the history of ketamine, its pharmacology, proposed mechanisms of action, and current clinical applications.

Fifty years ago, Corssen and Domino (1966) published the first clinical study on ketamine as a human anesthetic. Ketamine induces a unique state termed “dissociative anesthesia,” a concept coined by Domino’s wife in 2010. In this state, patients may appear awake with preserved airway reflexes and respiratory drive, yet are unresponsive to sensory input (Domino et al., 1965). Ketamine also offers potent analgesia with a remarkable safety profile, making it a preferred anesthetic induction agent across various patient populations and settings.

Initially developed as an anesthetic, ketamine has evolved over decades to reveal broader medical applications. Extensive literature highlights its clinical efficacy in diverse fields, including pain management and treatment-resistant depression. Simultaneously, ongoing research into ketamine’s mechanisms of action provides new insights into the relationship between consciousness and anesthesia.

Since its clinical debut, ketamine has emerged as one of the most distinctive and promising anesthetic agents available today. This article aims to provide an overview of ketamine’s historical development, pharmacological properties, proposed mechanisms of action, and current clinical uses.

History: Ketamine’s history traces back to the discovery of phencyclidine in 1956, a compound with unique pharmacology synthesized by chemists at the Parke Davis Company (Maddox et al., 1965). Phencyclidine induced various effects in animal models, including anesthesia in monkeys and cataleptoid states in pigeons (Domino and Luby, 2012). Despite its efficacy as an anesthetic in humans, phencyclidine’s prolonged emergence delirium made it unsuitable for clinical use (Greifenstein et al., 1958; Johnstone et al., 1959; Domino and Luby, 2012).

Subsequent efforts focused on developing shorter-acting analogs of phencyclidine with similar anesthetic potential but reduced emergence delirium. Ketamine, initially identified as CI-581, was synthesized by Parke Davis consultant and organic chemist Calvin Stevens in 1962 (Domino, 1980). As a structural analog one-tenth as potent as phencyclidine, ketamine was selected for human trials. On August 3, 1964, the first human anesthetic dose of ketamine was administered by Dr. Edward Domino of Pharmacology and Dr. Guenter Corssen of Anesthesiology at the University of Michigan (Domino et al., 1965). Their initial study in 20 humans demonstrated ketamine’s safety and efficacy as a clinical anesthetic (Domino et al., 1965). In 1966, Corssen and Domino published the first clinical report on ketamine, documenting its anesthetic effects in 130 patients across various age groups undergoing surgical procedures (Corssen and Domino, 1966). They noted ketamine’s ability to rapidly induce profound analgesia and altered consciousness, with minimal side effects and less severe emergence delirium compared to phencyclidine (Corssen and Domino, 1966). Ketalar (1970) subsequently became the first ketamine preparation approved by the FDA for human use.

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