[History of Ketamine: An ancient molecule that is still popular today]. / Histoire de la kétamine : une molécule ancienne qui a toujours la cote.

The history of ketamine begins in 1962, when Calvin Stevens of the pharmaceutical laboratory Parke-Davis synthesizes it from phencyclidine, a molecule with psychodysleptic, hallucinogenic and dissociative properties. Following the first administration of ketamine to humans in 1964 in Jackson prison (Michigan, USA), its dissociative effects associated with short anaesthesia were reported, and a patent for its human use was filed in 1966. In the 1990s, the discovery of opioid-induced hyperalgesia sparked interest in ketamine as an analgesic. In recent years, the human use of ketamine, and in particular its esketamine enantiomer, has shifted towards the treatment of depression. The first cases of ketamine abuse were reported in 1992 in France, leading to special surveillance by the health authorities, and its inclusion in the list of narcotic drugs in 1997. Today, ketamine has become an attractive substance for recreational use, gradually emerging from alternative techno circles to spread to more commercial party scenes. These elements represent a public health concern, associated with the risk of developing new chemically synthesized analogues, the harmful effects of which are still little known.

Rapid-acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective.

Major depressive disorder (MDD) is one of the most disabling psychiatric disorders. Approximately one-third of the patients with MDD are treatment resistant to the current antidepressants. There is also a significant therapeutic time lag of weeks to months. Furthermore, depression in patients with bipolar disorder (BD) is typically poorly responsive to antidepressants. Therefore, there exists an unmet medical need for rapidly acting antidepressants with beneficial effects in treatment-resistant patients with MDD or BD. Accumulating evidence suggests that the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine produces rapid and sustained antidepressant effects in treatment-resistant patients with MDD or BD. Ketamine is a racemic mixture comprising equal parts of (R)-ketamine (or arketamine) and (S)-ketamine (or esketamine). Because (S)-ketamine has higher affinity for NMDAR than (R)-ketamine, esketamine was developed as an antidepressant. On 5 March 2019, esketamine nasal spray was approved by the US Food and Drug Administration. However, preclinical data suggest that (R)-ketamine exerts greater potency and longer-lasting antidepressant effects than (S)-ketamine in animal models of depression and that (R)-ketamine has less detrimental side-effects than (R,S)-ketamine or (S)-ketamine. In this article, the author reviews the historical overview of the antidepressant actions of enantiomers of ketamine and its major metabolites norketamine and hydroxynorketamine. Furthermore, the author discusses the other potential rapid-acting antidepressant candidates (i.e., NMDAR antagonists and modulators, low-voltage-sensitive T-type calcium channel inhibitor, potassium channel Kir4.1 inhibitor, negative modulators of γ-aminobutyric acid, and type A [GABAA ] receptors) to compare them with ketamine. Moreover, the molecular and cellular mechanisms of ketamine's antidepressant effects are discussed.

The Domino Effect: Ed Domino's early studies of Psychoactive Drugs.

University of Michigan Pharmacology Professor Ed Domino is an expert in the field of neuropsychopharmacology. For over six decades, Dr. Domino has made many contributions to our understanding of psychoactive drugs, but is most well-known for his role in the development of ketamine anesthesia. This article covers the story behind this discovery, along with many other fascinating personal and professional anecdotes, all of which provide insight into the career of a remarkable scientist.

Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings).

For more than 50 years, ketamine has proven to be a safe anesthetic drug with potent analgesic properties. The active enantiomer is S(+)-ketamine. Ketamine is mostly metabolized in norketamine, an active metabolite. During "dissociative anesthesia", sensory inputs may reach cortical receiving areas, but fail to be perceived in some association areas. Ketamine also enhances the descending inhibiting serotoninergic pathway and exerts antidepressive effects. Analgesic effects persist for plasma concentrations ten times lower than hypnotic concentrations. Activation of the (N-Methyl-D-Aspartate [NMDA]) receptor plays a fundamental role in long-term potentiation but also in hyperalgesia and opioid-induced hyperalgesia. The antagonism of NMDA receptor is responsible for ketamine's more specific properties. Ketamine decreases the "wind up" phenomenon, and the antagonism is more important if the NMDA channel has been previously opened by the glutamate binding ("use dependence"). Experimentally, ketamine may promote neuronal apoptotic lesions but, in usual clinical practice, it does not induce neurotoxicity. The consequences of high doses, repeatedly administered, are not known. Cognitive disturbances are frequent in chronic users of ketamine, as well as frontal white matter abnormalities. Animal studies suggest that neurodegeneration is a potential long-term risk of anesthetics in neonatal and young pediatric patients.

Taming the ketamine tiger. 1965.

Pharmacologic actions of CI-581, a chemical derivative of phencyclidine, were determined in 20 volunteers from a prison population. The results indicate that this drug is an effective analgesic and anesthetic agent in doses of 1.0 to 2.0 mg per kilogram. With intravenous administration the onset of action is within 1 min and the effects last for about 5 to 10 min, depending on dosage level and individual variation. No tachyphylaxis was evident on repeat doses. Respiratory depression was slight and transient. Hypertension, tachycardia, and psychic changes are undesirable characteristics of the drug. Whether these can be modified by preanesthetic medication was not determined in this study. Recovery from analgesia and coma usually took place within 10 min, although from electroencephalographic evidence it may be assumed that subjects were not completely normal until after 1 to 2 h. No evidence of liver or kidney toxicity was obtained. CI-581 produces pharmacologic effects similar to those reported for phencyclidine, but of shorter duration. The drug deserves further pharmacologic and clinical trials. It is proposed that the words "dissociative anesthetic" be used to describe the mental state produced by this drug.

'The Drug of War'--a historical review of the use of Ketamine in military conflicts.

Anaesthesia for surgery during armed conflict was traditionally based on simple and reliable techniques. These often required a minimum of equipment and drugs while ensuring rapid and safe patient recovery. Ketamine, which first became available in Britain in the 1970s, was thought to offer certain favorable characteristics for use as a military anaesthetic agent. This article discusses the use of ketamine in many of the major armed conflicts that have occurred since its introduction. It also catalogues the methods used by anaesthetists at the time and their opinions of the drug's success.

Ketamina, una antigua droga que renace ante el dolor: parte I / Ketamine, and old drug coming back for pain management: part I

La Ketamina es una antigua droga usada como inductor anestésico, que debido a sus efectos adversos alucinatorios se subutilizó en las últimas décadas, pero debido al avance de las neurociencias y al conocimiento del dolor, renace como un potente medicamento analgésico (antihiperalgésico). Es un bloqueador no competitivo de los receptores NMDA, que son los receptores que se activan cuando el dolor es intenso, se postula que se podría utilizar para disminuir la percepción del dolor. es un neuromodulador del dolor y potenciador de la acción analgésica de los opioides. Los estudios clínicos han evidenciado su uso en el manejo del dolor postoperatorio dentro de una modalidad multimodal, con menor incidencia de náuseas y vómitos que al usar opioides solos y con reacciones adversas de tipo alucinatorias escasas. Las dosis ideales para los distintos tipos de cirugía, actualmente se basan en opiniones de expertos y se requieren mayores estudios. En dolor neuropático y en dolor por cáncer existe evidencia tipo IV, basadas en serie de casos que muestra ser útil. En tolerancia por opioides y en cronificación del dolor postoperatorio existen buenos estudios, pero aún no concluyentes. En conclusión, la ketamina es un fármaco útil, pero se debe conocer muy bien su farmacología para poder usarlo de manera segura y con un buen criterio clínico para el manejo del dolor moderado y/o intenso.

Ketamine is an old drug used in the induction of anesthesia that due to adverse hallucinatory effects has been under utilized during the past decades. However, the advances in neuroscience and a deeper knowledge of pain, ketamine is reborn as a strong analgesic (antihyperalgesic) aid. Ketamine is a non competitive blocker of NMDA receptors that are activated by severe pain and it could be used in pain reduction. Ketamine is a pain neuromodulator and enhancer of the opioids analgesic action. Clinicals trials showed it can be used in post surgery pain management in a number of ways with lessened side effects sunch as nausea and vomiting and scare hallucinatory effects compared to those caused by opioid treatment alone. the ideal dosage for different types of surgery now relies on the opinion of experts, however, further research is required. In neuropathic and cancer pain there is type IV evidence based on a number of cases that proves to be useful. Good trials, but not yet conclusive have been made in matters of tolerance to opioids and post surgery chronic pain. In conclusion, Ketamine is a useful drug, however, a deep knowledge of the same as well as good judgement are required for using it in moderate and/or severe pain management.

Ketamina: Nuevas observaciones sobre su consumo, consumidores y efectos / Ketamine: further observations on use, users and consequences

La ketamina es un anestésico disociativo que continúa siendo muy aceptado tanto en la medicina humana como veterinaria. Sin embargo, la ketamina tiene también importantes propiedades alucinógenas, psicodélicas y estimulantes que han hecho aumentar su consumo para fines no médicos en los últimos veinte años. La droga afecta a distintos sistemas del cerebro, como por ejemplo, los de glutamato, dopamina (con efectos muy similares a la cocaína, incluyendo el bloqueo de la recaptación de dopamina), serotonina, opioides, noradrenalina y cortisol, entre otros. En términos generales, los consumidores se dividen en dos grupos: trabajadores o personas allegadas a centros hospitalarios y veterinarios que tienen acceso a la droga y suelen inyectarse el líquido, con efectos sobre todo psicodélicos, e individuos vinculados principalmente al mundo de la cultura “dance” que consumen ketamina por vía intranasal, en forma de polvos, con efectos más estimulantes. Este artículo analiza la historia de la ketamina desde su invención en 1962, los efectos por los que se consume fuera del contexto médico, incluyendo la reproducción de la experiencia de la cercanía de la muerte, el modo en que estos efectos pueden aparecer, la neurociencia de la ketamina, la naturaleza de las poblaciones consumidoras de dicha droga, y los efectos negativos, tanto psicológicos como físicos, que pueden derivarse de su consumo, incluyendo el problema cada vez mayor de la adicción a la ketamina (AU)

Ketamine is a dissociative anesthetic which continues to have an accepted place in both human and animal medicine. However, ketamine also has powerful hallucinogenic, psychedelic and stimulant properties which have resulted in increased non-medical use over the past two decades. The drug affects many different systems in the brain, including glutamate, dopamine (with effects closely resembling cocaine, including the blockade of dopamine reuptake), serotonin, opioid, noradrenalin, cortisol and other systems. Users are broadly divided into hospital and veterinarylinked staff and their friends who have access to the drug and are more likely to inject the liquid, resulting in primarily psychedelic effects, and users primarily linked with the dance culture who takes ketamine powder by the intranasal route, resulting in more stimulant effects. This paper will consider the history of ketamine since its invention in 1962, the effects for which it is taken in a non-medical context including reproduction of the near-death experience, how these effects may arise, the neuroscience of ketamine, the nature of ketamine-using populations, and the psychological and physical adverse effects that may result from this use, including the growing problem of ketamine dependence (AU)

New drugs of abuse.

Newer drugs of abuse, such as MDMA, GHB, GBL, 1,4-BD and ketamine, are frequently used in the settings of raves and are often promoted on the internet. The popularity of these agents is increasing; therefore, emergency physicians should become familiar with the clinical presentations and management of the toxicity induced by these agents.

[20 years of ketamine--a backward look]. / 20 Jahre Ketamin--ein Rückblick.

Twenty years ago, ketamine was introduced into clinical use in Germany. Since this time, advantages and disadvantages of "dissociative anesthesia" with ketamine have been reported in many studies. Improvements were seen in stabilization of blood pressure during induction of shock patients, induction of patients with asthma, and preservation of spontaneous breathing as well as protective reflexes. On the other hand, psychomimetic reactions and an increase in cardiac oxygen consumption restricted the clinical use of ketamine. The incidence of these side effects was reduced when ketamine was combined with benzodiazepines. In the course of time ketamine was used in obstetrics, as an analgesic agent, in burn patients, and in emergency and disaster medicine. The influence of ketamine on intracranial pressure and the endocrine stress response was investigated as well. Unconventional aspects were reported by several authors concerning oral, intrathecal, epidural, nasal, and rectal administration and the use of ketamine for intravenous regional anesthesia, whereby the local anesthetic properties of ketamine became evident. In conclusion, intravenous and intramuscular "sympathomimetic anesthesia" with ketamine has found its place in anesthesiology. Insufficient hypnotic properties can be diminished by combination with benzodiazepines. The main indications for ketamine are anesthesia and analgesia in emergency and disaster medicine. In clinical use, the substance is of benefit in the induction of anesthesia for cesarean section, in shock situations, for asthma patients, and for short operations and painful diagnostic procedures. Intramuscular administration is preferred in uncooperative patients and children. In intensive care medicine, ketamine is of special interest in patients with hypotensive circulatory dysregulation and in ventilator treatment of asthma patients.