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Frontiers in Pharmacology 2020Ketamine, an N-methyl-D-aspartate receptor antagonist, is widely known as a dissociative anesthetic and phencyclidine derivative. Due to an undesirable adverse event... (Review)
Review
Ketamine, an N-methyl-D-aspartate receptor antagonist, is widely known as a dissociative anesthetic and phencyclidine derivative. Due to an undesirable adverse event profile when used as an anesthetic it had widely fallen out of human use in favor of more modern agents. However, it has recently been explored for several other indications such as treatment resistant depression and chronic pain. Several recent studies and case reports compiled here show that ketamine is an effective analgesic in chronic pain conditions including cancer-related neuropathic pain. Of special interest is ketamine's opioid sparing ability by counteracting the central nervous system sensitization seen in opioid induced hyperalgesia. Furthermore, at the sub-anesthetic concentrations used for analgesia ketamine's safety and adverse event profiles are much improved. In this article, we review both the basic science and clinical evidence regarding ketamine's utility in chronic pain conditions as well as potential adverse events.
PubMed: 33708116
DOI: 10.3389/fphar.2020.599721 -
Biomolecules Jun 2020N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP), dizocilpine (MK-801) and ketamine have long been considered a model of schizophrenia, both... (Review)
Review
N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP), dizocilpine (MK-801) and ketamine have long been considered a model of schizophrenia, both in animals and humans. However, ketamine has been recently approved for treatment-resistant depression, although with severe restrictions. Interestingly, the dosage in both conditions is similar, and positive symptoms of schizophrenia appear before antidepressant effects emerge. Here, we describe the temporal mechanisms implicated in schizophrenia-like and antidepressant-like effects of NMDA blockade in rats, and postulate that such effects may indicate that NMDA receptor antagonists induce similar mechanistic effects, and only the basal pre-drug state of the organism delimitates the overall outcome. Hence, blockade of NMDA receptors in depressive-like status can lead to amelioration or remission of symptoms, whereas healthy individuals develop psychotic symptoms and schizophrenia patients show an exacerbation of these symptoms after the administration of NMDA receptor antagonists.
Topics: Animals; Brain; Depression; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Humans; Ketamine; Phencyclidine; Receptors, N-Methyl-D-Aspartate; Schizophrenia
PubMed: 32585886
DOI: 10.3390/biom10060947 -
International Journal of Molecular... May 2022Mental illness modeling is still a major challenge for scientists. Animal models of schizophrenia are essential to gain a better understanding of the disease... (Review)
Review
Mental illness modeling is still a major challenge for scientists. Animal models of schizophrenia are essential to gain a better understanding of the disease etiopathology and mechanism of action of currently used antipsychotic drugs and help in the search for new and more effective therapies. We can distinguish among pharmacological, genetic, and neurodevelopmental models offering various neuroanatomical disorders and a different spectrum of symptoms of schizophrenia. Modeling schizophrenia is based on inducing damage or changes in the activity of relevant regions in the rodent brain (mainly the prefrontal cortex and hippocampus). Such artificially induced dysfunctions approximately correspond to the lesions found in patients with schizophrenia. However, notably, animal models of mental illness have numerous limitations and never fully reflect the disease state observed in humans.
Topics: Animals; Antipsychotic Agents; Behavior, Animal; Disease Models, Animal; Hippocampus; Humans; Prefrontal Cortex; Schizophrenia
PubMed: 35682647
DOI: 10.3390/ijms23115968 -
Annales Pharmaceutiques Francaises Jan 2022The history of ketamine begins in 1962, when Calvin Stevens of the pharmaceutical laboratory Parke-Davis synthesizes it from phencyclidine, a molecule with... (Review)
Review
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.
Topics: Anesthetics, Dissociative; History, 20th Century; History, 21st Century; Humans; Ketamine; Stereoisomerism; Substance-Related Disorders
PubMed: 33915159
DOI: 10.1016/j.pharma.2021.04.005 -
Nature Oct 2020Advanced imaging methods now allow cell-type-specific recording of neural activity across the mammalian brain, potentially enabling the exploration of how brain-wide...
Advanced imaging methods now allow cell-type-specific recording of neural activity across the mammalian brain, potentially enabling the exploration of how brain-wide dynamical patterns give rise to complex behavioural states. Dissociation is an altered behavioural state in which the integrity of experience is disrupted, resulting in reproducible cognitive phenomena including the dissociation of stimulus detection from stimulus-related affective responses. Dissociation can occur as a result of trauma, epilepsy or dissociative drug use, but despite its substantial basic and clinical importance, the underlying neurophysiology of this state is unknown. Here we establish such a dissociation-like state in mice, induced by precisely-dosed administration of ketamine or phencyclidine. Large-scale imaging of neural activity revealed that these dissociative agents elicited a 1-3-Hz rhythm in layer 5 neurons of the retrosplenial cortex. Electrophysiological recording with four simultaneously deployed high-density probes revealed rhythmic coupling of the retrosplenial cortex with anatomically connected components of thalamus circuitry, but uncoupling from most other brain regions was observed-including a notable inverse correlation with frontally projecting thalamic nuclei. In testing for causal significance, we found that rhythmic optogenetic activation of retrosplenial cortex layer 5 neurons recapitulated dissociation-like behavioural effects. Local retrosplenial hyperpolarization-activated cyclic-nucleotide-gated potassium channel 1 (HCN1) pacemakers were required for systemic ketamine to induce this rhythm and to elicit dissociation-like behavioural effects. In a patient with focal epilepsy, simultaneous intracranial stereoencephalography recordings from across the brain revealed a similarly localized rhythm in the homologous deep posteromedial cortex that was temporally correlated with pre-seizure self-reported dissociation, and local brief electrical stimulation of this region elicited dissociative experiences. These results identify the molecular, cellular and physiological properties of a conserved deep posteromedial cortical rhythm that underlies states of dissociation.
Topics: Action Potentials; Animals; Behavior; Brain Waves; Cerebral Cortex; Dissociative Disorders; Electrophysiology; Female; Humans; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Ketamine; Male; Mice; Mice, Inbred C57BL; Neurons; Optogenetics; Self Report; Thalamus
PubMed: 32939091
DOI: 10.1038/s41586-020-2731-9 -
The American Journal of Drug and... Mar 2023Although the misuse of ketamine constitutes a worldwide issue, ketamine is quickly taking its place as a therapeutic option in the management of several mental...
Although the misuse of ketamine constitutes a worldwide issue, ketamine is quickly taking its place as a therapeutic option in the management of several mental disorders. However, the use of ketamine and/or its analogues, as well as combinations with other drugs, can be fatal. To outline the cases of overdoses and deaths related to the use of ketamine and/or its analogues, as reported in the scientific literature. To investigate if ketamine is safe in a therapeutic context, particularly in its use as an antidepressant. Electronic searches were performed on three medical databases. Articles describing cases of overdose and/or death associated with ketamine and/or its analogues were included. After the removal of duplicates, title analysis and full-text analysis, 34 articles were included in this review. Eighteen articles described fatal cases and sixteen described overdoses. Poly-substance use was mentioned in 53% of the selected articles. Most cases were males and the ages varied from two to 65 years old. A total of 312 overdose cases and 138 deaths were reported. In both death reports and overdose cases, ketamine was preponderant: 89.1% and 79%, respectively. No cases of overdose or death related to the use of ketamine as an antidepressant in a therapeutic setting were found; most of the deaths occurred in the circumstances of polydrug use and overdoses left no sequelae. There is legitimate concern about the risks involving the use of ketamine and its analogues, especially in recreational settings. On the other hand, ketamine as medicine is considered safe and it is listed as an essential medicine by the World Health Organization. Although clinicians must remain vigilant, this should not deter appropriate prescription.
Topics: Male; Humans; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Female; Ketamine; Drug Overdose; Substance-Related Disorders; Analgesics, Opioid
PubMed: 36410032
DOI: 10.1080/00952990.2022.2132506 -
ACS Chemical Neuroscience Jun 2023Dextromethorphan (DXM) was introduced in 1958 as the first non-opioid cough suppressant and is indicated for multiple psychiatric disorders. It has been the most used... (Review)
Review
Dextromethorphan (DXM) was introduced in 1958 as the first non-opioid cough suppressant and is indicated for multiple psychiatric disorders. It has been the most used over-the-counter cough suppressant since its emergence. However, individuals quickly noticed an intoxicating and psychedelic effect if they ingested large doses. DXM's antagonism at -methyl-d-aspartate receptors (NMDAr) is thought to underly its efficacy in treating acute cough, but supratherapeutic doses mimic the activity of dissociative hallucinogens, such as phencyclidine and ketamine. In this Review we will discuss DXM's synthesis, manufacturing information, drug metabolism, pharmacology, adverse effects, recreational use, abuse potential, and its history and importance in therapy to present DXM as a true classic in chemical neuroscience.
Topics: Humans; Antitussive Agents; Dextromethorphan; Hallucinogens; Phencyclidine; Ketamine; Receptors, N-Methyl-D-Aspartate
PubMed: 37290117
DOI: 10.1021/acschemneuro.3c00088