The clinical toxicology of ketamine

Schep, Leo J.; Slaughter, Robin J; Watts, Martin; MacKenzie, Elliot; Gee, Paul

doi:10.1080/15563650.2023.2212125

Cited by 18 publications

(16 citation statements)

References 161 publications

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“…[40][41][42] Ketamine is a noncompetitive blocker of NMDA receptors (NMDARs). 43 It has an analgesic effect without causing adverse reactions such as cardiovascular and respiratory depression that common anesthetics have. It is one of the general anesthetics commonly used in clinical anesthesia for children and infants.…”

Section: Discussionmentioning

confidence: 99%

“…So based on previous research, we chose to inject clinical doses of ketamine (20 mg/kg) into newborn mice on the 7th, 8th, and 9th days after birth 40–42 . Ketamine is a noncompetitive blocker of NMDA receptors (NMDARs) 43 . It has an analgesic effect without causing adverse reactions such as cardiovascular and respiratory depression that common anesthetics have.…”

Section: Discussionmentioning

confidence: 99%

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Impaired synaptic plasticity and decreased excitability of hippocampal glutamatergic neurons mediated by BDNF downregulation contribute to cognitive dysfunction in mice induced by repeated neonatal exposure to ketamine

Wan,

Ma,

Jiao

et al. 2024

CNS Neurosci Ther

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AimRepeated exposure to ketamine during the neonatal period in mice leads to cognitive impairments in adulthood. These impairments are likely caused by synaptic plasticity and excitability damage. We investigated the precise role of brain‐derived neurotrophic factor (BDNF) in the cognitive impairments induced by repeated ketamine exposure during the neonatal period.MethodsWe evaluated the cognitive function of mice using the Morris water maze test and novel object recognition test. Western blotting and immunofluorescence were used to detect the protein levels of BDNF. Western blotting, Golgi‐Cox staining, transmission electron microscopy, and long‐term potentiation (LTP) recordings were used to assess synaptic plasticity in the hippocampus. The excitability of neurons was evaluated using c‐Fos. In the intervention experiment, pAdeno‐CaMKIIα‐BDNF‐mNeuronGreen was injected into the hippocampal CA1 region of mice to increase the level of BDNF. The excitability of neurons was enhanced using a chemogenetic approach.ResultsOur findings suggest that cognitive impairments in mice repeatedly exposed to ketamine during the neonatal period are associated with downregulated BDNF protein level, synaptic plasticity damage, and decreased excitability of glutamatergic neurons in the hippocampal CA1 region. Furthermore, the specific upregulation of BDNF in glutamatergic neurons of the hippocampal CA1 region and the enhancement of excitability can improve impaired synaptic plasticity and cognitive function in mice.ConclusionBDNF downregulation mediates synaptic plasticity and excitability damage, leading to cognitive impairments in adulthood following repeated ketamine exposure during the neonatal period.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Impaired synaptic plasticity and decreased excitability of hippocampal glutamatergic neurons mediated by BDNF downregulation contribute to cognitive dysfunction in mice induced by repeated neonatal exposure to ketamine

Wan,

Ma,

Jiao

et al. 2024

CNS Neurosci Ther

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“…Ketamine is extensively metabolized by the liver. Both isomers of ketamine are metabolized to norketamine by N-demethylation via CYP2B6, CYP3A4, and CYP2C9 [ 8 ]. Norketamine then undergoes further glucuronic acid conjugation and is eliminated by the kidneys [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

“…Both isomers of ketamine are metabolized to norketamine by N-demethylation via CYP2B6, CYP3A4, and CYP2C9 [ 8 ]. Norketamine then undergoes further glucuronic acid conjugation and is eliminated by the kidneys [ 8 ]. The mechanism by which ketamine causes liver injury is not fully understood, but several hypotheses have been generated.…”

Section: Discussionmentioning

confidence: 99%

A Case of Hepatotoxicity Induced by Therapeutic Ketamine Use for Sedation

Yoo,

Thomas,

Bender

et al. 2024

Case Reports in Critical Care

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Ketamine, initially developed as an anesthetic, has shown versatility in medical applications, including pain management, treatment-resistant depression, and sedation in the intensive care unit (ICU). While generally well-tolerated, long-term use at high doses raises concerns about potential toxicities, particularly in the liver. We present a case of a 27-year-old female with a complex medical history who received ketamine infusion for ICU sedation and experienced a sudden rise in liver function tests (LFTs), indicating possible ketamine-induced liver injury (KILI). The patient’s liver function normalized after ketamine discontinuation. KILI is infrequent with short-term ketamine use, but emerging case reports suggest it may be associated with chronic or intermittent exposure. The underlying mechanisms for KILI are not fully understood but may involve the accumulation of ketamine metabolites, causing direct toxic effects on the liver. As ketamine’s use expands, especially in critical care settings, clinicians should be vigilant for the potential development of KILI. Further research is needed to better understand its risk factors and mechanisms, as early detection and management of KILI are crucial to ensuring patient safety and optimizing ketamine’s therapeutic benefits.

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“…The antidepressant effects of ketamine are remarkably rapid, evident within hours of a single infusion, and distinguish ketamine from therapeutics like serotonin-selective reuptake inhibitors which require weeks of daily dosing for efficacy. Ketamine therapy also has some limitations: its profound psychoactive effects require monitoring, single infusions of ketamine improve symptoms of depression for only 1-2 weeks, and long-term ketamine use may be associated with neurological and urological toxicity 5 . Efforts to improve the safety and durability of ketamine have primarily focused on its antagonism at Nmethyl-D-aspartate receptors (NMDARs) in the prefrontal cortex and hippocampus.…”

Section: Introductionmentioning

confidence: 99%

Opioid receptor expressing neurons of the central amygdala gate behavioral effects of ketamine in mice

Pomrenze,

Vaillancourt,

Llorach

et al. 2024

Preprint

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Ketamine has anesthetic, analgesic, and antidepressant properties which may involve multiple neuromodulatory systems. In humans, the opioid receptor (OR) antagonist naltrexone blocks the antidepressant effect of ketamine. It is unclear whether naltrexone blocks a direct effect of ketamine at ORs, or whether normal functioning of the OR system is required to realize the full antidepressant effects of treatment. In mice, the effect of ketamine on locomotion, but not analgesia or the forced swim test, was sensitive to naltrexone and was therefore used as a behavioral readout to localize the effect of naltrexone in the brain. We performed whole-brain imaging of cFos expression in ketamine-treated mice, pretreated with naltrexone or vehicle, and identified the central amygdala (CeA) as the area with greatest difference in cFos intensity. CeA neurons expressing both μOR (MOR) and PKCδ were strongly activated by naltrexone but not ketamine, and selectively interrupting MOR function in the CeA either pharmacologically or genetically blocked the locomotor effects of ketamine. These data suggest that MORs expressed in CeA neurons gate behavioral effects of ketamine but are not direct targets of ketamine.

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The clinical toxicology of ketamine

Cited by 18 publications

References 161 publications

Impaired synaptic plasticity and decreased excitability of hippocampal glutamatergic neurons mediated by BDNF downregulation contribute to cognitive dysfunction in mice induced by repeated neonatal exposure to ketamine

Impaired synaptic plasticity and decreased excitability of hippocampal glutamatergic neurons mediated by BDNF downregulation contribute to cognitive dysfunction in mice induced by repeated neonatal exposure to ketamine

A Case of Hepatotoxicity Induced by Therapeutic Ketamine Use for Sedation

Opioid receptor expressing neurons of the central amygdala gate behavioral effects of ketamine in mice

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