Nonanesthetic Effects of Ketamine: A Review Article

Eldufani and colleagues frame ketamine not only as a dissociative anaesthetic but as a drug with multiple non‑anaesthetic properties that have attracted clinical interest since its introduction in the 1960s. Earlier research established ketamine's primary pharmacology as antagonism at N‑methyl‑D‑aspartate (NMDA) receptors and recognised its broad pharmacologic profile—sedation, analgesia, bronchodilation, sympathetic stimulation and psychotomimetic effects—but uncertainties remain about mechanisms underlying its non‑anaesthetic uses and the balance of benefits and harms in those indications. This review seeks to synthesise the published literature on ketamine’s non‑anaesthetic effects, focusing on mechanisms and clinical evidence for applications including chronic refractory pain, cognitive function and neuroprotection, depression (including treatment‑resistant depression), acute brain injury, dementia/Alzheimer’s disease and immunomodulation. The study aims to present the potential benefits and risks of ketamine across these domains and to identify gaps needing further research.

The extracted text does not include a dedicated Methods section or a description of systematic search methods, inclusion/exclusion criteria, databases searched, or dates of the literature covered. From the structure and content it appears to be a narrative review that summarises preclinical and clinical studies across several topic areas rather than a formal systematic review or meta‑analysis. Because methodological details are not reported in the extracted text, it is not possible to determine how studies were identified or selected, whether quality or risk of bias assessments were performed, or how conflicting results were reconciled. The review draws on experimental animal work, mechanistic pharmacology, small clinical trials and observational reports; specific study designs and sample sizes are variably reported in the text but not consistently described in a methods framework. Where doses, concentrations or study protocols are cited (for example, single‑dose 0.5 mg/kg intravenous ketamine in perioperative studies or comparisons of 0.1–0.4 mg/kg in depression), the extraction contains some unclear or inconsistent numeric details. The lack of an explicit methods statement means that the review’s coverage and selection criteria cannot be verified from the provided text.

Pharmacology: The review summarises ketamine’s pharmacology as rapid central nervous system penetration with primary action as a non‑competitive NMDA receptor antagonist. Additional pharmacodynamic actions discussed include effects on AMPA and kainate receptors, GABA‑A, inhibition of voltage‑gated sodium and potassium channels, and reduced reuptake of serotonin and dopamine. The authors also describe interactions with the nitric oxide pathway and opioid receptors as part of ketamine’s multimodal mechanism. Chronic pain: Ketamine is presented as useful in a range of chronic refractory pain syndromes, particularly neuropathic conditions such as complex regional pain syndrome, postherpetic neuralgia and diabetic neuropathic pain. Low intravenous doses are reported to produce potent analgesia, attributed mainly to NMDA antagonism but also to enhancement of descending inhibitory pathways and anti‑inflammatory effects. Clinical studies cited suggest ketamine can reduce opioid consumption and improve analgesia in chronic cancer pain when used adjunctively with morphine. Preclinical data indicating a role for the µ‑opioid receptor in ketamine analgesia are noted, along with mechanistic discussion of spinal dorsal horn NMDA receptor upregulation in chronic nociceptive sensitisation. Cognitive function: Short‑term ketamine infusions are associated with transient impairment of working memory and episodic memory encoding, and in some patients semantic memory impairment is reported; these deficits typically resolve after infusion cessation. The long‑term cognitive effects of repeated low‑dose ketamine for chronic pain are described as poorly reported and therefore uncertain. The authors cite a small study in which high‑dose, multi‑day (anesthetic) ketamine given for complex regional pain syndrome did not produce severe cognitive deficits, and perioperative single‑dose ketamine (0.5 mg/kg at induction) is reported in some investigations to reduce postoperative cognitive dysfunction and markedly lower postoperative delirium incidence (reported reduction from 31% to 3% in one study). Mechanistically, ketamine’s effects on glutamate signalling and activation of the mammalian target of rapamycin (mTOR) pathway in prefrontal cortex are discussed as potentially relevant to cognitive and neuroprotective actions. Clinical significance / Dementia and Alzheimer’s disease: The review reiterates ketamine’s NMDA antagonism as a rationale for use in conditions with proposed glutamatergic hyperactivity, such as Alzheimer’s disease, drawing parallels to memantine. Animal data are cited showing that single subanaesthetic ketamine doses can increase lipid peroxidation and protein damage in the hippocampus and impair learning and retrieval in certain behavioural paradigms, while not affecting consolidation when given post‑training. The text notes ketamine’s actions on cholinergic and dopaminergic transmission and its antagonism at nicotinic and muscarinic receptors, but clinical evidence for cognitive benefit in Alzheimer’s disease is not robustly presented. Depression: Ketamine is summarised as having rapid antidepressant effects in animal models and human studies, with potential utility in treatment‑resistant depression (TRD). The review discusses mechanistic evidence implicating brain‑derived neurotrophic factor (BDNF) and downstream mTOR signalling in ketamine’s antidepressant response; animal experiments in BDNF‑deficient models attenuate ketamine’s behavioural effects. The authors note dose‑dependent mood effects reported in one study comparing 0.1–0.4 mg/kg, with greater improvement at the higher dose, and they mention emerging evidence that ketamine may rapidly reduce suicidality and ameliorate post‑traumatic stress disorder symptoms alongside its antidepressant action. Acute brain injury: Earlier concerns that ketamine elevates intracranial pressure are said to have been refuted in ventilated patients. Preclinical studies are reported to show neuroprotective effects across models of stroke, traumatic brain injury and status epilepticus, including reduced infarct size and haemorrhagic necrosis. The review highlights ketamine’s antagonism of NR2B‑containing extrasynaptic NMDA receptors and antiglutamatergic effects as mechanisms that could reduce glutamate‑mediated neuronal death and might be beneficial in delayed cerebral ischemia after subarachnoid haemorrhage. Immune system and inflammation: Ketamine is described as inhibiting proinflammatory mediators—tumour necrosis factor alpha, interleukins (including IL‑1β and IL‑6) and nitric oxide—and suppressing LPS‑induced mRNA synthesis in activated macrophages. These anti‑inflammatory actions are proposed to contribute to both analgesic and neuroprotective effects. The authors also report that ketamine inhibits high mobility group box 1 (HMGB1)‑induced endothelial activation via pathways involving NF‑κB and toll‑like receptors, a mechanism that could mitigate detrimental inflammation and leukocyte transmigration after CNS injury. Safety and tolerability: Cognitive adverse effects after single short infusions are reported as transient. The long‑term safety profile is emphasised as inadequately characterised in the extracted text; the authors call for further study of prolonged efficacy and safety in non‑anaesthetic indications. Specific numerical dosing details appear in the text (for example 0.5 mg/kg IV in perioperative studies) but some reported concentrations and units in the extraction are unclear and cannot be reliably interpreted.

Eldufani and colleagues interpret the assembled literature as indicating that ketamine exerts a range of non‑anaesthetic effects with plausible mechanistic bases—NMDA antagonism, modulation of other ionotropic receptors, opioid interactions, anti‑inflammatory activity and engagement of neurotrophic signalling pathways such as BDNF–mTOR. They position these mechanisms as supporting ketamine’s observed efficacy in neuropathic and refractory chronic pain, its rapid antidepressant effects (including in treatment‑resistant cases), potential neuroprotection after acute brain injury, and immunomodulatory effects that could be clinically useful. The authors acknowledge important limitations and uncertainties: much of the mechanistic evidence comes from preclinical models, clinical data are heterogeneous and often limited in size or duration, and the long‑term cognitive and safety consequences of repeated or prolonged non‑anaesthetic ketamine use remain inadequately characterised. Where clinical studies are cited, details on methodology and longer‑term follow‑up are sparse in the extraction, limiting confidence in the generalisability of findings. In terms of implications, the review suggests that ketamine merits further clinical investigation across several indications—especially for long‑term efficacy and safety trials in depression, chronic pain and neuroprotection after stroke or head injury. The authors call for more systematic research to define optimal dosing regimens, duration of benefit, and the balance of therapeutic effects versus potential neurotoxicity or cognitive harm, particularly for chronic administration.

The review concludes that substantial research supports ketamine’s non‑anaesthetic mechanisms relevant to antidepressant, anti‑inflammatory, analgesic and neuroprotective effects. Eldufani and colleagues state that further studies are needed to evaluate long‑term efficacy and safety when ketamine is used outside anaesthesia for conditions such as treatment‑resistant depression, cognitive enhancement in Alzheimer’s disease and reduction of brain injury after stroke. The authors summarise that the review provides supporting evidence for the effectiveness and tolerability of ketamine in managing chronic pain conditions while emphasising the need for additional research in other proposed indications.