Chronic Ketamine Use Research Articles

Abnormalities in White Matter Microstructure Associated with Chronic Ketamine Use

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that has been found to induce schizophrenia-type symptoms in humans and is a potent and fast-acting antidepressant. It is also a relatively widespread drug of abuse, particularly in China and the UK. Acute administration has been well characterized, but the effect of extended periods of ketamine use-on brain structure in humans-remains poorly understood. We measured indices of white matter microstructural integrity and connectivity in the brain of 16 ketamine users and 16 poly-drug-using controls, and we used probabilistic tractography to quantify changes in corticosubcortical connectivity associated with ketamine use. We found a reduction in the axial diffusivity profile of white matter in a right hemisphere network of white matter regions in ketamine users compared with controls. Within the ketamine-user group, we found a significant positive association between the connectivity profile between the caudate nucleus and the lateral prefrontal cortex and dissociative experiences. These findings suggest that chronic ketamine use may be associated with widespread disruption of white matter integrity, and white matter pathways between subcortical and prefrontal cortical areas may in part predict individual differences in dissociative experiences due to ketamine use.

In response to: AMPA receptor potentially participates in the mediation of the increased brain-derived neurotrophic factor following chronic ketamine use by Yang, Jianjun; Zhou, Zhiqiang; Yang, Chun

In response to: AMPA receptor potentially participates in the mediation of the increased brain-derived neurotrophic factor following chronic ketamine use by Yang, Jianjun; Zhou, Zhiqiang; Yang, Chun

AMPA receptor potentially participates in the mediation of the increased brain-derived neurotrophic factor following chronic ketamine use

We read with great interest the recently published article “Chronic ketamine use increases serum levels of brain-derived neurotrophic factor” by Ricci et al. (2011). In this study, the authors considered that the mechanism underlying the increased serum levels of BDNF in chronic ketamine use are attributed to the antagonistic action of N-methyl-D-aspartate (NMDA) receptor. However, the intracellular glutamate release increased by ketamine administration preferentially favors α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor over NMDA receptor because the latter is occupied by ketamine (Machado-Vieira et al. 2009). Moreover, several studies have demonstrated that AMPA receptor mediates the increase of BDNF via two distinct signaling pathways. The first pathway involves the increases in intracellular calcium concentration, which subsequently leads to the upregulation of BDNF gene expression through calcium response elements (Tao et al. 1998). The second pathway depends on the activation of Lyn, a member of the src family of protein tyrosine kinases, which upregulates the mitogen-activated protein kinase pathway and then leads to the increases of BDNF expression (Hayashi et al. 1999).

Chronic ketamine use increases serum levels of brain-derived neurotrophic factor

Ketamine is a non-competitive N-methyl-D: -aspartate (NMDA) receptor antagonist which interferes with the action of excitatory amino acids (EAAs) including glutamate and aspartate. The use of ketamine at subanaesthetic doses has increased because of its psychotomimetic properties. However, long-term ketamine abuse may interfere with memory processes and inhibit the induction of long-term potentiation (LTP) in the hippocampus, an effect probably mediated by its NMDA antagonist action. Neurotrophins such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) serve as survival factors for selected populations of central nervous system neurons, including cholinergic and dopaminergic neurons. In addition, neurotrophins, particularly BDNF, may regulate LTP in the hippocampus and influence synaptic plasticity. The purpose of this study was to test the hypothesis that ketamine use in humans is associated with altered serum levels of neurotrophins. We measured by enzyme-linked immunosorbent assay the NGF and BDNF serum levels in two groups of subjects: frequent ketamine users and healthy subjects. Our data show that BDNF serum levels were increased in chronic ketamine users as compared to healthy subjects, while NGF levels were not affected by ketamine use. These findings suggest that chronic ketamine intake is associated with increases in BDNF serum levels in humans. Other studies are needed to explore the pharmacological and molecular mechanism by which ketamine, and/or other NMDA antagonists, may induce modification in the production and utilization of BDNF and alter normal brain function.

Reduced Dorsal Prefrontal Gray Matter After Chronic Ketamine Use

Use of ketamine as a recreational drug is spreading rapidly among young people all over the world. Epidemiological studies have linked chronic ketamine use with a number of problems, including cognitive impairments, bladder dysfunction, and ketamine-related death. However, little is known about the long-term effects of ketamine use on brain structure and function. We used voxel based morphometry in conjunction with statistical parametric mapping on the structural magnetic resonance images of ketamine-dependent (n = 41) and drug-naive control individuals (n = 44) to assess differences in gray matter volume between the two groups. We observed significant decreases in gray matter volume in bilateral frontal cortex (left superior frontal gyrus and right middle frontal gyrus) of ketamine users in comparison with control subjects (p < .05 corrected for multiple comparisons at cluster-level). Duration of ketamine use was negatively correlated with gray matter volume in bilateral frontal cortex, whereas the estimated total lifetime ketamine consumption was negatively correlated with gray matter volume in left superior frontal gyrus. We have demonstrated a reduction in frontal gray matter volume in patients after chronic ketamine use. The link between frontal gray matter attenuation and the duration of ketamine use and cumulative doses of ketamine perhaps suggests a dose-dependent effect of long-term use of the drug. Our results have important connotations for the clinical picture that is likely to emerge with the growing recreational use of ketamine and is also relevant to the status of the drug as a model for schizophrenia.

Frontal white matter abnormalities following chronic ketamine use: a diffusion tensor imaging study

Ketamine abuse has been shown to have a deleterious impact on brain function. However, the precise mechanisms of ketamine dependence-induced pathological change remain poorly understood. Although there is evidence for white matter changes in drug abuse, the presence of white matter abnormalities in chronic ketamine users has not been studied. White matter volumes were measured using in vivo diffusion tensor magnetic resonance imaging data in 41 ketamine-dependent subjects and 44 drug-free healthy volunteers. White matter changes associated with chronic ketamine use were found in bilateral frontal and left temporoparietal cortices. There was also evidence that frontal white matter fractional anisotropy correlated with the severity of drug use (as measured by estimated total ketamine consumption). We provide direct evidence for dose-dependent abnormalities of white matter in bilateral frontal and left temporoparietal regions following chronic ketamine use. The findings suggest a microstructural basis for the changes in cognition and experience observed with prolonged ketamine use. Moreover, the similarities of these changes to those observed in chronic schizophrenia have implications for the glutamate model of this illness.

Cystitis associated with chronic ketamine abuse

KETAMINE HYDROCHLORIDE, an N-methyl-D-aspartic acid (NMDA) receptor antagonist, is increasingly used as a recreational drug.1 Ketamine abusers have anecdotally reported the suffering from cystitis while using this substance. Herein we present the case of two subjects who abused ketamine, who had severe urinary tract symptoms. Informed consent was obtained from both subjects. The first subject was a 24-year-old woman who had been snorting powdered ketamine for 2 years. By the time of her admission for depressive disorder and ketamine dependence, she described a rapid increase of ketamine use up to 2 g/day in 6 months, and that during this period severe dysuria, urinary frequency and urgency developed. She had visited several gynecologists and urologists, but a series of examinations, including urinalysis, urine culture, pelvic examination and hysteroscopy, were all negative and interstitial cystitis was diagnosed. The symptoms subsided significantly, however, within 2 weeks of discontinuation of ketamine in the restricted environment of the psychiatric ward. The second patient, a 26-year-old man, has abused ketamine for 6 years and denied other substance use. Self-reportedly, he used ketamine up to 6 g/day by either snorting or smoking in the last 2 years. For the past 6 months he had visited urologists frequently due to dysuria and urinary frequency but there were no abnormal findings. He was admitted to a psychiatric ward under advice for the management of ketamine abstinence. On the first day of admission he went to the toilet nearly every 5 minutes. All laboratory data were within normal range. The symptoms of cystitis were improved, although not completely resolved, after 1 week. Although the concept of ketamine dependence is generally accepted and has been described at World Health Organization drug conferences, the chronic effects of high-dose ketamine have not been well delineated in psychiatry. Both of the present cases demonstrated strong temporal association between ketamine use and cystitis. In addition to antagonism on NMDA receptor, ketamine also has some opiate receptor activity and profoundly inhibits muscarinic signaling.2 Hence, repeated high-dose ketamine use may lead to cholinergic dysregulation and urinary tract symptoms. The ulcerative cystitis, described as a new clinical entity due to chronic ketamine use, was suggested to be caused by the toxicity of ketamine and its active metabolite on the bladder mucosa.3 Furthermore, one case report indicated a dose-related effect of ketamine on the bladder,4 a finding that may explain the limited symptom resolution in the second case, in which a higher dose of ketamine was involved. Taken together, as ketamine-associated cystitis has become increasingly noted,5 psychiatrists need to be alert to these potential long-term sequelae when managing patients with ketamine dependence.

Urinary tract disease associated with chronic ketamine use

Urinary tract disease associated with chronic ketamine use

Urinary tract disease is associated with chronic ketamine use, according to an article in the BMJ.

Urinary tract disease is associated with chronic ketamine use, according to an article in the BMJ.

Ketamine-Associated Ulcerative Cystitis: A New Clinical Entity

Ketamine hydrochloride is an N-methyl-D-aspartic acid receptor antagonist used as an anesthetic agent in human and veterinary procedures. Increasingly, it is being used as a recreational drug. Recreational ketamine users have anecdotally reported increased lower urinary tract symptoms while using the substance. We describe a series of 9 patients, all of whom were daily ketamine users, who presented with severe dysuria, frequency, urgency, and gross hematuria. Investigations, including urine culture, microscopy, and cytology, in addition to computed tomography, cystoscopy, and bladder biopsies, were performed to identify a relationship between recreational ketamine use and these symptoms. The urine cultures were sterile in all cases. Computed tomography revealed marked thickening of the bladder wall, a small capacity, and perivesicular stranding, consistent with severe inflammation. At cystoscopy, all patients had severe ulcerative cystitis. Biopsies in 4 patients revealed epithelial denudation and inflammation with a mild eosinophilic infiltrate. Cessation of ketamine use, with the addition of pentosan polysulfate, appeared to provide some symptomatic relief. This case series has described a new clinical entity of severe ulcerative cystitis as a result of chronic ketamine use. As illicit ketamine becomes more easily available, ulcerative cystitis and potential long-term bladder sequelae related to its use may be a more prevalent problem confronting urologists.

Acute and chronic effects of ketamine upon human memory: a review

Ketamine is attracting increasing research interest not only because of its powerful amnestic effects but also as a putative model of schizophrenia and as a substance with an expanding following of recreational users. This article reviews the existing literature on the effects of acute ketamine on the memory of healthy volunteers and of repeated doses of ketamine in recreational users. Although there have been relatively few, often methodologically diverse, studies to date of the mnemonic effects of ketamine, there is an emerging consensus that an acute dose of the drug impairs the manipulation of information in working memory and produces decrements in the encoding of information into episodic memory. Preliminary evidence suggests that ketamine may differ from other classic amnestic drugs in impairing aspects of semantic memory. Acute-on-chronic effects in ketamine users generally mimic the pattern seen in controlled studies with healthy volunteers. However, chronic ketamine use may be associated with a more specific pattern of memory decrements and with episodic memory impairment, which might not abate following cessation of use. An important aim of future research should be to detail the specificity of ketamine's amnestic effects on both a neuropharmacological and a cognitive level.