Chronic Ketamine Use Research Articles

Recreational ketamine use and its impact on health

Ketamine, also known as 2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone, is a dissociative anesthetic that has gained popularity as a recreational substance among young people, especially in nightclubs and at parties. It acts as a noncompetitive NMDA receptor antagonist, inducing a dissociative state that manifests as catalepsy, unconsciousness and amnesia. Recreational use of ketamine and the number of illicit seizures of ketamine have increased in recent years, prompting a review of current evidence on its toxicity. Recreational ketamine use is associated with a number of toxic effects, both acute and chronic. Predominant among the acute effects are psychotic symptoms, hallucinations and aggression, which can lead to serious injuries. Chronic ketamine use leads to intractable urological problems and neuropsychiatric problems, Long-term effects also include gastrointestinal problems such as abdominal pain and liver function abnormalities. This review summarizes current evidences on the acute and chronic ketamine toxicity associated with its recreational use.

"K Cramps," Recurrent Abdominal Pain in a Patient with Chronic Ketamine Use: A Case Report.

Medical and nonmedical ketamine use is increasing in the United States. This will likely lead to an increase in emergency department (ED) visits in individuals experiencing associated side effects. Physicians will need to be able to effectively recognize and manage ketamine-related complications. A 31-year-old male with a three-year history of inhalational, intramuscular, and intravenous nonmedical ketamine use presented to the ED twice within a week with symptoms of severe atraumatic back pain, abdominal pain, and dyspepsia. A comprehensive workup, including advanced imaging, was unrevealing for identifiable causes, and the patient was discharged with instructions for primary care follow-up for further evaluation. The patient used information shared on Reddit, an online forum and social network, to identify that the cause of his pain was related to chronic ketamine use. Subsequently, upon discontinuation of ketamine, the pain improved in 24 hours. The patient self-navigated to addiction treatment. Emergency physicians should consider sequelae of chronic ketamine use as a possible cause for gastrointestinal and urologic symptoms in the ED. In addition to thorough examination and assessment for other acute medical problems, patients should be offered education, symptomatic treatment, and linkage to harm reduction and substance use disorder treatment services.

S1871 A Case of Ketamine-Induced Cholangiopathy: A Novel Diagnosis Associated With Chronic Recreational Ketamine Use

Introduction: Ketamine, an analgesic commonly used for procedural sedation, has become a popular agent for recreational use among young adults. The diagnosis of ketamine-induced cholangiopathy is uncommon. We report a case of a young adult with clinical and radiological features consistent with cholangiopathy induced by chronic ketamine use. Case Description/Methods: A 19-year-old female with past medical history of peptic ulcer disease presented to emergency department (ED) with one year history of severe epigastric abdominal pain. On further questioning, patient reported chronic recreational ketamine use. Physical exam revealed mild epigastric and RUQ tenderness. Liver function test demonstrated elevated alkaline phosphatase of 174 U/L, AST of 237 U/L and ALT of 224 U/L. All other hematology and chemistry results were within normal limits. RUQ ultrasound showed minimally dilated common bile duct (CBD). An MRCP was obtained, showing mild-to-moderate dilatation of intra-/extra-hepatic bile ducts and dilated cystic duct (CD) without obvious intraductal calculi (Figure A). Endoscopic ultrasonography (EUS) was performed showing dilatation of CBD, minimal dilatation of common hepatic duct, and minimal dilatation of CD, once again without obvious calculi (Figure B). These imaging findings are compatible with ketamine-induced cholangiopathy. After being admitted for 6 days, the patient demonstrated significant improvement in her abdominal pain, with gradually improving liver test values. She was discharged with the recommendation to abstain from ketamine use and outpatient gastroenterology follow-up. Discussion: Chronic exposure to ketamine has been known to cause urologic injury, referred to as ketamine-induced ulcerative cystitis. In comparison to the urologic complications of chronic ketamine use, its effects on the biliary system have been less commonly reported. Existing reports have mostly come from regions of Asia where recreational ketamine use is more prevalent. The nonspecific gastrointestinal symptoms that are typically reported by patients with ketamine-induced cholangiopathy may make the diagnosis more challenging to recognize. Due to increasing recreational ketamine use among young adults in recent years, cases of ketamine-induced cholangiopathy are likely to rise. Therefore, a better understanding of the clinical and radiological features of this condition are needed to allow for prompt recognition of ketamine-induced cholangiopathy.Figure 1.: A. MRCP image showing mild-to-moderate dilatation of the intrahepatic and extrahepatic bile ducts and dilatation of the cystic duct. There are no visible stones or evidence of other etiology for the dilatation. B. EUS image displaying CBD dilatation measuring up to 10.6 mm in the head region, with smooth tapering to the ampulla where it measured 2.7 mm.

S2919 Bile Duct Injury Due to Ketamine Use

Introduction: Ketamine is used routinely in the hospital for anesthesia, but is also used recreationally for its hallucinogenic and dissociative side effects. Chronic recreational use has been linked to bile duct damage and ulcerative cystitis. We report a case of ketamine induced sclerosing cholangiopathy. Case Description/Methods: A 42-year-old Cantonese woman with past medical history of bilateral hydronephrosis with stents leading to chronic kidney disease presented with abdominal pain associated with abnormal transaminases. Alkaline phosphatase was high at 1,017 IU/L with gamma glutamyl transferase of 2,310 IU/L with normal bilirubin. Abdominal imaging showed diffuse dilatation of the common bile duct. Viral serologies and anti-mitochondrial antibody were negative. She reported chronically elevated liver tests of unknown etiology. Social history was notable for prior alcohol abuse. She denied family history of liver diseases. Her pain resolved and plan was for outpatient follow-up, but she re-presented with sepsis with a rise in bilirubin to 2.9 mg/dL (Table 1). Given prior abnormal imaging, a magnetic resonance cholangiopancreatography was obtained, which showed increased intra- and extrahepatic bile duct dilation with irregular appearance of the central intrahepatic ducts with possible stricture. Differential diagnoses were recurrent pyogenic cholangitis, sclerosing cholangitis, and IgG4 disease. Her IgG level was high at 2,779 mg/dL with IgG4 elevated at 213 mg/dL. Liver biopsy showed chronic cholestatic liver injury consistent with sclerosing cholangitis (Image 1). IgG4 stain was negative. Upon further investigation, patient admitted to at least a decade of daily ketamine use, which was likely the culprit of both her kidney and liver diseases. Discussion: Due to her age, race, gender and rarity of ketamine induced cholangiopathy, she was not directly asked about ketamine use. Since the early 2000s, ketamine has emerged as the illicit drug of choice in Hong Kong and has seen increased use throughout Asia. The biliary damage from ketamine has been studied by a Chinese group that found 62% of the 257 chronic ketamine users had biliary tract anomalies. The greater the alkaline phosphatase, the higher the likelihood of finding biliary tract anomalies on imaging. Ketamine cessation has resulted in normalization of liver tests and imaging, however worsening cholangiopathy has been seen despite abstinence. In patients who present with unexplained cholangiopathy, chronic ketamine use should be considered.Figure 1.: Liver biopsy: A mild lymphoplasmacytic inflammation is noted in some triads with focal and mild interface activity. The bile ducts are injured (irregular contour, unevenly distributed nuclei, intracytoplasmic vacuoles) with focal periportal cholestasis. Immunohistochemical stain for keratin 7 confirms predominantly periportal cholestatic hepatocytes. Keratin 19 shows widespread loss of canals of Hering and focal bile duct loss. Rhodanine stain confirms periportal hepatocellular copper accumulation compatible with a chronic cholestatic process. Table 1. - Patient's hepatic function panels during initial encounter, subsequent encounter, and at least 6 months after subsequent encounter Liver Tests Reference Range & Units Initial Hospitalization Subsequent Hospitalization Most Recent Liver Tests Total bilirubin 0.2 – 1.2 mg/dL 0.8 2.9 4.5 Direct bilirubin 0 – 0.5 mg/dL 0.7 1.8 3.3 Aspartate aminotransferase 5 – 34 IU/L 75 104 88 Alanine transaminase 0 – 37 IU/L 74 129 91 Alkaline phosphatase 40 – 150 IU/L 1017 1106 845 Gamma glutamyl transferase 12 – 43 IU/L 2310 2516 1897

Abnormal fractional Amplitude of Low-Frequency Fluctuation in chronic ketamine users

BackgroundKetamine has become a major substance of abuse worldwide. Nevertheless, The long-term effects of ketamine use on intrinsic spontaneous neural activity remain unknown. ObjectivesIn the present study, rs-fMRI was used to explore whether chronic ketamine use changes the intrinsic spontaneous neural activity, and whether the intrinsic spontaneous neural activity changes in chronic ketamine users(CKUs) are associated with cognitive impairments observed in chronic ketamine users. Methods28 CKUs and 30 healthy controls(HC) were enrolled. The fractional amplitude of low-frequency fluctuations (fALFF) was measured to evaluate the intrinsic spontaneous neural activity in multiple brain regions. Cognitive alterations were assessed using MATRICS Consensus Cognitive Battery (MCCB). ResultsCKUs showed higher fALFF in the right parahippocampal gyrus(PHG), right anterior cingulate cortex(ACC), left cerebellar vermis, left posterior cingulate cortex(PCC), bilateral caudate, and lower fALFF in the right middle occipital gyrus(MOG), left cuneus, right precuneus. The fALFF in the right PHG, left cerebellar vermis, bilateral caudate, right ACC of CKUs presented a negative correlation with the average quantity of ketamine use/day(g) and estimated total ketamine consumption. The fALFF in left PCC had a negative correlation with the average quantity of ketamine use/day(g). Speed of processing on MCCB presented a negative correlation with the fALFF in the right MOG. ConclusionOur study found abnormal fALFF in multiple brain areas in CKUs, which indicated the changes of intrinsic spontaneous neural activity in multiple brain areas. The changes of fALFF were associated with the severity of ketamine use and cognitive impairment in CKUs.

Response After Repeated Ketamine Injections in a Rat Model of Neuropathic Pain.

Ketamine, an N-methyl-D-aspartate antagonist, reduces pain by decreasing central sensitization and pain windup. However, chronic ketamine use can cause tolerance, dependency, impaired consciousness, urinary symptoms, and abdominal pain. This study aimed to investigate the effects of repeated ketamine injections and ketamine readministration after discontinuation in a rat model of neuropathic pain. To induce neuropathic pain, partial sciatic nerve ligation (PSNL) was performed in 15 male Wistar rats, and these animals were divided into three groups: PSNL (control), PSNL + ketamine 5 mg/kg (K5), and PSNL + ketamine 10 mg/kg (K10; n=5 each). Ketamine was injected intraperitoneally daily for 4 weeks, discontinued for 2 weeks, and then readministered for 1 week. Following PSNL, the mechanical withdrawal threshold was determined weekly using the Von Frey. The K10 group showed a significant increase in the mechanical withdrawal threshold, presented here as the target force (in g), at 21 and 28 days compared to the time point before ketamine injection (mean±SE, 276.0±24.0 vs. 21.6±2.7 and 300.0±0.0 vs. 21.6±2.7, respectively; P<0.01) and at 14, 21, and 28 days compared to the control group (108.2±51.2 vs. 2.7±1.3, 276.0±24.0 vs. 2.5±1.5, and 300.0±0.0 vs. 4.0±0.0, respectively; P<0.05). However, in the K10 group, the ketamine effects decreased significantly at 7 days after readministration compared to those after 28 days of repeated injections (P<0.05). In the K10 group, repeated ketamine injections showed a significant increase in antinociceptive effect for >2 weeks, but this ketamine effect decreased after drug readministration.

Acquired Methemoglobinemia in a Ketamine-induced Ulcerative Cystitis Patient: A Case Report.

IntroductionAs ketamine gains traction as an alternative to opiates in the treatment of chronic pain, ketamine-induced ulcerative cystitis is now being recognized as a complication of its use. The first-line treatment is phenazopyridine, an over-the-counter medication for dysuria that historically has been known to cause methemoglobinemia. This report details the case of a patient presenting to the emergency department (ED) with methemoglobinemia.Case ReportA 66-year-old woman with a complicated medical history presented to the ED with anemia and hypoxia after extended use of phenazopyridine for treatment of ketamine-induced ulcerative cystitis. She was found to have methemoglobinemia secondary to phenazopyridine used to treat her ketamine-induced ulcerative cystitis, a previously undocumented sequelae of chronic ketamine use. She was admitted to the hospital for three days and made a full recovery.ConclusionThis case highlights the need to suspect ketamine-induced ulcerative cystitis in patients who use ketamine chronically and be judicious in the use of phenazopyridine for symptom management to prevent life-threatening complications.

Increased Nectin-4 levels in chronic ketamine abusers and the relationship with lower urinary tract symptoms

Persistent ketamine use causes susceptibility to addiction and bladder toxicity. We examined the association of lower urinary tract symptoms and levels of Nectin-4, a member of the cell adhesion molecules that is essential for maintaining the urothelium barrier in chronic ketamine abusers. We measured the plasma levels of Nectin-4 in 88 patients with ketamine dependence and 69 controls. Patients with ketamine dependence were assessed for ketamine use variables, psychological symptoms, and lower urinary tract symptoms. We found Nectin-4 levels were increased in ketamine-dependent patients compared to the controls (p < 0.0001). Patients with urinary tract symptoms exhibited lower Nectin-4 levels than those without (p = 0.021). Our results suggest an up-regulation of Nectin-4 following chronic and heavy ketamine use. Patients with ketamine dependence with a compromised upregulation of Nectin-4 are likely to have more severe urinary tract symptoms. The mechanisms underlying the involvement of Nectin-4 in ketamine addiction and bladder toxicity warrant future investigation.

Neurofilament light chain as novel blood biomarker of disturbed neuroaxonal integrity in patients with ketamine dependence

Objectives Chronic and heavy ketamine use has been associated with persistent neurocognitive impairment and structural brain abnormalities. Blood levels of neurofilament light chain (NFL) was recently proposed as a measure of axonal integrity in several neuropsychiatric disorders. We aimed to characterise the axonal neurotoxicity of chronic ketamine use and its relationship to relevant clinical outcomes. Methods We enrolled 65 treatment-seeking ketamine-dependent patients (55 males and 10 females) and 60 healthy controls (51 males and 9 females). Blood NFL levels measured by single molecule array (SiMoA) immunoassay. We compared NFL levels between groups and used regression analyses to identify clinical variables related to NFL levels. Results Ketamine-dependent patients had significantly higher NFL levels compared to controls (p < 0.001). A multivariate regression showed that age (p < 0.05) and lifetime history of major depressive disorder (MDD) (p < 0.01) predicted high NFL blood levels in patients. Subsequent group comparisons showed that specifically ketamine-dependent patients with a lifetime history of MDD had significantly increased NFL levels than those without (p < 0.05). Conclusions These results suggest substantial neuroaxonal alterations following chronic and heavy ketamine use. The pronounced increase of NFL levels in the MDD subgroup warrants further investigation of a potential neuroaxonal vulnerability of depressed patients to ketamine.

Cortical Thickness Changes in Chronic Ketamine Users.

Background: Previous studies have examined the effects of long-term ketamine use on gray matter volume. But it is unclear whether chronic ketamine use alters cortical thickness and whether cortical thickness changes in chronic ketamine users are associated with cognitive deficits observed in chronic ketamine users.Methods: Here, 28 chronic ketamine users and 30 healthy controls (HCs) were recruited. Cortical morphometry based on Computational Anatomy Toolbox (CAT12) was used to measure cortical thickness. Cognitive performance was measured by MATRICS Consensus Cognitive Battery (MCCB). Two-sample t-test was used to assess differences in cortical thickness and cognitive performance between the two groups. Partial correlation analysis was used for assessing correlations between cortical thickness changes and clinical characteristics, cognitive performance in chronic ketamine users.Results: Chronic ketamine users exhibited significantly reduced cortical thickness in frontal, parietal, temporal, and occipital lobes compared to HC [false discovery rate (FDR) corrected at p < 0.05]. In chronic ketamine users, the average quantity (g) of ketamine use/day was negatively correlated with cortical thickness in the left superior frontal gyrus (SFG), right caudal middle frontal gyrus (MFG), and right paracentral lobule. The frequency of ketamine use (days per week) was negatively correlated with cortical thickness in the left isthmus cingulate cortex. Duration of ketamine use (month) was negatively correlated with cortical thickness in the left precentral gyrus. The chronic ketamine users showed significantly poorer cognitive performance on the working memory (P = 0.009), visual learning (P = 0.009), speed of processing (P < 0.000), and Matrics composite (P = 0.01). There was no correlation between scores of domains of MCCB and reduced cortical thickness.Conclusion: The present study observed reduced cortical thickness in multiple brain areas, especially in the prefrontal cortex (PFC) in chronic ketamine users. Dose, frequency, and duration of ketamine use was negatively correlated with cortical thickness of some brain areas. Our results suggest that chronic ketamine use may lead to a decrease of cortical thickness. But the present study did not observe any correlation between reduced cortical thickness and decreased cognitive performance in chronic ketamine users.

Ketamine-Associated Bladder Dysfunction—a Review of the Literature

The purpose of this review is to study the epidemiology, presentation, pathogenesis and management of ketamine cystitis and its complications. Recent data suggest that the toxicity of ketamine can be due to direct cytotoxicity, independent of a NMDA receptor-mediated mechanism. Bladder barrier dysfunction, neurogenic inflammation with abnormal neurotransmission and immunological mechanisms have also been proposed, based on data from animal models and in vitro studies. Effects on the bladder are dependent on the dose and duration of ketamine use. Clinical studies have showed that the model of outreach clinics with involvement of local urology services holds most promise, with a tiered approach to management based on stage of the disease. Chronic ketamine use is associated with significant lower urinary tract symptoms including frequency, urgency, haematuria and bladder pain. This may progress to irreversible bladder dysfunction with poor capacity and compliance and upper tract dysfunction may also occur. The key to successful treatment is ketamine cessation. The role of medications is not well established but there may be benefit from drugs used for IC/BPS and bladder Botox. Patients with end stage disease will require surgery, but there is a high complication rate.

Depression in chronic ketamine users: Sex differences and neural bases

Chronic ketamine use leads to cognitive and affective deficits including depression. Here, we examined sex differences and neural bases of depression in chronic ketamine users. Compared to non-drug using healthy controls (HC), ketamine-using females but not males showed increased depression score as assessed by the Center of Epidemiological Studies Depression Scale (CES-D). We evaluated resting state functional connectivity (rsFC) of the subgenual anterior cingulate cortex (sgACC), a prefrontal structure consistently implicated in the pathogenesis of depression. Compared to HC, ketamine users (KU) did not demonstrate significant changes in sgACC connectivities at a corrected threshold. However, in KU, a linear regression against CES-D score showed less sgACC connectivity to the orbitofrontal cortex (OFC) with increasing depression severity. Examined separately, male and female KU showed higher sgACC connectivity to bilateral superior temporal gyrus and dorsomedial prefrontal cortex (dmPFC), respectively, in correlation with depression. The linear correlation of sgACC-OFC and sgACC-dmPFC connectivity with depression was significantly different in slope between KU and HC. These findings highlighted changes in rsFC of the sgACC as associated with depression and sex differences in these changes in chronic ketamine users.

A REVIEW OF KETAMINE ABUSE AND DIVERSION.

Ketamine was discovered in the 1960s and released for public use in 1970. Originally developed as a safer alternative to phencyclidine, ketamine is primarily used in clinical settings for analgesia and sedation. In recent years, other uses have been developed, including pain management and treatment of asthma and depression. Clinical use of ketamine causes dissociation and emergence delirium. These effects have led to recreational abuse. Although death from direct pharmacologic effects appears rare, the disinhibition and altered sensory perceptions caused by ketamine puts users at risk of environmental harm. Ketamine has also been implicated in nonconsensual sexual intercourse. Data continue to build that chronic ketamine use may lead to morbidity. Impairment of memory and persistent dissociative, depressive, and delusional thinking has also been reported with long-term use. Lower urinary tract symptoms, including cystitis have been described. Gastric and hepatic pathology have also been noted, including abnormal liver function tests, choledochal cysts and dilations of the common bile duct. S-ketamine, an enantiomer in racemic ketamine, has been shown to be hepatotoxic in vitro. Abstinence from ketamine may reduce the adverse effects of chronic use and is considered the mainstay of treatment. Specialized urine drug testing may be required to detect use, as not all point of care urine drug screens include ketamine.

Chronic exposure to ketamine induces neuronal lose and glial reaction in CA4 region of hippocampus

Abstract Introduction: Studies have shown that even acute single dose of ketamine is associated with neurodegeneration in hippocampus. The aim of this study was to examine the effects of chronic exposure to ketamine on hippocampus proper in young adult male rats. Materials and Method: Twenty young adult male wistar rats weighing 120-150 g were randomly divided into two groups. Experimental group received ketamine intraperitoneally at the dose of 10mg/kg for one week. The control animals only received saline. At the end ofweek animals were anesthetized and the hippocampus and adrenal were harvested for further study. Results: Cytological examination of cresyl violet stained sections of ketamine group showed dark neurons in CA4 region. The number of dark neurons in CA4 (15±3) showed meaningful difference with control (P&lt;0.001). The weight ofwet brain in ketamine group (1.34±0.04 gr) showed significant level of difference in comparison with those of control (1.6±.2gr) (P&lt;0.05). The presence of oligodendrocytes aggregation around degenerating and healthy looking neurons was only recognized in ketamine group. Also in ketamine exposed animals, hypertrophic astrocytes especially in white matter hilar region, were observed. Conclusion: According to our findings it could be concluded repeated or chronic ketamine use is associated neurodegeneration in CA4region of hippocampus and sever glial reaction.

Ceftriaxone reverses ketamine-induced lasting EEG and astrocyte alterations in juvenile mice

BackgroundKetamine, an N-methyl-d-aspartate receptor antagonist, is used as a pediatric anesthetic because of its favorable safety profile. It is also being investigated as an antidepressant. Unfortunately, ketamine causes adverse reactions including hallucinations and is associated with a high prevalence of abuse among adolescents. Although chronic ketamine use has been shown to produce cognitive impairments even years following cessation, little is known about its long-term consequences on adolescents. The beta-lactam ceftriaxone has been shown to attenuate alcohol withdrawal, and alleviate early brain injury and memory impairments following subarachnoid hemorrhage. However, its ability to reverse the effects of adolescent ketamine exposure is not known. Previous data indicate that ketamine causes a reduction in the number of Excitatory Amino Acid Transporter Type 2 (EAAT2)-containing astrocytes. Additionally, the beta lactam antibiotic ceftriaxone increased expression of EAAT2. As EAAT2 is a principal mechanism of glutamate clearance from the synapse, the current study tests the hypothesis that ceftriaxone may reverse functional consequences of ketamine exposure. MethodsWe examined the effects of chronic ketamine in juvenile mice as well as reversal by ceftriaxone using electroencephalography (EEG). Subsequently, we assessed the effects of these treatments on markers of astrocyte proliferation, using Glial Fibrillary Acidic Protein (GFAP), and function, as evidenced by EAAT2. ResultsJuvenile mice exposed to chronic ketamine showed lasting alterations in EEG measurements as well as markers of astrocyte number and function. These alterations were reversed by ceftriaxone. ConclusionsData suggest that ceftriaxone may be able to ameliorate ketamine-induced long-term disturbances in adolescent brains.

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Chronic therapeutic ketamine use associates with metabolic changes: mitochondrial proliferation and respiratory complex 1 deficiency in buccal tissue and inferred hepatic STAT3/STAT5 signaling

Chronic therapeutic ketamine use associates with metabolic changes: mitochondrial proliferation and respiratory complex 1 deficiency in buccal tissue and inferred hepatic STAT3/STAT5 signaling

Ketamine users have high rates of psychosis and/or depression.

Ketamine has been linked to psychosis and used in the treatment of depression. However, no study has examined the prevalence of psychotic and depressive disorders in dependent ketamine users. This study aimed to examine the frequency of various psychopathologies among a series of patients seeking treatment for ketamine use in Hong Kong, China. The case records of 129 patients with a history of ketamine use receiving treatment at three substance use clinics between January 2008 and August 2012 were retrieved for data collection. Patients' demographic data, patterns of substance misuse, and comorbid psychiatric diagnoses were recorded and entered into analyses. The mean age of onset and length of ketamine use were 17.7 ± 4.4 and 8.7 ± 5.7 years, respectively. All patients were dependent on ketamine at the time of data collection. Multiple substance misuse was common. Eighty-four of the 129 (65.1%) patients were found to have comorbid psychiatric disorders, most commonly substance-induced psychotic disorder (31.8%) followed by depressive disorder (27.9%). Psychosis and/or depression were common in ketamine-dependent patients referred to a psychiatric substance use clinic. The findings provide evidence of an association between chronic ketamine use and the presence of psychosis and/or depression. The results raise the issue of safety when using ketamine in the long-term treatment of depression.

Chronic administration of ketamine mimics the perturbed sense of body ownership associated with schizophrenia.

Subanaesthetic ketamine infusion in healthy volunteers induces experiences redolent of early psychosis, including changes in the experience of one's own body. It is not clear, however, whether repeated self-administration of ketamine has a sustained effect on body representation that is comparable to that found during acute administration. We sought to establish whether chronic ketamine use resulted in disturbances to sense of body ownership. Following on from our work on the effects of acute ketamine infusion, we used the rubber hand illusion (RHI) to experimentally manipulate the sense of body ownership in chronic ketamine users, compared to healthy controls. Chronic ketamine users experienced the RHI more strongly and reported more body-image aberrations, even though they had not recently taken the drug. These findings suggest that the chronic ketamine model for psychosis models more long-lasting changes in sense of ownership, perhaps more akin to schizophrenia.

Three months of methoxetamine administration is associated with significant bladder and renal toxicity in mice

Context. Methoxetamine is a ketamine analogue that has recently emerged as a novel psychoactive substance. Chronic ketamine use is associated with significant bladder and renal toxicity. Methoxetamine has been marketed as “bladder friendly”, but there is no data to be able to substantiate this claim. Objective. To characterise the patterns of bladder and renal toxicity associated with 3 months of methoxetamine administration in an animal model. Materials and methods. Two-month-old Institute of Cancer Research mice were administered 30 mg/kg methoxetamine intraperitoneally (n = 5) or saline (n = 3 control) for 3 months. The animals were then sacrificed and histological examination, immuno-cytochemistry using polyclonal anti-CD4 antibodies and sirius-red staining for collagen were performed. Results. The kidneys of methoxetamine-treated animals showed inflammatory cell infiltration, tubular cell necrosis and glomerular damage (1.9 ± 0.3% shrunken glomeruli in control, 9.8 ± 0.8% in methoxetamine-treated mice (p < 0.0001); 2.9 ± 0.3% tubular cell degeneration in control, 20.4 ± 1.1% in methoxetamine-treated mice (p < 0.0001)). There was a greater density of mononuclear cells in the bladder lamina propria and submucosa in methoxetamine-treated mice (43.0 ± 2.1 per 250 × 250 μm) than controls (7.1 ± 1.2 per 250 × 250 μm), p < 0.001. CD4-positive staining was seen in the bladder submucosa and lamina propria of all methoxetamine-treated mice and muscle-layer of two methoxetamine-treated mice; these changes were not seen in the control mice. There was an increase in sirius-red collagen in the bladder sub-mucosa and muscle-layer in the methoxetamine-treated mice compared with control mice. Discussion. This study has shown that 3 months of daily 30 mg/kg intra-peritoneal methoxetamine results in significant bladder and renal toxicity in mice. Changes in the bladder included inflammatory changes with subsequent fibrosis and changes in the kidney were seen at both a tubular and glomerular level. These changes are similar to those seen in comparable animal models of chronic ketamine administration. Further work is required to determine the time course of the onset of these effects and whether the effects are reversible with methoxetamine cessation.