Chronic Ketamine Abuse Research Articles

Current approaches for the treatment of ketamine-induced cystitis.

Ketamine is a dissociative anesthetic, historically used in a clinical setting for the induction and maintenance of anesthesia. Ketamine usage can produce undesirable psychological manifestations including hallucinations and long-term psychotomimetic effects. As a results of its fast onset and short period of action, ketamine is widely used as a recreational drug. Chronic abuse of ketamine can lead to significant urinary system complications including ketamine-induced cystitis (KIC). Common side effects of chronic ketamine abuse are urinary pain and discomfort and decreased bladder compliance and voiding pressure. Cessation of ketamine use is associated with improvement of symptoms however the exact pathophysiology of KIC remains unknown, complicating the ability of clinicians to treat this condition. A literature search was performed using the National Center for Biotechnology Information (NCBI) Pubmed database up to May 2021. Animal models of KIC are necessary to further our understanding of KIC pathophysiology and explore potential treatment options. In all cases, cessation of ketamine use is the first line of treatment and is most effective in managing KIC. In addition to cessation, treatment plans must be tailored to the individual, based on the severity of symptoms and disease progression, and include options such as: oral anti-inflammatories, intravesical treatment and in the most severe cases, surgical intervention. KIC is a painful condition that currently lacks standardized treatment methods. Both animal models of KIC and clinical trials to further elucidate the mechanism of KIC pathophysiology must be explored to create targeted treatment plans.

Association of urinary ketamine and APOA1 levels with bladder dysfunction in ketamine abusers revealed via proteomics and targeted metabolite analyses

Chronic ketamine abuse is associated with bladder dysfunction and cystitis. However, the effects of ketamine abuse on the urinary proteome profile and the correlations among urinary proteins, urinary ketamine (and metabolites) and clinicopathological features of ketamine-induced bladder dysfunction remain to be established. Here, we recruited 56 ketamine abusers (KA) and 40 age-matched healthy controls (HC) and applied the iTRAQ-based proteomics approach to unravel quantitative changes in the urine proteome profile between the two groups. Many of the differentially regulated proteins are involved in the complement and coagulation cascades and/or fibrotic disease. Among them, a significant increase in APOA1 levels in KA relative to control samples (392.1 ± 59.9 ng/ml vs. 13.7 ± 32.6 ng/ml, p < 0.0001) was detected via ELISA. Moreover, urinary ketamine, norketamine and dehydronorketamine contents (measured via LC-SRM-MS) were found to be positively correlated with overactive bladder syndrome score (OABSS) and APOA1 levels with urinary RBC, WBC, OABSS and numeric pain rating scale in KA. Collectively, our results may aid in developing new molecular tool(s) for management of ketamine-induced bladder dysfunction. Moreover, information regarding the differentially regulated proteins in urine of KA provides valuable clues to establish the molecular mechanisms underlying ketamine-induced cystitis.

1348 The Ketamine Connection: Ulcerative Cystitis and Biliary Dilatation in the Setting of Chronic Ketamine Abuse

INTRODUCTION: Recreational ketamine abuse can present with a unique constellation of symptoms, and limited literature on this topic makes this case a rare learning opportunity. CASE DESCRIPTION/METHODS: A 37-year-old male with diffuse psoriasis and a one-year-history of ketamine inhalation presented to the ER complaining of recurrent episodes of epigastric pain. The pain was described as colicky, non-radiating, and 10/10 in intensity; he related the pain acutely worsened in the 3 days prior to admission. He also had a remote history of cocaine and marijuana abuse. He denied vomiting, diarrhea, melena, dysphagia, odynophagia, fevers, or chills. Physical exam findings were negative for a Murphy's sign. Laboratory studies were significant for eosinophilia and an elevated lipase. A CT of the abdomen revealed hypodensities in the liver parenchyma and dilatation of the intrahepatic biliary ducts, common bile duct, gallbladder, and pancreatic duct. These findings suggested an obstructing stone or mass lesion at the ampulla. Furthermore, a pelvic CT also revealed an asymmetric, markedly thickened anterior urinary bladder wall and bladder dome; these findings were concerning for underlying malignancy of the bladder. A urinalysis revealed elevated white blood cells and red blood cells, but cytology was negative. A re-evaluation of the patient revealed symptoms of difficulty urinating, with sensation of having to push to void and dysuria at the end of micturition. Of note, the patient denied any history of freshwater swimming or exposure to factory chemicals. The patient underwent an EUS, which revealed a dilated common bile duct without stones, an acalculous gallbladder, and a deformed ampulla. A bedside cystoscopy was performed, revealing no tumors or strictures, but revealed a high-riding median lobe of the prostate at the bladder neck. Additionally, the posterior dome showed a thickened, erythematous area, and another rounded area consistent with ulcerative cystitis. Urology scheduled the patient for a repeat cystoscopy with biopsy, but unfortunately he left against medical advice as his pain and other symptoms had resolved. DISCUSSION: Ketamine, known for its hallucinogenic effects, is used recreationally among various populations. Hepatic-dominant metabolization, with urinary (90%) and biliary (10%) excretion leave these organs exposed to ketamine metabolites and their effects. This case emphasizes the importance of drug history in patients presenting with biliary colic and urinary symptomatology.

Chronic ketamine abuse is associated with orexin-A reduction and ACTH elevation.

Ketamine has emerged as a major substance of abuse worldwide. Evidence suggests a role of orexin system in reward processing, withdrawal, and stress response. It also interacts with the stress mechanisms of hypothalamic-pituitary-adrenal (HPA) axis to regulate drug-taking behavior. The study aimed to explore the relevance of orexin and stress hormones to chronic ketamine abuse. We enrolled 67 ketamine-dependent (KD) patients and 64 controls. The levels of orexin-A, adrenocorticotropic hormone (ACTH), and cortisol were measured at baseline, 1week, and 2weeks after ketamine discontinuation. KD patients were assessed by Beck Depression Inventory, Beck Anxiety Inventory, and Visual Analogue Scale for ketamine craving at baseline. Compared with the controls, KD patients had significantly lower orexin-A (0.65 ± 0.12 vs. 0.74 ± 0.10ng/mL, p < 0.001) and increased ACTH (32.3 ± 16.3 vs. 22.3 ± 11.0pg/mL, p = 0.008) levels at baseline, whereas cortisol levels were similar between two groups. Levels of the three markers did not correlate with ketamine use variables, craving, depression, or anxiety symptoms. The levels did not alter after 1 or 2weeks of ketamine discontinuation. Notably, those with higher anxiety had lower orexin-A but increased cortisol levels than did those with lower anxiety. This study showed that KD patients had persistent orexin-A reduction and stress hormone dysregulation in early abstinence. The anxious phenotype of KD might be associated with a lower orexin-A expression. These results point to a promising pathway to investigate the neurochemical mechanisms of ketamine addiction.

Decreased Blood Levels of Oxytocin in Ketamine-Dependent Patients During Early Abstinence.

Background: Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is a common drug of abuse worldwide. Existing evidence suggest a disruption of oxytocin system involves in the development of addiction. In this study, we aimed to investigate the role of oxytocin in ketamine addiction by measuring the blood oxytocin levels in ketamine-dependent (KD) patients.Methods: Sixty-five KD patients and 65 controls were enrolled. Fasting plasma levels of oxytocin were determined at baseline and 1 and 2 weeks after ketamine withdrawal. Ketamine use variables, Beck Depression Inventory, Beck Anxiety Inventory (BAI), Visual Analog Scale for craving, and Childhood Trauma Questionnaire-short form were assessed in KD patients.Results: KD patients had significantly lower levels of oxytocin at baseline compared to controls (5.89 ± 2.13 vs. 9.53 ± 4.17 ng/mL, P < 0.001). Oxytocin levels increased after one (6.74 ± 2.63, P < 0.002) and 2 weeks (6.89 ± 2.69, P = 0.01) of withdrawal in KD patient despite the levels were still lower than controls (P = 0.001 and 0.002, respectively). The clinical variables did not correlate with baseline oxytocin levels except BAI scores, which showed a negative correlation with the levels (r = −0.263; P = 0.039).Conclusion: We found a distinctively reduced oxytocin level in KD patients and the level did not normalize after early abstinence. Lower oxytocin might be associated with anxious phenotype of ketamine dependence. These results suggest that oxytocin system dysregulated following chronic ketamine abuse and might provide insight in evaluating the potential therapeutic use of oxytocin for treating ketamine dependence.

Cognitive profile of ketamine-dependent patients compared with methamphetamine-dependent patients and healthy controls.

Ketamine has emerged as a major substance of abuse worldwide and has been listed with methamphetamine (METH) as two of the most widely available illicit substances in Taiwan. Only a few studies have examined the long-term consequences of chronic and heavy ketamine abuse. We compared the cognitive function of ketamine-dependent patients with that of METH-dependent patients and healthy controls. We recruited 165 participants (58 ketamine-dependent and 49 METH-dependent patients who sought treatment and 58 healthy controls) and evaluated them by using a cognitive test battery, the Brief Assessment of Cognition in Schizophrenia, with scores being estimated in reference to normative data in general population. The ketamine-dependent patients had significantly poorer performance than did the controls in many cognitive tests, including verbal memory, motor speed, verbal fluency, and attention and processing speed, and the battery as a whole. METH-dependent patients exhibited poorer function in motor speed, verbal fluency, and attention and processing speed. The ketamine group performed poorer than did METH group in the domains of verbal memory, working memory, and attention and processing speed and the composite battery scores. A previous experience of ketamine-induced psychotomimetic symptoms, using higher doses of ketamine, and longer abstinence appeared to be associated with performance in some tests; however, the significance disappeared after multiple comparison correction. The ketamine-dependent patients had impaired cognitive function, and METH-dependent patients exhibited intermediate performance between ketamine-dependent patients and healthy controls. Given the growing population of ketamine abusers, public education on the cognitive consequences should be provided.

Recurrent Subanesthetic Ketamine Infusions for Complex Regional Pain Syndrome Leading to Biliary Dilation, Jaundice, and Cholangitis: A Case Report.

Complex regional pain syndrome is a chronic pain condition that may be resistant to many treatment modalities. Ketamine infusions have demonstrated some promising results, though their use may be associated with a number of adverse effects limiting their widespread applicability. Hepatotoxicity and cholangiopathy have been described in chronic ketamine abuse, though rarely in therapeutic use. We report the impact of recurrent short subanesthetic ketamine infusions for the treatment of complex regional pain syndrome resulting in biliary dilation, jaundice, and cholangitis. We recommend that prescribing physicians consider this and monitor liver function tests throughout the treatment period to minimize morbidity.

Similar psychotic and cognitive profile between ketamine dependence with persistent psychosis and schizophrenia

BackgroundKetamine has been used to probe the biology of psychosis and cognitive dysfunction in humans. High levels of ketamine abuse are associated with persisting psychosis (KPP) in a minority of users. However, relatively little is known about cognitive function among KPP patients and whether the cognitive impairments associated with KPP resemble those of schizophrenia (SZ). MethodsWe recruited 149 treatment-seeking patients, including nonpsychotic ketamine users (KNP, n=51), KPP (n=23), and SZ (n=75) patients. The Positive and Negative Syndrome Scale (PANSS) was used to evaluate psychopathology and the Cogstate Brief Battery to assess cognitive function including psychomotor processing speed, attention, working memory, verbal and visual learning and memory, spatial problem solving, and social-emotional cognition. ResultsKetamine-dependent patients had an extensive history of ketamine use (average duration=7.1±4.2years, average consumption=3.8±2.7g per day). Although KPP patients used relatively less average ketamine daily dose than KNP patients, KPP patients exhibited significantly greater total PANSS score and subscale scores, while these scores in KPP and SZ patients did not differ significantly. After adjusting for demographic characteristics and antipsychotic dose, KPP and SZ patients showed impairments in spatial problem solving and verbal memory compared to KNP patients, but KPP and SZ patients did not significantly differ from each other. ConclusionThese data suggest that the symptom profile and cognitive impairments associated with persisting psychosis due to chronic heavy ketamine abuse resemble those of schizophrenia, while KNP patients showed significantly less severe symptom profile and cognitive impairment than KPP and SZ.

Patient characteristics for different therapeutic strategies in the management ketamine cystitis.

Long-term ketamine abuse results in severely inflamed bladder and intractable bladder pain. Currently there is no guideline for clinician to follow how to manage patients with ketamine cystitis (KC). This study analyzed the KC patient characteristics between who received conservative management and augmentation enterocystoplasty (AE). A total of 53 patients with chronic ketamine abuse and lower urinary tract symptoms were included in this study. All of the patients have been initially treated conservatively but fail. They were admitted for detailed urological examinations. Patients were classified according to their maximal bladder capacity (MBC). The patients with extremely small MBC (<100 ml) with or without upper urinary tract damage and very small MBC with upper urinary tract damage were recommended to receive AE. The patient characteristics and treatment outcome are compared between patients with AE and conservative treatment. Among them, 28 patients underwent AE and 25 were managed with conservative treatment. The only significant difference between groups was more patients with urgency urinary incontinence underwent AE. Patients underwent AE had significantly smaller MBC, thicker bladder wall, and higher incidence of vesicoureteral reflux. Patients underwent AE reported a good outcome. Most of patients received conservative treatment had a fair result. KC patients who already developed a contracted bladder with extremely small bladder capacity (<300 ml) with irreversible urinary tract change, partial cystectomy, and AE seems necessary for early restoration of a normal lower urinary tract function. The treatment outcome of AE is better than patients with conservative treatment. Neurourol. Urodynam. 36:687-691, 2017. © 2016 Wiley Periodicals, Inc.

Profiling the psychotic, depressive and anxiety symptoms in chronic ketamine users

ObjectiveAlthough concern about chronic ketamine abuse has grown, the characteristic symptomatology of chronic ketamine users has yet to be examined. This study aims to measure the psychotic, depressive and anxiety symptoms in chronic ketamine users. MethodsA group of chronic ketamine users in Guangzhou, China were evaluated. The socio-demographic and drug use characteristics of subjects were documented. Symptoms of psychosis, depression, anxiety were evaluated by the Positive and Negative Syndrome Scale (PANSS), Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI). The severity of the symptoms was identified by standard severity cutoffs. ResultsThe PANSS total score, positive symptom, negative symptom, general psychopathology subscale score were 45.3±8.4, 8.0±1.7, 13.2± 3.9 and 24.2± 4.9 respectively. BDI and BAI score was 13.1±6.5 and 15.7±9.6 respectively. 77.5% and 46.0% of the subjects showed moderate to severe depressive symptoms and anxiety symptoms respectively. The BDI score was positively correlated with ketamine use frequency. The BAI score was positively correlated with ketamine use frequency. ConclusionsDepressive symptoms were commonly presented in chronic ketamine users. The higher ketamine use frequency and dosage were associated with more severe depressive symptoms.

Bladder leiomyosarcoma in a patient with chronic ketamine abuse: A case report.

Bladder leiomyosarcoma is a rare mesenchymal tumour, accounting for less than 0.5% of all primary bladder malignancies. Adult women of reproductive age have the higher incidence of bladder leiomyosarcoma. Exposure to local pelvic radiotherapy or systemic chemotherapy, especially cyclophosphamide therapy, is also a significant risk factor. We describe a case of a 31-year-old male who developed urinary bladder leiomyosarcoma. The patient had no history of radiotherapy, systemic chemotherapy, or other significant event, except a 5-year history of ketamine abuse. The tumour was found on the left bladder wall and was definitively diagnosed by transurethral resection of the bladder tumour. A partial cystectomy was performed. There are no known reports of urinary bladder leiomyosarcoma associated with chronic ketamine abuse; therefore, we speculate that chronic ketamine abuse may be a factor in the development of this infrequent bladder malignancy.

Long-Term Heavy Ketamine Use is Associated with Spatial Memory Impairment and Altered Hippocampal Activation

Ketamine, a non-competitive N-methyl-d-aspartate receptor antagonist, is rising in popularity as a drug of abuse. Preliminary evidence suggests that chronic, heavy ketamine use may have profound effects on spatial memory but the mechanism of these deficits is as yet unclear. This study aimed to examine the neural mechanism by which heavy ketamine use impairs spatial memory processing. In a sample of 11 frequent ketamine users and 15 poly-drug controls, matched for IQ, age, years in education. We used fMRI utilizing an ROI approach to examine the neural activity of three regions known to support successful navigation; the hippocampus, parahippocampal gyrus, and the caudate nucleus during a virtual reality task of spatial memory. Frequent ketamine users displayed spatial memory deficits, accompanied by and related to, reduced activation in both the right hippocampus and left parahippocampal gyrus during navigation from memory, and in the left caudate during memory updating, compared to controls. Ketamine users also exhibited schizotypal and dissociative symptoms that were related to hippocampal activation. Impairments in spatial memory observed in ketamine users are related to changes in medial temporal lobe activation. Disrupted medial temporal lobe function may be a consequence of chronic ketamine abuse and may relate to schizophrenia-like symptomatology observed in ketamine users.

Ketamine-an update on its clinical uses and abuses.

This review highlights the recent clinical research that supports the therapeutic utility of ketamine as a multifaceted drug. After long-term use as a dissociative anesthetic, it has re-emerged as a useful agent for ameliorating pain, asthmaticus, and depression. In addition, it is also a substance of abuse. Chronic ketamine abuse over prolonged periods (weeks, months, and years) can produce toxicity to the gastrointestinal and urinary tract. In this review, we described the recent progress on its clinical uses and abuses.

Repeated ketamine administration alters N-methyl-D-aspartic acid receptor subunit gene expression: implication of genetic vulnerability for ketamine abuse and ketamine psychosis in humans.

For more than 40 years following its approval by the Food and Drug Administration (FDA) as an anesthetic, ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, has been used as a tool of psychiatric research. As a psychedelic drug, ketamine induces psychotic symptoms, cognitive impairment, and mood elevation, which resemble some symptoms of schizophrenia. Recreational use of ketamine has been increasing in recent years. However, little is known of the underlying molecular mechanisms responsible for ketamine-associated psychosis. Recent animal studies have shown that repeated ketamine administration significantly increases NMDA receptor subunit gene expression, in particular subunit 1 (NR1 or GluN1) levels. This results in neurodegeneration, supporting a potential mechanism where up-regulation of NMDA receptors could produce cognitive deficits in chronic ketamine abuse patients. In other studies, NMDA receptor gene variants are associated with addictive behavior. Here, we focus on the roles of NMDA receptor gene subunits in ketamine abuse and ketamine psychosis and propose that full sequencing of NMDA receptor genes may help explain individual vulnerability to ketamine abuse and ketamine-associated psychosis.

Multiorgan Dysfunction Related to Chronic Ketamine Abuse

Ketamine abuse is being increasingly reported worldwide. The drug can produce a dissociative state and hallucinations, making ketamine a favorite recreational agent among drug addicts. Chronic ketamine abuse can damage many organs, including the brain, heart, liver, gastrointestinal tract, and genitourinary system. We report a patient with chronic ketamine abuse who presented with severe cachexia, upper gastrointestinal involvement, hepatobiliary dysfunction, and acute kidney injury.

Ketamine

Ketamine is a dissociative anesthetic and substance of abuse. Numerous effects can result from the abuse of ketamine. Death from acute direct toxicity is rare. Ketamine can alter numerous functions in the brain including color perception, memory, attention, cognition, reaction time, and sense of time and can produce psychological addiction. Chronic ketamine abuse can produce toxicity to the gastrointestinal and urinary tract. Gastrointestinal changes include epigastric pain, hepatic dysfunction, and impaired gallbladder activity. The most common urological condition from ketamine is cystitis but renal failure has been reported.

Primary yolk sac tumour of the urinary bladder: A case report and review of the literature

We present a case of rare primary yolk sac tumour of the urinary bladder in adulthood. A 31-year-old female patient presented with a history of chronic ketamine abuse, which has not previously been shown to be associated with malignancy development. The final diagnosis was established only after radical cystectomy. A computed tomography (CT) scan showed paraaortic lymph node metastasis. The patient was treated with systemic chemotherapy. A review of the literature revealed that surgical excision and cisplatin-based chemotherapy remain to be the standard of care for extragonadal yolk sac tumours.

Clinical outcomes of augmentation cystoplasty in patients suffering from ketamine-related bladder contractures

To evaluate the outcomes of augmentation cystoplasty in patients with bladder contractures secondary to chronic ketamine abuse. Patients who had received augmentation cystoplasty to treat ketamine-related bladder contractures in two hospitals in our region were reviewed retrospectively. Their history of ketamine consumption, presenting symptoms, history of treatment, surgical information and post-operative conditions were retrieved from clinical records and then summarized. Between 2006 and 2011, four patients (three women and one man), aged 21-30 years (mean 27 years), underwent augmentation cystoplasty for ketamine-related bladder contractures. The duration of ketamine consumption ranged from 3 to 15 years, and all four patients resumed ketamine consumption after surgery. The mean maximal baseline and post-operative bladder capacity was 37.5 cc (range 25-50 cc) and up to 400-500 cc, respectively. Three patients experienced a further deterioration in renal function that was secondary to new-onset ureteral strictures in two cases and to sepsis in the other. At the time of the last follow-up, three patients could void spontaneously and one required regular intermittent catheterization. Ketamine cystitis is an emerging medical condition that requires a multi-disciplinary approach to manage the patients. Simple surgical management of the physical component of the contracted bladder may produce only suboptimal results, and could even cause further problems in some patients. The importance of compliance with post-operative care and abstinence from drug use should be stressed to the patients before surgery. In view of the high complication rate, the option of a simple ileal conduit should also be discussed prior to surgical intervention.

Brain damages in ketamine addicts as revealed by magnetic resonance imaging

Ketamine, a known antagonist of N-methyl-D-aspartic (NMDA) glutamate receptors, had been used as an anesthetic particularly for pediatric or for cardiac patients. Unfortunately, ketamine has become an abusive drug in many parts of the world while chronic and prolonged usage led to damages of many organs including the brain. However, no studies on possible damages in the brains induced by chronic ketamine abuse have been documented in the human via neuroimaging. This paper described for the first time via employing magnetic resonance imaging (MRI) the changes in ketamine addicts of 0.5–12 years and illustrated the possible brain regions susceptible to ketamine abuse. Twenty-one ketamine addicts were recruited and the results showed that the lesions in the brains of ketamine addicts were located in many regions which appeared 2–4 years after ketamine addiction. Cortical atrophy was usually evident in the frontal, parietal or occipital cortices of addicts. Such study confirmed that many brain regions in the human were susceptible to chronic ketamine injury and presented a diffuse effect of ketamine on the brain which might differ from other central nervous system (CNS) drugs, such as cocaine, heroin, and methamphetamine.

Chronic Ketamine Abuse Associated with Cholestasis and Cholangitis: A Case Report

Ketamine is an anesthetic drug that has been used in clinical settings since the 1960s. Unfortunately, this medication has been abused as a recreational drug among partygoers and youth over the last 30 years. Recently, a lot of evidence has shown the association between chronic ketamine abuse and urinary tract complications. However, not many are aware that chronic ketamine abuse may also be responsible for cholestasis and cholangitis. We report a case of urinary tract complication from chronic ketamine abuse in combination with cholestasis, cholangitis, and early liver cirrhosis related to the drug. Public awareness about ketamine abuse and its complications should be communicated. Physicians should have a high index of suspicion for ketamine abuse in someone presenting with lower urinary tract symptoms along with jaundice, abdominal pain, and abnormal liver function.