Chronic ketamine use resulting in a reversible cholangiopathy: A case series from a single Canadian centre and review of the literature

Abstract

Background:

Ketamine-related cholangiopathy is increasingly being described in America, Europe, and Asia, paralleling increases in ketamine use globally. However, ketamine-related cholangiopathy has not been described in Canada previously. We report three cases of ketamine-related cholangiopathy in Calgary, Alberta.

Results:

Between May 2024 and April 2025, three patients were assessed by the University of Calgary Liver Unit in Calgary, Alberta, Canada. Case 1 was a 28-year-old female referred for elevated liver enzymes and features concerning for sclerosing cholangitis identified on magnetic resonance cholangiopancreatography. Case 2 was a 40-year-old male referred due to features of sclerosing cholangitis identified on magnetic resonance cholangiopancreatography. Case 3 was a 33-year-old female referred for elevated liver enzymes with biliary dilation on abdominal CT scan. In all cases, a history of chronic ketamine use and a negative comprehensive workup for other etiologies strongly suggested ketamine as the cause of their presentations. Case 1 had normalization of liver enzymes and marked improvement of radiographic biliary changes at 3-month follow-up after complete cessation of ketamine. Case 2 reduced ketamine use by 50% and experienced similar clinical improvement at 3-month follow-up. Case 3 continued using ketamine, resulting in worsening liver enzyme elevations and persistent biliary tree imaging abnormalities.

Conclusions:

Chronic ketamine use should be considered in patients presenting with liver enzyme elevation and/or imaging evidence of biliary dilation. Increased awareness in Canada is essential to ensuring health care providers consider ketamine-related cholangiopathy in patients presenting with these clinical findings, as with ketamine cessation liver injury and biliary abnormalities are potentially reversible.

Lay Summary

Ketamine is a drug that can be used clinically to treat chronic pain and severe depression. However, ketamine is increasingly being used recreationally due to its hallucinogenic and dissociative side effects. Multiple adverse effects can develop with prolonged use of ketamine, including liver and biliary injuries, which have been termed ketamine-related cholangiopathy. Patients with ketamine-related cholangiopathy may present with liver disease occurring from bile flow obstruction and can be associated with marked abnormalities of the bile ducts on ultrasound and magnetic resonance imaging. Some patients have been reported to develop advanced forms of liver disease from ketamine, including cirrhosis. Importantly, if identified early, the liver injury and biliary changes seen on imaging often appear to be reversible with ketamine cessation. Increased awareness of the potential liver and biliary complications that can arise with ketamine use will be critical for preventing this reversible cause of bile duct and liver damage.

Introduction

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist used since the 1960s as an anesthetic agent (1). Over recent decades, the clinical use of ketamine has expanded, including as an analgesic in chronic pain syndromes and management of treatment-resistant depression (2). However, ketamine is also used as a recreational dissociative drug with high addictive potential (3). In both North America and Europe, the use of recreational ketamine has significantly increased over the past few decades (4,5). The 2023 Canadian Substance Use Survey, which included 36,180 respondents, reported that <1% of the population had used recreational dissociative drugs, including ketamine (6). A higher prevalence of dissociative drug use was noted in Alberta (1.2%) and British Columbia (1.3%) compared with all other provinces (0.2%–0.6%), in males compared with females, in those with a lower self-reported mental health status, and among individuals experiencing housing and income insecurity. In addition, community surveys indicated that among 186 Canadian rave attendees, 8.6% reported using ketamine, and of 9,112 Ontario students between grades 7 and 12, 1.6% had used ketamine recreationally (7,8).

Adverse events from ketamine use in both clinical and recreational settings include laryngospasm, hemodynamic instability, cardiac dysrhythmia, and genitourinary complications, including cystitis and hydronephrosis (3,9). Interestingly, hepatobiliary adverse events associated with ketamine use are less commonly reported and are notably absent on the Government of Canada controlled and illegal drugs website (3).

Ketamine-related cholangiopathy (KRC), also called ketamine-induced sclerosing cholangitis, has been increasingly documented in the literature over the last decade (10–19). Cases of KRC secondary to recreational ketamine use have predominately been reported from east and southeast Asia, where the lifetime prevalence rate of recreational ketamine use ranges from 0.3% to 2.0% within the general population and approximately 40% in persons using illicit recreational substances (13). KRC can also develop with clinical use of ketamine. During the COVID-19 pandemic, KRC was reported in mechanically ventilated patients infected with SARS-CoV-2 who required ketamine for sedation (14,16,17). Furthermore, KRC has occurred with medically supervised parenteral ketamine administration for chronic pain syndrome management (15).

Clinical, biochemical, radiographic, and histologic features reported in patients with KRC obtained from case reports and cross-sectional studies include features also seen in other cholestatic liver diseases (Table 1). Importantly, the presentation of KRC may be confused with primary sclerosing cholangitis as histologic and radiographic features of the diseases are remarkably similar (19). To our knowledge, there have been no reports of KRC within the Canadian population. Here we describe three patients diagnosed with KRC assessed at a single Canadian tertiary care medical centre.

Table 1:

Clinical, biochemical, radiographic, and histologic features associated with ketamine-related cholangiopathy documented in case reports and cohort studies

Category	Feature
Clinical	– Abdominal pain (epigastric or right upper quadrant) – Nausea and emesis – Jaundice – Fever Cholangitis
Biochemical	– Liver enzyme elevation (cholestatic > hepatocellular) – Total bilirubin elevation – C-reactive protein elevation
Radiographic	– Diffuse intrahepatic biliary dilatation* – Diffuse extrahepatic biliary dilatation* – Fusiform dilatation of the common bile duct* – Distal tapering of the common bile duct – Intrahepatic biliary stricturing or beading
Histologic	– Biliary epithelial disarray – Lymphocytic cholangitis – Ductular reaction – Portal tract mononuclear inflammatory cell infiltration – Cholestasis – Concentric periductal fibrosis – Aberrant cytokeratin 7 expression in periportal hepatocytes – METAVIR fibrosis stages F1–F4

^*Occurring in the absence of intrinsic or extrinsic biliary obstruction

Case Descriptions

Between May 2024 and May 2025, three patients were assessed by the University of Calgary Liver Unit in Alberta, Canada, and were subsequently diagnosed with KRC. The relevant index and follow-up laboratory investigations and non-invasive assessments of liver fibrosis for each case are outlined in Table 2. Details pertaining to index and follow-up radiologic studies are outlined in Figures 1 and 2, respectively. Each case underwent a comprehensive workup, which did not identify an alternative hepatobiliary etiology for their presentation. Specifically, all patients had negative viral, metabolic, genetic, and autoimmune investigations (Supplementary Table 1, online) and denied taking any alternative medicines, herbal preparations, or health supplements.

Table 2:

Demographic and clinical characteristics of our ketamine-related cholangiopathy cases

Characteristic	Case 1		Case 2		Case 3
Age (years)	28		40		33
Sex	Female		Male		Female
Alcohol use pattern	Never		1–2 standard drinks/day × 10 years		1–2 standard drinks/week
Other recreational substance use?	Yes		Yes		Yes
Index compared to follow-up investigations	Index (Oct 2024)	Follow-up (Jan 2025)	Index (Oct 2024)	Follow-up (Jan 2025)	Index (May 2024)	Follow-up (Mar 2025)
ALT U/L (N: <45 U/L)	356*	18	34	–	115*	135*
AST U/L (N: <50 U/L)	204*	26	–	–	116*	183*
ALP U/L (N: 40–120 U/L)	156*	63	103	–	491*	1294*
GGT U/L (N: <50 U/L)	636*	19	112	–	1584*	6713*
TB μmol/L (N: <20 μmol/L)	14	18	5	–	12	15
Albumin g/L (N: 30-45 g/L)	33	–	40	–	31	26*
INR (N: 0.8–1.2)	1	–	1	–	1	1.1
PLT count × 109/L (N: 140–400 × 109/L)	271	281	377	–	405*	321
Creatinine μmol/L (N: 40–100 μmol/L)/eGFR mL/min/1.73m2 (N: > 59 mL/min/1.73m2)	47 / 130	–	112 / 70	–	267 / 20*	168 / 34*
Urinalysis	Proteinuria, no hematuria,	–	–	–	Proteinuria, microscopic hematuria	Proteinuria, microscopic hematuria
Liver elastography kPa (IQR)	4.1 (10%)	3.4 (12%)	5.4 (13%)	6.5 (9%)	6.2 (NR)	–

*Abnormal lab value based on local reference ranges

ALP = Alkaline phosphatase; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma-glutamyl transferase; HPF = High-power field; INR = International normalized ratio; N = Normal; NR = Not recorded; PLT = Platelet; TB = Total bilirubin

“-” indicates that the investigation was not performed

Figure 1: (A) Index MRCP (October 2024) of Case 1 (28-year-old female) demonstrating multifocal intrahepatic ductal dilation and narrowing with abrupt narrowing/thickening of the CBD at the level of the ampulla (arrow) without CBD dilation; (B) Index MRCP (October 2024) of Case 2 (40-year-old male) demonstrating diffuse multifocal wall thickening and mild dilation of the central intrahepatic ducts with abrupt narrowing of the CBD over 11 mm length at the level of the ampulla (arrow) along with 12 mm dilation of the CBD; (C) Index MRCP (May 2024) of Case 3 (33-year-old female) demonstrating no intrahepatic ductal dilation or narrowing but a dilated CBD to 10 mm with normal calibre noted at the level of the ampulla.

Bilateral nephrostomy tubes and hydronephrosis identified (arrowhead)

CBD = Common bile duct; MRCP = Magnetic resonance cholangiopancreatography

Figure 2: (A) Follow-up MRCP (January 2025) of Case 1 (28-year-old female) demonstrating relative multifocal narrowing of the intrahepatic ducts without dilation and now resolved narrowing/thickening of the CBD at the level of the ampulla (arrow) without CBD dilation; (B) Follow-up ultrasound (December 2024) of Case 2 (40-year-old male) demonstrating resolved wall thickening and dilation of the intrahepatic ducts and resolved narrowing of the CBD at the level of the ampulla (arrow) with 7 mm dilation of the CBD; (C) Follow-up ultrasound (March 2025) of Case 3 (33-year-old female) demonstrating no intrahepatic ductal dilation or narrowing but a persistently dilated CBD to 10 mm with normal calibre noted at the level of the ampulla.

MRCP = Magnetic resonance cholangiopancreatography; CBD = Common bile duct

Case 1

A 28-year-old female was referred for assessment of chronically elevated liver enzymes since June 2020 (alanine aminotransferase [ALT]: 356 U/L [normal: <50 U/L]; aspartate transaminase [AST]: 204 U/L [normal: <45 U/L]; alkaline phosphatase [ALP]: 156 U/L [normal: <120 U/L]; gamma-glutamyl transferase [GGT]: 636 U/L [normal: <50 U/L]) and features concerning for sclerosing cholangitis identified on magnetic resonance cholangiopancreatography (MRCP) (Figure 1A). She reported daily intranasal use of ketamine for approximately 6–7 years. She had a history of chronic abdominal pain and altered bowel habit with a historical diagnosis of irritable bowel syndrome. Additional medical history included attention deficit hyperactivity disorder (ADHD), asthma, bipolar disorder, fibromyalgia, endometriosis, and traumatic brain injury. Her only prescribed medication was lisdexamfetamine for ADHD. There was no history of jaundice or any features of advanced liver disease on examination. Workup for secondary causes of sclerosing cholangitis and chronic liver disease was unremarkable. She declined a colonoscopy, although she had an uncle with a history of Crohn's disease. There was no history of renal insufficiency or genitourinary symptoms.

Ketamine cessation was advised and was successfully achieved. At a 3-month follow-up appointment (January 2025), her liver enzymes had normalized (ALT: 18 U/L; AST: 26 U/L; ALP: 63 U/L; GGT: 19 U/L) (Table 1). A repeat MRCP demonstrated marked improvement of both the intra- and extrahepatic biliary tree changes (Figure 2A; mild irregularities in her intra- and extrahepatic biliary tree were noted), and her chronic abdominal pain had improved significantly. Unfortunately, she has since resumed ketamine use and developed recurrent symptoms of abdominal pain and elevation in her GGT (ALT: 33 U/L; AST: 26 U/L; ALP: 92 U/L; GGT: 106 U/L).

Case 2

A 40-year-old male was referred for assessment after features of sclerosing cholangitis were identified on abdominal ultrasound and MRCP (Figure 1B), which had been ordered by his primary care physician to investigate chronic right upper quadrant pain and nausea. Liver enzymes were all within normal limits except for a mildly high GGT level (112 U/L [normal: <50 U/L]). He reported daily inhalational ketamine use of about 1–2 g for the preceding 3 years and occasional cocaine use. His chronic abdominal pain had historically been diagnosed as irritable bowel syndrome. He had a history of gastroesophageal reflux disease, for which he was taking pantoprazole. There was no history of jaundice or features of advanced liver disease on examination. Interestingly, his total serum IgG4 was elevated at 2.4 g/L (normal: 0.04–0.86 g/L) and his PR3-ANCA was positive at 20 AI (normal: <1.0 AI). The workup for secondary causes of sclerosing cholangitis and chronic liver disease were otherwise unremarkable. A colonoscopy was performed and there was no evidence of inflammatory bowel disease. There was no history of renal insufficiency or genitourinary symptoms.

Ketamine cessation was advised, but he continued to use ketamine at approximately half of his prior use. A repeat abdominal ultrasound performed 3 months later (January 2025) showed resolution of the intra- and extrahepatic biliary ductal wall thickening and improvement in previously documented dilation of the common bile duct (Figure 2B). His symptoms of abdominal pain and nausea had resolved. At the time of writing, we are awaiting the results of repeat liver enzymes, serum IgG4 levels, and repeat PR3-ANCA testing.

Case 3

A 33-year-old female was initially referred for assessment of elevated, primarily cholestatic liver enzymes (ALT: 115 U/L [normal: <50 U/L]; AST: 116 U/L [normal: <45 U/L]; ALP: 491 U/L [normal: <120 U/L]; GGT: 1,584 U/L [normal: <50 U/L]) and evidence of non-specific intra- and extrahepatic biliary duct dilation on an abdominal CT scan ordered by her primary health care provider. Due to recent exposure to amoxicillin-clavulanic acid (2 months prior to presentation), her liver injury was initially considered possibly related to a drug-induced liver injury (DILI). She had been prescribed ursodeoxycholic acid 750 mg daily at the time of initial hepatology consultation to hasten recovery from suspected DILI. Despite avoidance of amoxicillin-clavulanic acid and starting ursodeoxycholic acid, her predominately cholestatic liver injury worsened (Table 2). A MRCP demonstrated common bile duct (CBD) dilation to 10 mm (Figure 1C). She was concurrently followed by urology for long-standing obstructive uropathy of unknown cause with bilateral hydronephrosis requiring chronic bilateral nephrostomy tubes for obstruction relief and to prevent recurrent infection. She also had episodic abdominal pain, nausea, and vomiting. Her medical history was otherwise notable for post-traumatic stress disorder and recurrent urinary tract infections in the context of her obstructive uropathy. There was no history of jaundice and no features of advanced liver disease on examination. A comprehensive workup for alternative causes of chronic liver disease was unremarkable apart from a low-positive anti-nuclear antibody screen titre (Supplementary Table 1 online). Serial ultrasounds demonstrated persistent CBD dilation (Figure 2C).

Eventually, after a year of follow-up, she disclosed that she had been using 1g of intranasal ketamine daily for the prior 1–2 years. Again, complete ketamine cessation was advised. However, she has since been lost to medical follow-up.

Discussion

To our knowledge, this is the first report of cases of KRC within a Canadian population. Our case series not only highlights the difficulty in establishing a diagnosis of KRC but the variability of disease presentation and clinical course. Reassuringly, as has been documented in prior cases, the hepatobiliary effects of chronic ketamine use appear to be reversible with drug cessation or dose reduction, highlighting the critical importance of taking a medical history that directly asks patients presenting with these clinical features about ketamine use.

Although recent surveys suggest a smaller proportion of Canadians use ketamine compared with residents in many other countries, certain at-risk Canadian populations do exhibit a high prevalence of dissociative drug use, including ketamine. Specifically, in 2023 the prevalence of dissociative drug use in Canada was higher when stratified across certain demographic variables, including for those aged 20–24 (1.4%) versus all other age groups (0%–1.1%), men (0.8%) versus women (0.6%), those living in large urban centres (0.8%) versus smaller population centres (0.1%–0.6%), and those with only a high school education (0.9%) versus those with higher education (0.6%), and it increased on a gradient from highest to lowest household income (0.4%–1.4%) (6). However, no studies have examined temporal trends in ketamine use in Canada. This lack of Canadian data is of concern as recreational use of ketamine appears to be rapidly rising in the US (20). Improved understanding of the epidemiology and trends in ketamine use and misuse in Canada would facilitate enhanced awareness of ketamine-associated complications, including KRC, within the medical community. Moreover, with greater clinical use of ketamine, including in intensive care and outpatient psychiatry departments, an increase in the number of patients with KRC referred for hepatology assessment is likely in the coming years (2).

The pathophysiology of KRC remains poorly understood. Glutamatergic, centrally mediated effects on gallbladder motility via the dorsal motor nucleus of the vagus (DMV) nerve have been implicated. Using a rabbit model, Liu et al (21) demonstrated enhanced gallbladder contraction when glutamate was injected into the DMV, an effect that was abolished following pre-treatment with ketamine. Peripheral neural control of biliary motility may also be influenced by ketamine, contributing to the development of KRC. Further, ketamine and its metabolite norketamine may precipitate as biliary casts leading to biliary obstruction and inflammation, potentially contributing to KRC development; however, these hypotheses remain speculative (22,23).

Patients with KRC may be entirely asymptomatic, have mild to severe liver enzyme derangements, have varying degrees of biliary imaging abnormalities, and may develop mild to advanced liver fibrosis histologically, including cirrhosis (19). Abdominal pain, nausea, and emesis, often referred to as k-cramps, occur in up to 25% of people who chronically use ketamine; however, whether the abdominal pain is secondary to a direct effect of ketamine on the gastrointestinal tract or an indirect result from biliary involvement remains unknown (24). Individuals providing liver care need to be aware of KRC given that the prognosis and management differ significantly from patients with primary sclerosing cholangitis (PSC). KRC can easily be mistaken for PSC as liver histology and hepatobiliary imaging, particularly MRCP, in patients with KRC closely mimics changes seen in PSC (19). In the largest prospective KRC cohort, Seto et al (13) did not identify extrahepatic stricturing disease on MRCP sequences as a feature of KRC, which they suggested was an important potential radiographic marker to help distinguish KRC from PSC. However, in contrast to the findings of Seto et al, we describe significant extrahepatic bile duct narrowing at the level of the ampulla in two of our cases (Figures 1A and 1B), consistent with extrahepatic stricturing disease.

Clinical guidance on KRC management is lacking. The European Association for the Study of the Liver (EASL) clinical practice guidelines on sclerosing cholangitis include ketamine as a toxic etiology of secondary sclerosing cholangitis, but KRC is not included in the American Association for the Study of Liver Diseases (AASLD) guidelines (25,26). In a 2025 Health Canada safety review, a possible connection between ketamine use and liver and bile duct damage was reported (27). Management of KRC is primarily focused on achieving ketamine abstinence as the clinical, biochemical, and radiographic features of KRC are often reversible with ketamine cessation (13,24). As documented in our cases, resolution or improvement of biochemical and radiographic features of KRC can be seen within 3 months after ketamine cessation or usage reduction. However as demonstrated in Case 3 and prior published reports, persistent hepatobiliary abnormalities remain with ongoing ketamine use, and can return with relapse use, as described in Case 1. Patients with persistent abdominal pain or features of cholangitis may require therapeutic endoscopic interventions, and symptomatic relief with CBD stenting via endoscopic retrograde cholangiopancreatography (ERCP) has been reported in patients with KRC (12,28). Although biliary sepsis as a complication of KRC was documented in only 3.1% of a cohort of 257 patients, it should be considered as a potential life-threatening complication in patients with KRC presenting in an acute care setting (13).

Interestingly, case 2 had a mild, non-diagnostic elevation of his serum IgG4 level and low titre positivity for PR3-ANCA. We are unaware of any reports definitively linking ketamine use to IgG4-related disease, although in a single case report of a 42-year-old woman with KRC, the authors noted an elevated serum IgG4 level without corresponding positive histologic stains for IgG4 on liver biopsy (29). Ketamine has been postulated as a potential trigger for drug-induced vasculitis and could possibly explain the emergence of PR3-ANCA positivity in Case 2. However, concomitant cocaine use has also previously been implicated in PR3-ANCA-related drug-induced vasculitis and may explain the findings in Case 2 (30). Importantly, we did not identify any clinical features of IgG4-related disease or vasculitis in Case 2 and are awaiting repeat serologic assessments of his IgG4 levels and PR3-ANCA status now that he has decreased his ketamine consumption and has improved clinically.

Conclusion

We have described the first reported cases of KRC within Canada. KRC may result from chronic recreational use of ketamine, in critical care settings when used as an adjunct for sedation, or in ambulatory settings when used to treat chronic pain and treatment-resistant depression. Given that the management of and outcomes for KRC differ significantly from PSC, providers need to be aware of KRC, as misdiagnosis can have serious clinical implications regarding patient morbidity and health care resource utilization. Further work is warranted to understand the pathophysiology of KRC and true epidemiology of KRC within the Canadian context and on a global scale.

Funding Statement

N/A

Contributions:

Conceptualization, B Tkachuk, L Swain, KW Burak, M Swain; Methodology, B Tkachuk, L Swain, KW Burak, M Swain; Formal Analysis, B Tkachuk, L Swain, KW Burak, M Swain; Investigation, B Tkachuk, L Swain, M Swain; Data Curation, B Tkachuk, L Swain, KW Burak, M Swain; Project Administration, M Swain.

Ethics Approval:

N/A

Informed Consent:

Informed consent was obtained directly from the patients included in this study.

Registry and the Registration No. of the Study/Trial:

N/A

Data Accessibility:

The data underlying this article are available in the article and in its online supplementary material.

Funding:

N/A

Disclosures:

BT, LS, KWB: No relevant financial or intellectual disclosures. MGS: advisory role: Gilead, Ipsen, Novo Nordisk, Advanz, Abbott, GSK, Boehringer Ingelheim, Mirum; clinical trial funding: Gilead, BMS, GSK, Cymabay, Intercept, Kowa, Novo Nordisk, Pfizer, Celgene, Ancella, Merck, Galectin, Calliditas, Ipsen, Madrigal, Roche, Altimmune, 89Bio, Inventiva, Boehringer Ingelheim.

Peer Review:

This article has been peer reviewed.

Animal Studies:

N/A