Two studies have shown that the recreational use of the drug ketamine (Ketalar, Par Sterile Products, LLC) can result in bladder damage. The damage occurs through drug-related toxicity in the urine, which leads to erosion of the bladder's epithelial lining.

"We report that the bladder damage observed in ketamine users is caused by direct contact of the epithelial bladder lining with urinary ketamine and not by a systemic change in the whole body that affects the organ, as has previously been suggested by others," first author Simon Baker, PhD, a senior postdoctoral research fellow with the Department of Biology, University of York, in the United Kingdom, told Medscape Medical News.

The findings represent the first insights into the mechanism of severe bladder pain and damage reported in relation to recreational ketamine use as a psychotropic "club drug." The implications go beyond the recreational use of ketamine, inasmuch as research into the use of ketamine for indications such as treatment-resistant depression and chronic pain is gaining momentum, Dr Baker added.

"We want psychiatrists who may not have heard of ketamine cystitis to remain vigilant and warn their patients that this might be a side effect. The risk for future drugs will depend on which chemical property of ketamine is important for alleviating depression and whether this is the same property that causes bladder damage," he said.

First Evidence of Direct Toxicity

In the United Kingdom, where the recreational use of ketamine is reported to be higher than in the rest of Europe, ketamine bladder syndrome is not uncommon.

An article published online by the BBC describes the effects of "K-bladder" as being potentially excruciating. Other reports indicate that pain can be so severe as to require cystectomy.

In the first study, which was published online December 29, 2015, in Urology, Dr Baker and his team evaluated a ketamine-related cystectomy case to better determine whether ketamine damage was triggered by urinary or systemic factors.

The study described a rare case of a urachal cyst found near the bladder dome in a patient undergoing cystectomy for pain related to ketamine abuse.

Whereas regions that were in contact with urine showed a near total loss of bladder urothelium, the urachal epithelium, which was not exposed to urine, remained healthy, the authors reported.

"This study supports the hypothesis that urinary (and not systemic) factors are the main driver of urothelial ulceration in ketamine-induced cystitis."

In a second study by Dr Baker and colleagues, published online March 18 in the American Journal of Pathology, epithelial cells taken from healthy patients and exposed to high concentrations of ketamine ― greater than 1 mmol/L ― showed deterioration of mitochondria, resulting in toxicity and apoptosis and the destruction of all epithelial cells.

"Damage to the urinary barrier initiates bladder pain, and in ketamine-induced cystitis, loss of urothelium from large areas of the bladder wall is a reported feature," the authors say.

"This study offers first evidence for a mechanism of direct toxicity of ketamine to urothelial cells by activating the intrinsic apoptotic pathway."

Misdiagnosis

Early reports of upper and lower urinary tract damage resulting from ketamine abuse involved symptoms that included urinary frequency/urgency, nocturia, hematuria, and suprapubic pain "accompanied by a thickened, contracted, and inflamed bladder," the authors write.

One study indicated that as many as 54% of recreational users of ketamine had consumed more than 1 g in a session. The authors explained that at that level of consumption, a toxic exposure in urine seems possible.

"A young adult male taking 1 g of ketamine could expect 85% of the drug to be excreted in the urine within 24 hours, and taking into account the average voiding rate of 6 × 300 mL per day, a urine concentration in excess of 1 mmol/L is theoretically possible, suggesting the scale of in vitro toxicity reported [in the study] and by others in cancer cell lines is relevant clinically," they explained.

"Formal support would require accurate quantification of ketamine/metabolite concentrations in the urine of symptomatic recreational users."

Accurate data on bladder pain in ketamine users is difficult to obtain because its recreational use is illegal in the United Kingdom. However, one survey of approximately 1300 people who had used the drug in the past year found that 11.3% experienced bladder pain and that 17.4% described the frequent need for urination.

A combination of higher doses, preferential urinary excretion, and the specific chemistry of ketamine likely account for why cystitis is more commonly observed with its abuse, compared with illicit use of other drugs, Dr Baker said.

In some cases, but not all, the damage appears reversible – in the UK survey, 51% of ketamine users reported improvement in urologic symptoms once they stopped using ketamine, Dr Baker added.

"The earlier a user stops taking ketamine, the more likely their bladder can recover and the pain will resolve. We believe there is a threshold of damage where so many epithelial cells have been lost that the remaining cells are too few to recover the bladder and restore an effective barrier to urine."

A case series on ketamine bladder syndrome in Wales, presented in 2015 at the annual meeting of the International Continence Society, in Montreal, Quebec, highlighted an important barrier to receiving appropriate treatment ― the stigma from reporting symptoms.

The study, which involved 12 patients with the syndrome, states that "fear and embarrassment adversely affected medical help seeking. Limited primary care assessments, repeated incorrect diagnoses, inappropriate treatments and inadequate advice and support were common."

Patients were commonly treated with antibiotics for what were incorrectly perceived as urinary tract infections, and the treatment therefore did not relieve symptoms, the authors note.

Low-Dose Ketamine Safe?

Commenting on the findings for Medscape Medical News, Alexander McGirr, MD, of the Department of Psychiatry, University of British Columbia, in Vancouver, Canada, said that research into the use subanesthetic infusions of ketamine for the treatment of severe depression have shown some effects upon the bladder, but not to the degree reported with recreational abuse of the drug.

Dr McGirr, who has conducted a meta-analysis of studies of this issue, said that "in trials examining single infusions of subanesthetic doses of ketamine, in less than 10% of patients there have been reports of increased urinary frequency or painful urination.

"These typically appear 24 hours after the infusion. Though the number of patients reporting this side effect has not statistically separated from those patients that instead received a placebo substance, the studies were not designed to do so," he added.

He noted, however, that the clinical benefit of single infusions often fade within a week, and as a consequence, ketamine research has expanded. Topics of investigation include use of repeated infusions and use of infusions in combination with established treatments. Safety issues will continue to be evaluated.

"It is important to consider safety concerns of novel applications of ketamine, such as the treatment of depression, in light of the clinical parameters in which they are being used."

Dr McGirr added that in Dr Baker's study, cells were exposed to ketamine for 72 hours at concentrations several thousand times greater than the peak serum levels achieved in patients undergoing subanesthetic infusions of ketamine.

"It is important to be mindful of toxicity and that certain individuals may be hypersensitive, yet it is unclear how this study informs risk in patients receiving low-dose ketamine in a monitored setting," he said.

The study received support from the Wellcome Trust. One coauthor received support from York Against Cancer. Dr McGirr has disclosed no relevant financial relationships.

Urology. Published online December 29, 2015. Abstract

Am J Pathol. Published online March 18, 2016. Abstract