**2. Epidemiology of ketamine-associated cystitis**

The exact prevalence of ketamine-associated cystitis is difficult to ascertain, as most users are reluctant to seek medical attention despite symptoms. A study in Taiwan conducted in 2019 by Li et al. reported that whilst 84% of chronic ketamine abusers demonstrated urinary tract symptoms, only 48% sought treatment [7]. A survey involving 3806 participants in the United Kingdom by Winstock et al. found that 26.6% of ketamine users report urinary symptoms and that the symptoms are significantly related to both frequency and duration of use [8]. Similarly, Pal et al. from the United States conducted a survey involving 18,802 participants which reported a 30% prevalence of lower urinary tract symptoms (LUTS) among recent ketamine users [9].

Lower urinary tract symptoms, as well as dysuria and haematuria, are the most common symptoms caused by chronic ketamine abuse. LUTS in the setting of ketamine cystitis usually comprises urinary frequency, feeling of incomplete bladder emptying, and nocturia. More than 50% of users complain of urinary frequency after using ketamine for about 2 years [7]. The severity and number of symptoms are correlated with not only the duration of use but also the route of administration. Ketamine may be cut up into a powder form before being inhaled or smoked with pipe-like devices. Snorting causes significantly more symptoms than smoking. This is possibly due to a higher amount of ketamine entering the circulation via the nasal mucosa [7].

The combined use of ketamine with other substances such as marijuana and 3,4-methylenedioxy-methamphetamine (MDMA) has also been found to significantly increase the severity of LUTS. Marijuana enhances the expression of cannabinoid receptors CB1 and CB2, which are found in the human bladder urothelium [10]. This is implicated in the worsening of storage symptoms such as frequency and urgency. The mechanism through which MDMA exacerbates LUTS remains to be elucidated.

#### **3. Pathogenesis of ketamine cystitis**

A number of mechanisms have been proposed to explain the pathogenic effects of ketamine on the urinary system. These include (1) direct toxicity of ketamine or its metabolites on the bladder tissues; (2) microvascular changes in the bladder and kidneys by ketamine or its metabolites; and (3) delayed (type IV) hypersensitivity against the urothelium due to ketamine or its metabolites [11]. Infection is unlikely to play a role in the primary pathogenesis of ketamine cystitis, as the vast majority of patients do not have a positive urine bacterial culture. As of yet, there has not been a single conclusive theory on the mechanism of ketamine-induced cystitis.

In vitro studies on human urothelial cells have demonstrated dose-dependent toxicity of ketamine to human urothelial cells. The damage is carried out by both ketamine itself and its primary metabolite (norketamine) [12]. Norketamine is generated as ketamine undergoes hepatic metabolism. Both ketamine and norketamine are subsequently excreted in the urine. Ketamine and norketamine are equally toxic to the urothelium in in vitro studies, but norketamine remains in the urine for longer than ketamine, and hence norketamine may be accountable for more of the damage

#### *Urological Effects of Ketamine Abuse DOI: http://dx.doi.org/10.5772/intechopen.91283*

done [13]. As with other toxic exposures, daily exposure has been found to be more damaging than a one-off exposure. The accepted anaesthetic dosage of ketamine for human medical use is 0.5–2 mg/kg, but much higher concentrations are abused in recreational use (up to 20 g per day in some users) [13]. As aforementioned in the previous section, it also takes approximately 2 years of abuse before cystitis symptoms arise. Therefore, as ketamine is used at much lower doses as well as frequency in the context of anaesthesia as compared to daily abuse, the medical use of ketamine for one-off anaesthesia is less likely to cause significant ketamine cystitis.

The hypothesis that ketamine and norketamine exert a direct effect on the urothelium is based on the knowledge that both chemicals are excreted by the urine and have a long contact time with the urothelium (ketamine 5 days, norketamine 6 days) after ingestion [14].

The urinary tract from the renal pelvis to the proximal urethra is covered by the urothelium, a highly specialised transitional epithelium capable of stretching to accommodate various degrees of distension in response to urine volume. The urothelium comprises three layers—superficial, intermediate, and basal. Under the urothelium lies the submucosa, then the detrusor muscle, and then the adventitia.

Classic histological changes found in ketamine cystitis include denudation of the urothelium, as well as inflammatory changes including oedematous vessels, and infiltration by eosinophils and T-lymphocytes [15]. The affected urothelium loses its superficial layer (which provides a barrier function), thus exposing the stroma to further insults from urinary ketamine and norketamine. This may be one of the mechanisms by which ketamine causes cystitis and the resultant symptoms. Some of these histological changes are similarly seen in interstitial cystitis (chronic bladder pain in the absence of an identifiable aetiology) [16]. Additionally, haematoxylin and eosin staining in the urothelium affected by ketamine cystitis may in some cases display apparent dysplastic changes with the loss of epithelial cohesion. Such changes mimic the histology of carcinoma in situ, and hence the clinical history of ketamine abuse should alert the clinician or pathologist to the possibility of misdiagnosis of carcinoma in situ [12].

The infiltration by T-lymphocytes suggests that a delayed (type IV) hypersensitivity reaction to ketamine may also play a role in the pathogenesis of ketamine cystitis [17]. This is because T-lymphocytes are heavily implicated in type IV hypersensitivity reaction, and it is known that type IV hypersensitivity reactions occur only after prolonged exposure to the causative agent. This reaction conforms to the temporal profile of the development of ketamine cystitis, where symptoms usually develop only after 2 years of abuse.
