Ketamine-Induced Cystitis: A Comprehensive Review of the Urologic Effects of This Psychoactive Drug

Ketamine is a common medical anesthetic and analgesic but is becoming more widely used as a recreational drug. Significant side effects on the urinary tract are associated with frequent recreational ketamine use most notably ketamine-induced cystitis (KIC). Regular ketamine consumption has been shown to increase the risk of cystitis symptoms by 3- to 4-fold, and cessation of ketamine use is usually associated with improvement of symptoms. Common KIC-related problems are urinary pain and discomfort, bladder epithelial barrier damage, reduced bladder storage and increased pressure, ureter stenosis, and kidney failure, all of which significantly impact patients’ quality of life. Furthermore, it becomes a vicious cycle when KIC patients attempt to manage their urinary pain with increased ketamine use. The precise pathophysiology of KIC is still unknown but several theories exist, most of which highlight the inflammatory signaling pathways leading to bladder epithelium damage due to presence of ketamine in the urine. Empirical treatment options for KIC are available and consist of ketamine cessation, noninvasive therapies, and surgery, and should be decided upon based on the time course and severity of the disease. Of note, cessation of use is strongly recommended for all KIC patients, and should be supplemented with motivational interviews and psychological and social support. It is crucial for clinicians to be familiar with KIC diagnosis and treatment, and to be prepared to have informed discussions with ketamine-using patients about the potential health consequences of ketamine.
1. Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI. Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy. Clin Pharmacokinet. 2016;55(9):1059-1077. doi:10.1007/s40262-016-0383-6
2. Bokor G, Anderson PD. Ketamine: an update on its abuse. J Pharm Pract. 2014;27(6):582-586. doi:10.1177/0897190014525754
3. Chu PSK, Ma WK, Wong SCW, et al. The destruction of the lower urinary tract by ketamine abuse: a new syndrome? BJU Int. 2008;102(11):1616-1622. doi:10.1111/j.1464-410x.2008.07920.x
4. Shahani R, Streutker C, Dickson B, Stewart RJ. Ketamine-associated ulcerative cystitis: a new clinical entity. Urology. 2007;69(5):810-812. doi:10.1016/j.urology.2007.01.038
5. Castellani D, Pirola GM, Gubbiotti M, et al. What urologists need to know about ketamine-induced uropathy: A systematic review. Neurourol Urodyn. 2020;39(4):1049-1062. doi:10.1002/nau.24341
6. Duan Q, Wu T, Yi X, Liu L, Yan J, Lu Z. Changes to the bladder epithelial barrier are associated with ketamine-induced cystitis. Exp Ther Med. 2017;14(4):2757-2762. doi:10.3892/etm.2017.4913
7. Chang T, Lin CC, Lin ATL, Fan YH, Chen KK. Ketamine-Induced Uropathy: A New Clinical Entity Causing Lower Urinary Tract Symptoms. Low Urin Tract Symptoms. 2012;4(1):19-24. doi:10.1111/j.1757-5672.2011.00101.x
8. Wei YB, Yang JR, Yin Z, Guo Q, Liang BL, Zhou KQ. Genitourinary toxicity of ketamine. Hong Kong Med J. 2013;19(4):341-348. doi:10.12809/hkmj134013
9. Winstock AR, Mitcheson L, Gillatt DA, Cottrell AM. The prevalence and natural history of urinary symptoms among recreational ketamine users. BJU Int. 2012;110(11):1762-1766. doi:10.1111/j.1464-410x.2012.11028.x
10. Lai Y, Wu S, Ni L, et al. Ketamine-associated urinary tract dysfunction: an underrecognized clinical entity. Urol Int. 2012;89(1):93-96. doi:10.1159/000338098
11. Smart C, Kabir M, Pati J. Treatment of ketamine-associated cystitis with chondroitin sulphate. Br J Nurs. 2013;22(Sup18):S4-S9. doi:10.12968/bjon.2013.22.sup18.s4
12. Zeng J, Lai H, Zheng D, et al. Effective treatment of ketamine-associated cystitis with botulinum toxin type a injection combined with bladder hydrodistention. J Int Med Res. 2017;45(2):792-797. doi:10.1177/0300060517693956
13. Chung SD, Wang CC, Kuo HC. Augmentation enterocystoplasty is effective in relieving refractory ketamine-related bladder pain. Neurourol Urodyn. 2014;33(8):1207-1211. doi:10.1002/nau.22477
14. Morgan CJA, Curran HV, Independent Scientific Committee on Drugs. Ketamine use: a review. Addiction. 2012;107(1):27-38. doi:10.1111/j.1360-0443.2011.03576.x
15. Stewart CE. Ketamine as a street drug. Emerg Med Serv. 2001;30(11).
16. Li CC, Wu ST, Cha TL, Sun GH, Yu DS, Meng E. A survey for ketamine abuse and its relation to the lower urinary tract symptoms in Taiwan. Sci Rep. 2019;9(1):7240. doi:10.1038/s41598-019-43746-x
17. Liu W, Wu W, Wei Y, et al. Epidemiologic characteristics and risk factors in patients with ketamine-associated lower urinary tract symptoms accompanied by urinary tract infection: A cross-sectional study. Medicine(Baltimore). 2019;98(23):e15943. doi:10.1097/md.0000000000015943
18. Yee CH, Ng CF, Hong YL, Lai PT, Tam YH. Substance abuse effects on urinary tract: methamphetamine and ketamine. Hong Kong Med J. 2019;25(6):438-443. doi:10.12809/hkmj19815419
19. Huang YC, Jeng CM, Cheng TC. Ketamine-associated ulcerative cystitis. Tzu Chi Med J. 2008;20(6):144-146. doi:10.1016/s1016-3190(08)60026-9
20. Yek J, Sundaram P, Aydin H, Kuo T, Ng LG. The clinical presentation and diagnosis of ketamine-associated urinary tract dysfunction in singapore. Singapore Medical Journal. 2015;56(12):660-665. doi:10.11622/smedj.2015185
21. Xie X, Liang J, Huang R, et al. Molecular pathways underlying tissue injuries in the bladder with ketamine cystitis. FASEB Journal. 2021;35(7). doi:10.1096/fj.202100437
22. Ho CCK, Pezhman H, Praveen S, et al. Ketamine-associated ulcerative cystitis: A case report and literature review. Malaysian Journal of Medical Sciences. 2010;17(2).
23. Jhang JF, Hsu YH, Kuo HC. Possible pathophysiology of ketamine-related cystitis and associated treatment strategies. Int J Urol. 2015;22(9):816-825. doi:10.1111/iju.12841
24. Jhang JF, Hsu YH, Jiang YH, Kuo HC. Elevated serum IgE may be associated with development of ketamine cystitis. Journal of Urology. 2014;192(4):1249-1256. doi:10.1016/j.juro.2014.05.084
25. Sultana S, Berger G, Cox A, Kelly MEM, Lehmann C. Rodent models of ketamine-induced cystitis. Neurourology and Urodynamics. 2021;40(7):1704-1719. doi:10.1002/nau.24763
26. Gu D, Huang J, Yin Y, Shan Z, Zheng S, Wu P. Long-term ketamine abuse induces cystitis in rats by impairing the bladder epithelial barrier. Mol Biol Rep. 2014;41(11):7313-7322. doi:10.1007/s11033-014-3616-5
27. Song M, Yu HY, Chun JY, et al. The fibrosis of ketamine, a noncompetitive N-methyl-D-aspartic acid receptor antagonist dose-dependent change in a ketamine-induced cystitis rat model. Drug and Chemical Toxicology. 2016;39(2):206-212. doi:10.3109/01480545.2015.1079916
28. Shen CH, Wang ST, Wang SC, et al. Ketamine-induced bladder dysfunction is associated with extracellular matrix accumulation and impairment of calcium signaling in a mouse model. Mol Med Report. 2019;19(4). doi:10.3892/mmr.2019.9907
29. Rajandram R, Ong TA, Razack AHA, MacIver B, Zeidel M, Yu W. Intact urothelial barrier function in a mouse model of ketamine-induced voiding dysfunction. American Journal of Physiology-Renal Physiology. 2016;310(9):F885-F894. doi:10.1152/ajpre nal.00483.2015
30. Chuang SM, Liu KM, Li YL, et al. Dual involvements of cyclooxygenase and nitric oxide synthase expressions in ketamine-induced ulcerative cystitis in rat bladder. Neurourol Urodynam. 2013;32(8):1137-1143. doi:10.1002/nau.22367
31. Lin CC, Yang AH, Lin ATL. Activation of the mTOR dependent signaling pathway underlies ketamine-induced uropathy. Neurourology and Urodynamics. 2017;36(8):1988-1995. doi:10.1002/na u.23234
32. Zhu Q, Li K, Li H, Han F, Tang Z, Wang Z. Ketamine induced bladder fibrosis through MTDH/P38 MAPK/EMT pathway. Front Pharmacol. 2022;12. doi:10.3389/fphar.2021.743682
33. Lin CC, Lin ATL, Yang AH, Chen KK. Microvascular injury in ketamine-induced bladder dysfunction. PLoS ONE. 2016;11(8):e0160578. doi:10.1371/journal.pone.0160578
34. Kim A, Yu HY, Heo J, et al. Mesenchymal stem cells protect against the tissue fibrosis of ketamine-induced cystitis in rat bladder. Sci Rep. 2016;6(1). doi:10.1038/srep30881
35. Kidger E, Stahlschmidt J, Garthwaite M, Fulford S, Southgate J, Baker SC. A Rare Urachal Cyst in a Case of Ketamine-induced Cystitis Provides Mechanistic Insights. Urology. 2016;90:223.e1-e7. doi:10.1016/j.ur ology.2015.12.015
36. Shen CH, Wang ST, Lee YR, et al. Biological effect of ketamine in urothelial cell lines and global gene expression analysis in the bladders of ketamine-injected mice. Molecular Medicine Reports. 2014;11(2):887-895. doi:10.3892/mmr.2014.2823
37. Kutscher E, Greene RE. Ketamine Cystitis: An Underrecognized Cause of Dysuria. J Gen Intern Med. 2022;37(5):1286-1289. doi:10.1007/s11606-021-07297-0
38. Vu DM, Freyre K, Opsha O, Opsha Y. Recreational ketamine-induced cholangiopathy and ulcerative cystitis. American Journal of Emergency Medicine. 2021;45:682.e7-e9. doi:10.1016/j.ajem.2020.12.025
39. Lamers G, van Dyck J, Schapmans S, de Coster K, Mortier D, Zabegalina N. Ketamine-induced uropathy: A diagnostic pitfall in an increasing healthcare issue in youngsters. Urology Case Reports. 2022;42:102019. doi:10.1016/j.eucr.2022.102019
40. Robles-Martinez M, Abad AC, Pérez-Rodriguez V, Ros-Cucurull E, Esojo A, Roncero C. Delayed urinary symptoms induced by ketamine. Journal of Psychoactive Drugs. 2018;50(2):129-132. doi:10.1080/02791072.2017.1371364
41. Middela S, Pearce I. Ketamine-induced vesicopathy: A literature review. International Journal of Clinical Practice. 2011;65(1):27-30. doi:10.1111/j.1742-1241.2010.02502.x
42. Lieb M, Bader M, Palm U, Stief CG, Baghai TC. Ketamine-induced vesicopathy. Psychiatr Prax. 2012;39(1):43-45. doi:10.1055/s-0031-1292789
43. Tsai YC, Kuo HC. Ketamine cystitis: Its urological impact and management. Urological Science. 2015;26(3):153-157. doi:10.1016/j.urols.2014.11.003
44. Myers FA Jr, Bluth MH, Cheung WW. Ketamine: A Cause of Urinary Tract Dysfunction. Clinics in Laboratory Medicine. 2016;36(4):721-744. doi:10.1016/j.cll.2016.07.008
45. Tran VH, Nelson M, Nogar J, Bramante RM. Bilateral hydronephrosis and cystitis resulting from chronic ketamine abuse. Western Journal of Emergency Medicine. 2014;15(4):382-384. doi:10.5811/westjem.2014.4.20571
46. Ou SH, Wu LY, Chen HY, et al. Risk of renal function decline in patients with ketamine-associated uropathy. International Journal of Environmental Research and Public Health. 2020;17(19):7260. doi:10.3390/ijerph17197260
47. Liu KM, Chuang SM, Long CY, et al. Ketamine-induced ulcerative cystitis and bladder apoptosis involve oxidative stress mediated by mitochondria and the endoplasmic reticulum. American Journal of Physiology-Renal Physiology. 2015;309(4):F318-F331. doi:10.1152/ajprenal.00607.2014
48. Oxley JD, Cottrell AM, Adams S, Gillatt D. Ketamine cystitis as a mimic of carcinomain situ. Histopathology. 2009;55(6):705-708. doi:10.1111/j.1365-2559.2009.03437.x
49. Chen WY, Huang MC, Lin SK. Gender differences in subjective discontinuation symptoms associated with ketamine use. Subst Abuse Treat Prev Policy. 2014;9(1). doi:10.1186/1747-597x-9-39
50. Wood D, Cottrell A, Baker SC, et al. Recreational ketamine: From pleasure to pain. BJU International. 2011;107(12):1881-1884. doi:10.1111/j.1464-410x.2010.10031.x
51. Meng E, Tsao CW, Tang SH, et al. Intravesical hyaluronic acid treatment for ketamine-associated cystitis: Preliminary results. Urological Science. 2015;26(3):176-179. doi:10.1016/j.urols.2015.07.001
52. Chueh KS, Huang KH, Lu JH, et al. Therapeutic effect of platelet-rich plasma improves bladder overactivity in the pathogenesis of ketamine-induced ulcerative cystitis in a rat model. International Journal of Molecular Sciences. 2022;23(10):5771. doi:10.3390/i jms23105771