INTRODUCTION: Ketamine, initially developed as an anesthetic and now increasingly prescribed for treatment-resistant depression, is also widely misused in recreational contexts. Chronic ketamine use, often leading to dependence, has been associated with severe physical complications, including ulcerative cystitis and gastrointestinal dysfunction, as well as cognitive, affective, and psychotic disturbances. Despite the growing clinical and public health relevance of ketamine misuse, the evidence on effective treatment approaches remains fragmented.

METHODS: A systematic review was conducted in accordance with PRISMA guidelines. We searched three literature databases (PubMed, Scopus, and Web of Science) from inception to April 2025. Original studies in English reporting clinical interventions for ketamine misuse were included. Data were extracted on sociodemographic and clinical characteristics, patterns of use, comorbidities, management strategies, and outcomes..

RESULTS: From 3183 records screened, 73 studies met the inclusion criteria, including 5 controlled clinical studies, 15 observational studies, 15 case series, and 38 case reports. Findings highlighted that management of ketamine misuse is heterogeneous and often based on evidence taken from either case reports or small series. Approaches included symptomatic medical care, psychotherapeutic interventions (e.g., motivational interviewing, cognitive-behavioral therapy, occupational therapy), and pharmacological treatments such as benzodiazepines, SSRIs, naltrexone, lamotrigine, and gabapentinoids, with varying degrees of effectiveness. Multidisciplinary strategies addressing both psychiatric and somatic complications, including "K-bladder" and "K-cramps", emerged as an essential component of the treatment/management package. Overall, the high rates of relapse into ketamine misuse and the limited length of follow-up may have reduced the strength of available evidence.

CONCLUSIONS: Current management of ketamine misuse relies mainly on supportive care, psychotherapy, and off-label pharmacological options, but robust evidence on efficacy is lacking. There is an urgent need for controlled studies and standardized treatment protocols. Integrated, multidisciplinary, models appear most promising in addressing the complex medical and psychiatric consequences of ketamine misuse.