Harm related to recreational ketamine use and its relevance for the clinical use of ketamine. A systematic review and comparison study

Backgrounds: Ketamine is a dissociative anesthetic that is currently considered for several new indications. Aim: To deduce the safety of long-term ketamine treatment using the harm of heavy recreational (non-medical) ketamine use as a proxy for maximal possible harm of ketamine treatment. Methods: Systematic literature review according to PRISMA guidelines to identify controlled studies on ketamine-related harm in heavy recreational ketamine users. Results were compared with serious adverse events (SAEs) in patients treated with ketamine according to three systematic reviews considering dosing regimen and cumulative dose. Results: The systematic search yielded 25 studies. Heavy recreational ketamine use can escalate to ketamine dependency and was often dose-dependently associated with other SAEs, including cognitive and mental disorders, and gastrointestinal and urinary tract symptoms, which disappeared upon marked reduction of ketamine use. Heavy ketamine users have a much higher cumulative exposure to ketamine than ketamine treated patients (>90 times), which may explain why SAEs in the clinical context are mostly mild and reversible and why ketamine dependence was not reported in these patients. Conclusion: Treatment of patients with ketamine is not associated with ketamine dependency or SAEs. However, caution is needed since data on long-term clinical ketamine use with a long-term follow-up is lacking.