Safety and tolerance of oral ketamine: A systematic review

Oral ketamine has gained increasing interest beyond anesthesia, particularly for treatment-resistant depression, chronic pain, and pediatric procedural sedation. Despite expanding off-label use, there is no standardized pharmaceutical formulation, and long-term safety remains uncertain. A synthesis of evidence on safety and tolerability of the oral route is therefore needed to inform clinical practice and regulatory development. This systematic review evaluated the safety and tolerability profile of oral ketamine in humans and characterized dosing strategies across randomized controlled trials. A systematic search was conducted in PubMed, Embase, Scopus, and Web of Science from inception to November 2025 (PROSPERO CRD420251065295). Randomized placebo-controlled trials evaluating oral (es)ketamine in any clinical population were included. Primary outcomes were safety and tolerability. Risk of bias was assessed using the RoB2 tool, and certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Eighteen trials were included, comprising adults, children, and healthy volunteers. In depression studies (n = 5; 427 participants), adverse effects were predominantly mild and transient. Pediatric premedication trials (n = 239) reported transient neurological effects without clinically significant safety concerns. Pain and experimental studies (n = 372) showed mostly mild adverse events, with dissociative symptoms at higher doses. Comparative analyses indicated higher rates of dizziness, sedation, and dissociative symptoms with ketamine, while serious adverse events were rare. Overall, oral ketamine demonstrates a favorable short-term safety profile. However, the certainty of evidence is low, and long-term safety remains uncertain.