Safety and tolerance of oral ketamine: A systematic review.
Nathalia Novaretti, Rebeca Mendes P Pessoa, Jaime Eduardo Cecílio Hallak, Rafael Guimarães Dos Santos, Marcos Hortes N Chagas
Psychiatry and clinical neurosciences May 30, 2026 Peer reviewed DOI: 10.1111/pcn.70091 via PubMed
Summary
Oral ketamine shows a favorable short-term safety profile, with mild and transient adverse effects reported in various clinical populations. In studies on depression involving 427 participants, adverse effects were mostly mild. Pediatric trials with 239 participants noted transient neurological effects without significant safety issues. Pain studies with 372 subjects indicated mild adverse events, including dissociative symptoms at higher doses. However, the certainty of evidence is low, and long-term safety remains uncertain.
Study at a glance
| Design | systematic review |
|---|---|
| Sample size | 1,038 |
| Population | adults, children, and healthy volunteers across various clinical populations |
| Key finding | Oral ketamine demonstrates a favorable short-term safety profile, with predominantly mild and transient adverse effects. |
Abstract
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.