Efficacy and tolerability of ketamine in moderate to severe obsessive-compulsive disorder: a systematic review

Approximately 40-60% of patients with obsessive-compulsive disorder (OCD) fail to respond to standard serotonergic and behavioral therapies. This systematic review evaluates the efficacy, durability, and safety of ketamine, a glutamate modulator, for moderate to severe OCD.

Following PRISMA guidelines, we searched electronic databases through January 2026 for studies treating moderate-to-severe OCD with ketamine. Fifteen studies were included (three RCTs, four open-label trials, and eight case reports), comprising 118 participants.

Randomized trials demonstrated that single-dose intravenous ketamine (0.5 mg/kg) yields rapid anti-obsessional response rates of 50-60%. However, benefits from monotherapy were typically transient, often dissipating within one week. Conversely, protocols integrating ketamine with concurrent exposure and response prevention (ERP) reported sustained remission lasting weeks to months, suggesting a synergistic effect. While intravenous and oral routes were effective, intranasal administration faced high refusal rates due to contamination fears. Safety analysis identified a specific signal of delayed-onset dysphoria and suicidal ideation (24-48 hours post-infusion) in a subset of patients, distinct from depression trials.

Ketamine may provide positive but short-lived symptom relief for moderate to severe OCD when used as a standalone intervention. Its clinical utility may be greatest when used as a pharmacological adjunct to behavioral therapy, potentially creating a therapeutic window that may facilitate effective ERP. Clinicians should implement extended monitoring for delayed psychiatric adverse events. Further longitudinal and mechanistic studies are warranted to delineate ketamine's optimal dosing parameters, timing, and integration strategies within multimodal OCD treatment frameworks.