Post-traumatic stress disorder (PTSD) is a debilitating disorder with limited pharmaceutical treatment options. Ketamine, a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist with rapid-onset effects, has emerged as a potential treatment, particularly for patients who do not respond to first-line therapies. This systematic review synthesizes the current evidence on the effectiveness and safety of ketamine for PTSD, with a focus on military and veteran populations. Eligible studies included adults with PTSD, who evaluated ketamine or esketamine, and reported efficacy and safety outcomes. Due to substantial clinical and methodological heterogeneity, a meta-analysis was not performed. Eight studies (N = 383) were included, comprising five randomized-controlled trials and three uncontrolled or observational studies. Most studies reported reductions in PTSD symptoms following ketamine administration. The largest effect size (d' = 2.17; representing a sample size-adjusted Cohen's d) was reported in a small uncontrolled open-label study of 15 veterans, in which six ketamine infusions were associated with an 80% PTSD remission rate. This finding warrants caution, given the small sample and the absence of a control group. Dissociative and hemodynamic adverse effects were frequently observed during infusion, but typically resolved afterward. No study reported cognitive decline associated with repeated ketamine administration. Current evidence suggests that ketamine may be associated with short-term reductions in PTSD symptoms in some populations; however, findings remain preliminary due to small samples, heterogeneous designs, brief follow-up, and inconsistent safety reporting.
