A randomized trial found that serial intravenous ketamine was not significantly more effective than the active placebo midazolam in reducing depressive symptoms or improving quality of life. The improvement in MADRS scores fell short of the minimal clinically important difference. The study had a small sample size of 63 participants and faced blinding failures, with 78% of patients and 90% of raters correctly identifying the ketamine group, suggesting results may have been influenced by unblinded expectations. Further research that controls for non-specific effects is needed.
For major depression, electroconvulsive therapy (ECT) is markedly more effective than ketamine after 3–4 weeks of treatment, based on a meta-analysis of 6 randomized head-to-head studies. However, in the two studies that tracked outcomes longer—at 2 and 10 months after treatment—no difference in effectiveness was found between the two treatments.
A randomized trial testing MDMA combined with psychotherapy for PTSD reported a large effect (0.9) over placebo plus the same therapy, but the blinding in that study nearly completely failed. Widespread public advocacy for psychedelics as therapy aids is generating a strong positivity bias that is compromising research quality and outcomes. A recent review therefore urges caution in interpreting existing studies on MDMA for PTSD.