To the Editor The Research Letter by Yoon and colleagues,1 published in JAMA Psychiatry, addresses our group鈥檚 recent finding that ketamine鈥檚 antidepressant effect is opioid-receptor dependent.2 Their Letter makes clear that a better understanding of ketamine鈥檚 abuse liability should be a high priority to the field, particularly given the recent US Food and Drug Administration approval of esketamine nasal spray for treatment-resistant depression. We agree with Yoon et al that 鈥淟arger randomized clinical trials are needed to better understand whether opiate receptor stimulation contributes to the antidepressant effects of ketamine,鈥�1 especially considering the small number of patients recruited in both studies. Unfortunately, there are several aspects of this study that significantly limit what conclusions can be drawn about the mechanism of ketamine鈥檚 antidepressant action.