Ketamine and other psychedelic-class therapies have promise for psychiatric disorders, however their acute psychoactive effects complicate successful masking in placebo-controlled trials. Inadequate masking may bias study outcomes if a research subject has a prior expectation about the treatment. We conducted a triple-masked, randomized, placebo-controlled trial of 40 patients with major depressive disorder presenting for elective surgery. Treatment allocation was successfully masked by surgical anesthesia. We were surprised to find that both ketamine and placebo groups reported marked improvement, comparable to many prior ketamine studies. We present several future directions for improving interpretability of psychedelic trials.