To the Editor In JAMA Psychiatry, Cubała et al report that inhaled mebufotenin (GH001) reduced depression severity by 15.5 points more than placebo on the Montgomery-Åsberg Depression Rating Scale (MADRS) at 1 week, with 57.5% of patients achieving remission vs 0% in the placebo group. The effect size (d = −2.0) overwhelmingly surpasses those of selective serotonin reuptake inhibitors, ketamine, and promising psilocybin trials. Remarkably, it also exceeds the theoretical maximum effect size (d = 1.75) achievable by perfectly effective antidepressants under normal placebo conditions. Such effect sizes are typically seen only in state-switch interventions like penicillin resolving bacterial infections or vaccines preventing them altogether. Against that backdrop, the effect size suggests methodological factors beyond pharmacology.
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