In mice, even high doses of AEF0117 did not produce any of the behavioral or neurohormonal effects (Extended Data Fig. 3) associated with CB1 antagonists that likely contribute to their poor tolerability: (1) reduced food intake; (2) increased anxiety-like and depression-like behaviors; (3) precipitated cannabinoid withdrawal; and (4) increased glucocorticoid secretion. This evidence concerns the gene CNR1 and major depressive disorder.